Myostatin  is a  protein  responsible for inhibiting  muscle  differentiation and growth.  Removing the myostatin  gene  or otherwise limiting its  expression  leads to an increase in muscle size and power. [ 6 ]   This has been demonstrated in  knockout mice  lacking the gene that were dubbed " Schwarzenegger  mice". [ 21 ]  Humans born with defective genes can also serve as "knockout models"; a German boy with a mutation in both copies of the myostatin gene was born with well-developed muscles. [ 22 ]   The advanced muscle growth continued after birth, and the boy could lift weights of 3 kg at the age of 4. [ 6 ]  In work published in 2009, scientists administered  follistatin   via gene therapy to the quadriceps of non-human primates, resulting in local muscle growth similar to the mice. [ 6 ]


Erythropoietin  is a  glycoprotein  that acts as a  hormone , controlling red blood cell production. Athletes have injected the EPO protein as a  performance-enhancing substance  for many years ( blood doping ). When the additional EPO increases the production of red blood cells in circulation, this increases the amount of oxygen available to muscle, enhancing an athlete's endurance. [ 6 ] [ 23 ]  Recent studies suggest it may be possible to introduce another EPO gene into an animal in order to increase EPO production  endogenously . [ 22 ]   EPO genes have been successfully inserted into mice and  monkeys , and were found to increase  hematocrits  by as much as 80 percent in those animals. [ 22 ]   However, the endogenous and  transgene  derived EPO elicited  autoimmune  responses in some animals in the form of severe  anemia . [ 22 ]


Insulin-like growth factor 1  is a protein involved in the mediation of the  growth hormone . Administration of IGF-1 to mice has resulted in more muscle growth and quicker muscle and nerve regeneration. [ 19 ] [ 6 ]  If athletes were to use this the sustained production of IGF-1 could cause heart disease and cancer. [ 19 ]


Modulating the levels of proteins that affect psychology are also potential goals for gene doping; for example pain perception depends on  endorphins  and  enkephalins ,  response to stress depends on  BDNF , and an increase in synthesis of  monamines  could improve the mood of athletes. [ 19 ]   Preproenkephalin  has been administered via gene therapy using a replication-deficient  herpes simplex virus , which targets nerves, to mice with results good enough to justify a Phase I clinical trial in people with terminal cancer with uncontrolled pain. [ 6 ]  Adopting that approach for athletes would be problematic since the pain deadening would likely be permanent. [ 6 ]


VEGF  has been tested in clinical trials to increase blood flow and has been considered as a potential gene doping agent; however long term follow up of the clinical trial subjects showed poor results. [ 6 ]   The same is true of  fibroblast growth factor . [ 6 ]   Glucagon-like peptide-1  increases the amount of  glucose  in the liver and has been administered via gene therapy to the livers of mouse models of diabetes and was shown to increase  gluconeogenesis ' for athletes this would make more energy available and reduce the buildup of  lactic acid . [ 6 ]


The  World Anti-Doping Agency  (WADA) is the main  regulatory  organization looking into the issue of the detection of gene doping. [ 9 ]   Both direct and indirect testing methods are being researched by the organization. Directly detecting the use of gene therapy usually requires the discovery of  recombinant proteins  or gene insertion  vectors , while most indirect methods involve examining the athlete in an attempt to detect bodily changes or structural differences between  endogenous  and recombinant proteins. [ 6 ] [ 24 ] [ 25 ]


Indirect methods are by nature more subjective, as it becomes very difficult to determine which anomalies are proof of gene doping, and which are simply natural, though unusual, biological properties. [ 6 ]   For example,  Eero Mäntyranta , an  Olympic   cross country skier , had a mutation which made his body produce abnormally high amounts of red blood cells.  It would be very difficult to determine whether or not Mäntyranta's red blood cell levels were due to an innate genetic advantage, or an artificial one. [ 26 ]


Gene doping detection idea started in 2004 when WADA has put gene doping in the banned list and started investigating a new method that can detect the inserted transgenes.


The first generation of gene doping detection techniques used  PCR  tests that targets the transgenes’ sequences. It can be obtained from a blood sample which will contain endogenous and transgene DNA since a small amount of the transgene will leak into the bloodstream. It can be easily distinguished from endogenous DNA because it lacks introns since the transgene will most likely use cDNA that is obtained by reverse transcriptase from RNA, which has removed its intones though  RNA splicing  leaving only exon-exon junction that include only the coding sequences and some important sequences like promoters since the  viral victors  has a limited capacity. Therefore, PCR can target these exon-exon junctions as a unique sequence that is not present in  gDNA [ 27 ]


PCR has many applications in molecular biology field including  DNA analysis . The main purpose of PCR is to amplify and double the DNA sequences exponentially.


In gene doping detection, If the sequence started to amplify producing an exponential graph, then the test is positive and indicates the presence of the gene in the sample obtained from that person. But if the sequence didn't amplify and a linear graph was produced, then the test is said to be negative and the targeted DNA sequence was not present in that person's sample. [ 28 ]


With the limitation of the first-generation detection methods, it was important to develop a new method that overcomes the previous failures with a high accuracy and can detect the manipulation in DNA sequences that could evade to be detected by PCR methods.


The solution was using  Next Generation Sequencing  (NGS) method that can determine the  nucleotide  orders of the whole genome or targets the exon-exon junctions in transgene and compare it with reference gene sequence. This method is fast accurate and is getting cheaper by the time and has opened a new field in science that wasn't possible before like sequencing the whole genome sequencing. [ 29 ]


DNA sequencing was established in the 1970s with the  two-dimensional chromatography  and kept improving until 2001 with the completion of  human genome project  which costed about three billion dollars and required 15 years to finish sequencing the whole genome. However, with nowadays sequencing technology,  whole genome sequencing  (WGS) takes only a single day and costs around a thousand dollars. Moreover, a new sequencing technology is under development that will cost only 100 dollars for WGS. [ 30 ]


There are many NGS techniques that are used in DNA sequencing but the most used method is the one done by illumina [ 31 ]


A 2016 review found that about 120 DNA polymorphisms had been identified in the literature related to some aspect of athletic performance, 77 related to endurance and 43 related to power.  11 had been replicated in three or more studies and six were identified in  genome-wide association studies , but 29 had not been replicated in at least one study. [ 20 ]


The 11 replicated markers were: [ 20 ]


The six GWAS markers were: [ 20 ]


The  World Anti-Doping Agency  (WADA) determined that any non-therapeutic form of genetic manipulation for enhancement of athletic performance is banned under its code. There are guidelines to determine if said technology should be prohibited in sport: if two of the three conditions are met, then the technology is prohibited in sport (harmful to one's health, performance enhancing, and/or against the "spirit of sport"). [ 32 ]


Kayser et al. argue that gene doping could  level the playing field  if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports. [ 33 ]


The high risks associated with gene therapy can be outweighed by the potential of saving the lives of individuals with diseases: according to Alain Fischer, who was involved in clinical trials of gene therapy in children with  severe combined immunodeficiency , "Only people who are dying would have reasonable grounds for using it. Using gene therapy for doping is ethically unacceptable and scientifically stupid." [ 34 ]   As seen with past cases, including the steroid tetrahydrogestrinone ( THG ), athletes may choose to incorporate risky genetic technologies into their training regimes. [ 3 ]


The mainstream perspective is that gene doping is dangerous and unethical, as is any application of a therapeutic intervention for non-therapeutic or enhancing purposes, and that it compromises the ethical foundation of medicine and the spirit of sport. [ 4 ] [ 35 ] [ 36 ] [ 7 ] [ 37 ]   Others, who support  human enhancement  on broader grounds, [ 38 ]  or who see a  false dichotomy  between "natural" and "artificial" or a denial of the role of technology in improving athletic performance, do not oppose or support gene doping. [ 39 ]


attribution  contains text from  Human genetic enhancement  as of 17:03, 26 October 2020


Gene therapy  is a  medical technology  that aims to produce a  therapeutic effect  through the manipulation of  gene expression  or through altering the biological properties of living cells. [ 1 ] [ 2 ] [ 3 ]


The first attempt at modifying human  DNA  was performed in 1980, by  Martin Cline , but the first successful nuclear gene transfer in humans, approved by the  National Institutes of Health , was performed in May 1989. [ 4 ]  The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by  French Anderson  in a trial starting in September 1990. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in  phase I . [ 5 ]  In 2003,  Gendicine  became the first gene therapy to receive regulatory approval. Since that time, further gene therapy drugs were approved, such as  alipogene tiparvovec  (2012),  Strimvelis  (2016),  tisagenlecleucel  (2017),  voretigene neparvovec  (2017),  patisiran  (2018),  onasemnogene abeparvovec  (2019),  idecabtagene vicleucel  (2021),  nadofaragene firadenovec ,  valoctocogene roxaparvovec  and  etranacogene dezaparvovec  (all 2022). Most of these approaches utilize  adeno-associated viruses  (AAVs) and  lentiviruses  for performing gene insertions,  in vivo  and  ex vivo , respectively. AAVs are characterized by stabilizing the  viral capsid , lower immunogenicity, ability to  transduce  both dividing and nondividing cells, the potential to integrate site specifically and to achieve long-term expression in the in-vivo treatment. [ 6 ]   ASO  /  siRNA  approaches such as those conducted by  Alnylam  and  Ionis Pharmaceuticals  require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of  GalNAc  transporters.


Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy.  Bone marrow transplantation  and  organ transplants  in general have been found to introduce foreign DNA into patients. [ 7 ]


Gene therapy was first conceptualized in the 1960s, when the feasibility of adding new genetic functions to  mammalian   cells  began to be researched. Several methods to do so were tested, including injecting  genes  with a micropipette directly into a living mammalian cell, and exposing cells to a precipitate of  DNA  that contained the desired genes. Scientists theorized that a  virus  could also be used as a vehicle, or vector, to deliver new genes into cells.


One of the first scientists to report the successful direct incorporation of functional  DNA  into a mammalian cell was  biochemist  Dr. Lorraine Marquardt Kraus (6 September 1922 – 1 July 2016) [ 8 ]  at the  University of Tennessee Health Science Center  in  Memphis, Tennessee . In 1961, she managed to genetically alter the  hemoglobin  of  cells  from  bone marrow  taken from a patient with  sickle cell anaemia . She did this by incubating the patient's  cells  in tissue culture with  DNA  extracted from a donor with normal  hemoglobin . In 1968, researchers  Theodore Friedmann , Jay Seegmiller, and John Subak-Sharpe at the  National Institutes of Health  (NIH), Bethesda, in the  United States  successfully corrected genetic defects associated with  Lesch-Nyhan syndrome , a debilitating  neurological disease , by adding foreign  DNA  to cultured cells collected from patients suffering from the disease. [ 9 ]


The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting  organ transplantation ) was performed by  geneticist   Martin Cline  of the  University of California, Los Angeles  in  California ,  United States  on 10 July 1980. [ 10 ] [ 11 ]  Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified. [ 12 ]


After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashanthi DeSilva was treated for  ADA - SCID . [ 13 ]


The first somatic treatment that produced a permanent genetic change was initiated in 1993. [ 14 ]  The goal was to cure malignant brain tumors by using recombinant DNA to transfer a gene making the tumor cells sensitive to a drug that in turn would cause the tumor cells to die. [ 15 ]


The polymers are either  translated  into  proteins , interfere with target  gene expression , or possibly correct  genetic mutations . The most common form uses  DNA  that encodes a functional, therapeutic  gene  to replace a  mutated  gene. The polymer molecule is packaged within a " vector ", which carries the molecule inside cells. [ medical citation needed ]


Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of 2014 [update] , it was still largely an experimental technique. [ 16 ]  These include treatment of  retinal diseases   Leber's congenital amaurosis [ 17 ] [ 18 ] [ 19 ] [ 20 ]  and  choroideremia , [ 21 ]   X-linked SCID , [ 22 ]  ADA-SCID, [ 23 ] [ 24 ]   adrenoleukodystrophy , [ 25 ]   chronic lymphocytic leukemia  (CLL), [ 26 ]   acute lymphocytic leukemia  (ALL), [ 27 ]   multiple myeloma , [ 28 ]   haemophilia , [ 24 ]  and  Parkinson's disease . [ 29 ]  Between 2013 and April 2014, US companies invested over $600 million in the field. [ 30 ]


The first commercial gene therapy,  Gendicine , was approved in China in 2003, for the treatment of certain cancers. [ 31 ]  In 2011,  Neovasculgen  was registered in Russia as the first-in-class gene-therapy drug for treatment of  peripheral artery disease , including  critical limb ischemia . [ 32 ]
In 2012,  alipogene tiparvovec , a treatment for a rare  inherited disorder ,  lipoprotein lipase deficiency , became the first treatment to be approved for clinical use in either the European Union or the United States after its endorsement by the  European Commission . [ 16 ] [ 33 ]


Following early advances in  genetic engineering  of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes. [ 34 ]  Scientists focused on diseases caused by single-gene defects, such as  cystic fibrosis , haemophilia,  muscular dystrophy ,  thalassemia , and  sickle cell anemia .  alipogene tiparvovec  treats one such disease, caused by a defect in  lipoprotein lipase . [ 33 ]


DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein. [ 35 ]  Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered  virus  to deliver the DNA into a  chromosome . [ 36 ] [ 37 ]   Naked DNA  approaches have also been explored, especially in the context of  vaccine  development. [ 38 ]


Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of  nuclease  function has led to more direct DNA editing, using techniques such as  zinc finger nucleases  and  CRISPR . The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 [update]  these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients. [ 39 ]


Gene editing  is a potential approach to alter the human genome to treat genetic diseases, [ 40 ]  viral diseases, [ 41 ]  and cancer. [ 42 ] [ 43 ]  As of 2020 [update]  these approaches are being studied in clinical trials. [ 44 ] [ 45 ]


In 1986, a meeting at the  Institute Of Medicine  defined gene therapy as the addition or replacement of a gene in a targeted cell type. In the same year, the FDA announced that it had jurisdiction over approving "gene therapy" without defining the term. The FDA added a very broad definition in 1993 of any treatment that would 'modify or manipulate the expression of genetic material or to alter the biological properties of living cells'. In 2018 this was narrowed to 'products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences'. [ 46 ]


Writing in 2018, in the Journal of Law and the Biosciences, Sherkow et al. argued for a narrower definition of gene therapy than the FDA's in light of new technology that would consist of any treatment that intentionally and permanently modified a cell's genome, with the  definition of genome  including episomes outside the nucleus but excluding changes due to episomes that are lost over time. This definition would also exclude introducing cells that did not derive from a patient themselves, but include ex vivo approaches, and would not depend on the vector used. [ 46 ]


During the  COVID-19  pandemic, some academics insisted that the  mRNA vaccines  for COVID were not gene therapy to prevent the spread of incorrect information that the vaccine could alter DNA, other academics maintained that the vaccines were a gene therapy because they introduced genetic material into a cell. [ 47 ]   Fact-checkers , such as  Full Fact , [ 48 ]   Reuters , [ 49 ]   PolitiFact , [ 50 ]  and  FactCheck.org [ 51 ]  said that calling the vaccines a gene therapy was incorrect. Podcast host  Joe Rogan  was criticized for calling mRNA vaccines gene therapy as was British politician  Andrew Bridgen , with fact checker Full Fact calling for Bridgen to be removed from the conservative party for this and other statements. [ 52 ] [ 53 ]


Gene therapy encapsulates many forms of adding different  nucleic acids  to a cell.  Gene augmentation  adds a new protein coding gene to a cell. One form of gene augmentiation is  gene replacement therapy , a treatment for  monogenic  recessive disorders where a single gene is not functional an additional functional gene is added. For diseases caused by multiple genes or a dominant gene,  gene silencing  or gene editing approaches are more appropriate but  gene   addition, a  form of gene augmentation where new gene is added, may improve a cells function without modifying the genes that cause a disorder. [ 54 ] : 117


Gene therapy may be classified into two types by the type of cell it affects: somatic cell and germline gene therapy.


In  somatic cell  gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a  gamete ,  germ cell ,  gametocyte , or undifferentiated  stem cell . Any such modifications affect the individual patient only, and are not inherited by  offspring . Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the  genome  or as an external  episome  or  plasmid ) is used to treat disease. [ 55 ]  Over 600  clinical trials  utilizing SCGT are underway [ when? ]  in the US. Most focus on severe genetic disorders, including  immunodeficiencies ,  haemophilia ,  thalassaemia , and  cystic fibrosis . Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages. [ 56 ] [ needs update ]


In  germline  gene therapy (GGT),  germ cells  ( sperm  or  egg cells ) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore  heritable  and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands [ 57 ]  prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations [ 57 ]  and higher risks versus SCGT. [ 58 ]  The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general). [ 57 ] [ 59 ] [ 60 ] [ 61 ]


In  in vivo  gene therapy, a vector (typically, a virus) is introduced to the patient, which then achieves the desired biological effect by passing the genetic material (e.g. for a missing protein) into the patient's cells. In  ex vivo  gene therapies, such as  CAR-T  therapeutics, the patient's own cells (autologous) or healthy donor cells (allogeneic) are modified outside the body (hence,  ex vivo ) using a vector to express a particular protein, such as a chimeric antigen receptor. [ 62 ]


In vivo  gene therapy is seen as simpler, since it does not require the harvesting of  mitotic  cells. However,  ex vivo  gene therapies are better tolerated and less associated with severe immune responses. [ 63 ]  The death of  Jesse Gelsinger  in a trial of an  adenovirus -vectored treatment for  ornithine transcarbamylase deficiency  due to a systemic inflammatory reaction led to a temporary halt on gene therapy trials across the United States. [ 64 ]  As of 2021 [update] ,  in vivo  and  ex vivo  therapeutics are both seen as safe. [ 65 ]


The concept of gene therapy is to fix a genetic problem at its source. If, for instance, a mutation in a certain gene causes the production of a dysfunctional protein resulting (usually recessively) in an inherited disease, gene therapy could be used to deliver a copy of this gene that does not contain the deleterious mutation and thereby produces a functional protein. This strategy is referred to as gene replacement therapy and could be employed to treat inherited retinal diseases. [ 17 ] [ 66 ]


While the concept of gene replacement therapy is mostly suitable for recessive diseases, novel strategies have been suggested that are capable of also treating conditions with a dominant pattern of inheritance.


In vivo, gene editing systems using  CRISPR  have been used in studies with mice to treat cancer and have been effective at reducing tumors. [ 72 ] : 18   In vitro, the CRISPR system has been used to treat HPV cancer tumors.  Adeno-associated virus ,  Lentivirus  based vectors have been to introduce the genome for the CRISPR system. [ 72 ] : 6


The delivery of DNA into cells can be accomplished by multiple  methods . The two major classes are  recombinant viruses  (sometimes called biological  nanoparticles  or viral vectors) and  naked DNA  or DNA complexes (non-viral methods). [ 73 ]


In order to  replicate ,  viruses  introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. [ 54 ] : 39    Retroviruses  go a stage further by having their genetic material copied into the nuclear genome of the host cell. Scientists exploit this by substituting part of a virus's genetic material with therapeutic DNA or RNA. [ 54 ] : 40  [ 74 ]  Like the genetic material (DNA or RNA) in viruses, therapeutic genetic material can be designed to simply serve as a temporary blueprint that degrades naturally, as in a  non-integrative vectors , or to enter the host's nucleus becoming a permanent part of the host's nuclear DNA in infected cells. [ 54 ] : 50


A number of viruses have been used for human gene therapy, including viruses such as  lentivirus ,  adenoviruses ,  herpes simplex ,  vaccinia , and  adeno-associated virus . [ 5 ]


Adenovirus viral vectors  (Ad) temporarily modify a cell's genetic expression with genetic material that is not integrated into the host cell's DNA. [ 75 ] : 5   As of 2017, such vectors were used in 20% of trials for gene therapy. [ 74 ] : 10   Adenovirus vectors are mostly used in cancer treatments and novel genetic vaccines such as the  Ebola vaccine , vaccines used in clinical trials for  HIV  and  SARS-CoV-2 , or  cancer vaccines . [ 75 ] : 5


Lentiviral vectors  based on  lentivirus , a  retrovirus , can modify a cell's nuclear  genome  to permanently express a gene, although vectors can be modified to prevent integration. [ 54 ] : 40,50   Retroviruses were used in 18% of trials before 2018. [ 74 ] : 10    Libmeldy  is an ex vivo stem cell treatment for  metachromatic leukodystrophy  which uses a lentiviral vector and was approved by the European medical agency in 2020. [ 76 ]


Adeno-associated virus  (AAV) is a virus that is incapable of transmission between cells unless the cell is infected by another virus, a helper virus. Adenovirus and the herpes viruses act as helper viruses for AAV. AAV persists within the cell outside of the cell's nuclear genome for an extended period of time through the formation of  concatemers  mostly organized as  episomes . [ 77 ] : 4   Genetic material from AAV vectors is integrated into the host cell's nuclear genome at a low frequency and likely mediated by the DNA-modifying enzymes of the host cell. [ 78 ] : 2647   Animal models suggest that integration of AAV genetic material into the host cell's nuclear genome may cause  hepatocellular carcinoma , a form of  liver cancer . [ 78 ]  Several AAV investigational agents have been explored in treatment of  wet age related macular degeneration  by both  intravitreal  and subretinal approaches as a potential application of AAV gene therapy for human disease. [ 79 ] [ 80 ]


Non-viral vectors for gene therapy [ 81 ]  present certain advantages over viral methods, such as large scale production and low host  immunogenicity . However, non-viral methods initially produced lower levels of  transfection  and  gene expression , and thus lower therapeutic efficacy. Newer technologies offer promise of solving these problems, with the advent of increased cell-specific targeting and subcellular trafficking control.


Methods for non-viral gene therapy  include the injection of naked DNA,  electroporation , the  gene gun ,  sonoporation ,  magnetofection , the use of  oligonucleotides , lipoplexes, dendrimers, and inorganic nanoparticles. These therapeutics can be administered directly or through  scaffold enrichment . [ 82 ] [ 83 ]


More recent approaches, such as those performed by companies such as  Ligandal , offer the possibility of creating cell-specific targeting technologies for a variety of gene therapy modalities, including RNA, DNA and gene editing tools such as CRISPR. Other companies, such as  Arbutus Biopharma  and  Arcturus Therapeutics , offer non-viral, non-cell-targeted approaches that mainly exhibit liver trophism. In more recent years, startups such as  Sixfold Bio ,  GenEdit , and  Spotlight Therapeutics  have begun to solve the non-viral gene delivery problem. Non-viral techniques offer the possibility of repeat dosing and greater tailorability of genetic payloads, which in the future will be more likely to take over viral-based delivery systems.


Companies such as  Editas Medicine ,  Intellia Therapeutics ,  CRISPR Therapeutics ,  Casebia ,  Cellectis ,  Precision Biosciences ,  bluebird bio ,  Excision BioTherapeutics , and  Sangamo  have developed non-viral gene editing techniques, however frequently still use viruses for delivering gene insertion material following genomic cleavage by guided  nucleases . These companies focus on gene editing, and still face major delivery hurdles.


BioNTech ,  Moderna Therapeutics  and  CureVac  focus on delivery of  mRNA  payloads, which are necessarily non-viral delivery problems.


Alnylam ,  Dicerna Pharmaceuticals , and  Ionis Pharmaceuticals  focus on delivery of  siRNA  (antisense oligonucleotides) for gene suppression, which also necessitate non-viral delivery systems.


In academic contexts, a number of laboratories are working on delivery of  PEGylated  particles, which form serum protein coronas and chiefly exhibit  LDL receptor  mediated uptake in cells  in vivo . [ 84 ]


There have been attempts to treat  cancer  using gene therapy. As of 2017, 65% of gene therapy trials were for cancer treatment. [ 74 ] : 7


Adenovirus vectors are useful for some cancer gene therapies because adenovirus can transiently insert genetic material into a cell without permanently altering the cell's nuclear genome. These vectors can be used to cause  antigens  to be added to cancers causing an immune response, or hinder  angiogenesis  by expressing certain proteins. [ 85 ] : 5   An Adenovirus vector is used in the commercial products  Gendicine  and  Oncorine . [ 85 ] : 10   Another commercial product,  Rexin G , uses a retrovirus-based vector and selectively binds to receptors that are more expressed in tumors. [ 85 ] : 10


One approach,  suicide gene therapy , works by introducing genes encoding enzymes that will cause a cancer cell to die. Another approach is the use  oncolytic viruses , such as Oncorine, [ 86 ] : 165   which are viruses that selectively reproduce in cancerous cells leaving other cells unaffected. [ 87 ] : 6  [ 88 ] : 280


mRNA  has been suggested as a non-viral vector for cancer gene therapy that would temporarily change a cancerous cell's function to create antigens or kill the cancerous cells and there have been several trials. [ 89 ]


Afamitresgene autoleucel , sold under the brand name Tecelra, is an autologous T cell immunotherapy used for the treatment of  synovial sarcoma . It is a T cell receptor (TCR) gene therapy. [ 90 ]  It is the first FDA-approved engineered cell therapy for a solid tumor. [ 91 ]  It uses a self-inactivating lentiviral vector to express a T-cell receptor specific for MAGE-A4, a melanoma-associated antigen. [ medical citation needed ]


Gene therapy approaches to replace a faulty gene with a healthy gene have been proposed and are being studied for treating some genetic diseases. As of 2017, 11.1% of gene therapy clinical trials targeted monogenic diseases. [ 74 ] : 9


Diseases such as  sickle cell disease  that are caused by  autosomal recessive disorders  for which a person's normal  phenotype  or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated, may be a good candidate for gene therapy treatment. [ 92 ] [ 93 ]  The risks and benefits related to gene therapy for sickle cell disease are not known. [ 93 ]


Gene therapy has been used in the eye . The eye is especially suitable for  adeno-associated virus  vectors.  Voretigene neparvovec  is an approved gene therapy to treat  Leber's hereditary optic neuropathy . [ 94 ] : 1354    alipogene tiparvovec , a treatment for  pancreatitis  caused by a genetic condition, and  Zolgensma  for the treatment of  spinal muscular atrophy  both use an adeno-associated virus vector. [ 78 ] : 2647


As of 2017, 7% of genetic therapy trials targeted infectious diseases. 69.2% of trials targeted  HIV , 11%  hepatitis  B or C, and 7.1%  malaria . [ 74 ]


Some genetic therapies have been approved by the U.S.  Food and Drug Administration  (FDA), the  European Medicines Agency  (EMA), and for use in Russia and China.


( Arylsulfatase A  gene encoding autologous  CD34+  cells)


Some of the unsolved problems include:


Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of  Jesse Gelsinger , who died in 1999, because of immune rejection response. [ 130 ] [ 131 ]  One X-SCID patient died of leukemia in 2003. [ 13 ]  In 2007, a  rheumatoid arthritis  patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy. [ 132 ]


Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. [ citation needed ]  There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies. [ citation needed ]


The  Helsinki Declaration  (Ethical Principles for Medical Research Involving Human Subjects) was amended by the  World Medical Association 's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the  Human Genome Organization  (HUGO) in 2001, provides a legal baseline for all countries. HUGO's document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research. [ 133 ]


No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the  Department of Health and Human Services , the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects. [ 134 ]


NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects. [ 135 ]


An NIH advisory committee published a set of guidelines on gene manipulation. [ 136 ]  The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient. [ 137 ]  The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial. [ 136 ]


As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as  clinical trials , must be reviewed and approved by the FDA and an  Institutional Review Board . [ 138 ] [ 139 ]


Athletes may adopt gene therapy technologies to improve their performance. [ 140 ]   Gene doping  is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could  level the playing field  if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports. [ 141 ]


Genetic engineering could be used to cure diseases, but also to change physical appearance,  metabolism , and even  improve  physical capabilities and mental faculties such as  memory  and  intelligence . Ethical claims about germline engineering include beliefs that every  fetus  has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases. [ 142 ] [ 143 ] [ 144 ]  For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery. [ 145 ] [ 146 ]  Another theorist claims that moral concerns limit but do not prohibit germline engineering. [ 147 ]


A 2020 issue of the journal  Bioethics  was devoted to moral issues surrounding germline genetic engineering in people. [ 148 ]


Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The  American Medical Association 's Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics." [ 149 ]


As early in the history of  biotechnology  as 1990, there have been scientists opposed to attempts to modify the human  germline  using these new tools, [ 150 ]  and such concerns have continued as technology progressed. [ 151 ] [ 152 ]  With the advent of new techniques like  CRISPR , in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the  human genome  in a way that can be inherited. [ 153 ] [ 154 ] [ 155 ] [ 156 ]  In April 2015, researchers sparked controversy when they  reported  results of  basic research  to edit the  DNA  of non-viable  human embryos  using CRISPR. [ 157 ] [ 158 ]  A committee of the American  National Academy of Sciences  and  National Academy of Medicine  gave qualified support to human genome editing in 2017 [ 159 ] [ 160 ]  once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight." [ 161 ]


In 1972, Friedmann and Roblin authored a paper in  Science  titled "Gene therapy for human genetic disease?". [ 162 ]  Rogers (1970) was cited for proposing that  exogenous good DNA  be used to replace the defective DNA in those with genetic defects. [ 163 ]


In 1984, a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes. [ 164 ]


The first approved gene therapy clinical research in the US took place on 14 September 1990, at the  National Institutes of Health  (NIH), under the direction of  William French Anderson . [ 165 ]  Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with  adenosine deaminase deficiency  (ADA-SCID), a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti's immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary. [ 166 ]


Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993). [ 167 ]  The treatment of  glioblastoma  multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocol no.1602 24 November 1993, [ 168 ]  and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.


In 1992,  Claudio Bordignon , working at the  Vita-Salute San Raffaele University , performed the first gene therapy procedure using  hematopoietic stem cells  as vectors to deliver genes intended to correct  hereditary diseases . [ 169 ]  In 2002, this work led to the publication of the first successful gene therapy treatment for ADA-SCID. The success of a multi-center trial for treating children with SCID ( severe combined immune deficiency  or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany. [ 170 ]


In 1993, Andrew Gobea was born with SCID following prenatal  genetic screening . Blood was removed from his mother's  placenta  and  umbilical cord  immediately after birth, to acquire stem cells. The  allele  that codes for  adenosine deaminase  (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years  T cells  (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed. [ 171 ]


In 1996,  Luigi Naldini  and  Didier Trono  developed a new class of gene therapy vectors based on  HIV  capable of infecting non-dividing cells that have since then been widely used in clinical and research settings, pioneering  lentivirals vector in gene therapy . [ 172 ]


Jesse Gelsinger 's death in 1999 impeded gene therapy research in the US. [ 173 ] [ 174 ]  As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices. [ 175 ]


The modified gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602) [ 168 ]  using antisense / triple helix anti-IGF-I approach was registered in 2002, by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors:  glioblastoma , cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.


Sickle cell disease  can be treated in mice. [ 176 ]  The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of  fetal hemoglobin  (HbF), which normally ceases to be produced shortly after birth. In humans, the use of  hydroxyurea  to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production. [ 177 ]


A new gene therapy approach repaired errors in  messenger RNA  derived from defective genes. This technique has the potential to treat  thalassaemia ,  cystic fibrosis  and some cancers. [ 178 ]


Researchers created  liposomes  25 nanometers across that can carry therapeutic DNA through pores in the  nuclear membrane . [ 179 ]


In 2003, a research team inserted genes into the brain for the first time. They used  liposomes  coated in a  polymer  called  polyethylene glycol , which unlike viral vectors, are small enough to cross the  blood–brain barrier . [ 180 ]


Short pieces of  double-stranded RNA  (short, interfering RNAs or  siRNAs ) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced. [ 181 ]


Gendicine  is a cancer gene therapy that delivers the  tumor suppressor  gene  p53  using an engineered  adenovirus . In 2003, it was approved in China for the treatment of  head and neck squamous cell carcinoma . [ 31 ]


In March, researchers announced the successful use of gene therapy to treat two adult patients for X-linked  chronic granulomatous disease , a disease which affects  myeloid  cells and damages the  immune system . The study is the first to show that gene therapy can treat the myeloid system. [ 182 ]


In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene. [ 183 ]  Similar to  organ transplantation , gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as  microRNAs . This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.


In August, scientists successfully treated metastatic  melanoma  in two patients using  killer T cells  genetically retargeted to attack the cancer cells. [ 184 ]


In November, researchers reported on the use of VRX496, a gene-based  immunotherapy  for the treatment of  HIV  that uses a  lentiviral   vector  to deliver an  antisense  gene against the  HIV envelope . In a  phase I clinical trial , five subjects with chronic HIV infection who had failed to respond to at least two  antiretroviral  regimens were treated. A single intravenous infusion of  autologous   CD4  T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV  antigens  and other  pathogens . This was the first evaluation of a lentiviral vector administered in a US human clinical trial. [ 185 ] [ 186 ]


In May 2007, researchers announced the first gene therapy trial for inherited  retinal disease . The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007. [ 187 ]


Leber's congenital amaurosis  is an inherited blinding disease caused by mutations in the  RPE65  gene. The results of a small clinical trial in children were published in April. [ 17 ]  Delivery of recombinant  adeno-associated virus  (AAV) carrying RPE65 yielded positive results. In May, two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects. [ 17 ] [ 18 ] [ 19 ] [ 20 ]


In September researchers were able to give  trichromatic vision  to  squirrel monkeys . [ 188 ]  In November 2009, researchers halted a fatal  genetic disorder  called  adrenoleukodystrophy  in two children using a  lentivirus  vector to deliver a functioning version of  ABCD1 , the gene that is mutated in the disorder. [ 189 ]


An April paper reported that gene therapy addressed  achromatopsia  (color blindness) in dogs by targeting  cone  photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs. [ 190 ]


In September it was announced that an 18-year-old male patient in France with  beta thalassemia  major had been successfully treated. [ 191 ]  Beta thalassemia major is an inherited  blood disease  in which  beta haemoglobin  is missing and patients are dependent on regular lifelong  blood transfusions . [ 192 ]  The technique used a lentiviral vector to transduce the human β-globin gene into purified blood and  marrow  cells obtained from the patient in June 2007. [ 193 ]  The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed. [ 193 ] [ 194 ]  Further clinical trials were planned. [ 195 ]   Bone marrow transplants  are the only cure for thalassemia, but 75% of patients do not find a matching donor. [ 194 ]


Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016). [ 196 ] [ 197 ]


In 2007 and 2008, a man ( Timothy Ray Brown ) was cured of HIV by repeated  hematopoietic stem cell transplantation  (see also  allogeneic stem cell transplantation ,  allogeneic bone marrow transplantation ,  allotransplantation ) with double-delta-32 mutation which disables the  CCR5  receptor. This cure was accepted by the medical community in 2011. [ 198 ]  It required complete  ablation  of existing  bone marrow , which is very debilitating. [ 199 ]


In August two of three subjects of a pilot study were confirmed to have been cured from  chronic lymphocytic leukemia  (CLL). The therapy used genetically modified  T cells  to attack cells that expressed the  CD19  protein to fight the disease. [ 26 ]  In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free. [ 200 ]


Human HGF plasmid DNA therapy  of  cardiomyocytes  is being examined as a potential treatment for  coronary artery disease  as well as treatment for the damage that occurs to the heart after  myocardial infarction . [ 201 ] [ 202 ]


In 2011,  Neovasculgen  was registered in Russia as the first-in-class gene-therapy drug for treatment of  peripheral artery disease , including  critical limb ischemia ; it delivers the gene encoding for  VEGF . [ 32 ]  Neovasculogen is a  plasmid  encoding the  CMV promoter  and the 165 amino acid form of  VEGF . [ 203 ] [ 204 ]


The FDA approved Phase I clinical trials on  thalassemia  major patients in the US for 10 participants in July. [ 205 ]  The study was expected to continue until 2015. [ 195 ]


In July 2012, the  European Medicines Agency  recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used  Alipogene tiparvovec  (Glybera) to compensate for  lipoprotein lipase deficiency , which can cause severe  pancreatitis . [ 206 ]  The recommendation was endorsed by the  European Commission  in November 2012, [ 16 ] [ 33 ] [ 207 ] [ 208 ]  and commercial rollout began in late 2014. [ 209 ]  Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012, [ 210 ]  revised to $1 million in 2015, [ 211 ]  making it the most expensive medicine in the world at the time. [ 212 ]  As of 2016 [update] , only the patients treated in clinical trials and a patient who paid the full price for treatment have received the drug. [ 213 ]


In December 2012, it was reported that 10 of 13 patients with  multiple myeloma  were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered  T cells  to target proteins  NY-ESO-1  and  LAGE-1 , which exist only on cancerous myeloma cells. [ 28 ]


In March researchers reported that three of five adult subjects who had  acute lymphocytic leukemia  (ALL) had been in remission for five months to two years after being treated with genetically modified  T cells  which attacked cells with  CD19  genes on their surface, i.e. all  B cells , cancerous or not. The researchers believed that the patients' immune systems would make normal T cells and B cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease. [ 27 ]


Following encouraging Phase I trials, in April, researchers announced they were starting Phase II clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients [ 214 ]  at several hospitals to combat  heart disease . The therapy was designed to increase the levels of  SERCA 2, a protein in heart muscles, improving muscle function. [ 215 ]  The U.S.  Food and Drug Administration  (FDA) granted this a  breakthrough therapy  designation to accelerate the trial and approval process. [ 216 ]  In 2016, it was reported that no improvement was found from the CUPID 2 trial. [ 217 ]


In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had  metachromatic leukodystrophy , which causes children to lose cognitive and motor skills. [ 218 ]  The other children had  Wiskott–Aldrich syndrome , which leaves them to open to infection, autoimmune diseases, and cancer. [ 219 ]  Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising. [ 220 ] [ 221 ]


In October researchers reported that two children born with  adenosine deaminase severe combined immunodeficiency disease  (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress. [ 24 ]  In 2014, a further 18 children with ADA-SCID were cured by gene therapy. [ 222 ]  ADA-SCID children have no functioning immune system and are sometimes known as "bubble children". [ 24 ]


Also in October researchers reported that they had treated six people with haemophilia in early 2011 using an adeno-associated virus. Over two years later all six were producing  clotting factor . [ 24 ] [ 223 ]


In January researchers reported that six  choroideremia  patients had been treated with adeno-associated virus with a copy of  REP1 . Over a six-month to two-year period all had improved their sight. [ 66 ] [ 224 ]  By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting. [ 21 ]  Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.


In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation ( CCR5  deficiency) known to protect against HIV with promising results. [ 225 ] [ 226 ]


Clinical trials of gene therapy for  sickle cell disease  were started in 2014. [ 227 ] [ 228 ]


In February  LentiGlobin BB305 , a gene therapy treatment undergoing clinical trials for treatment of  beta thalassemia  gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease. [ 229 ]


In March researchers delivered a  recombinant gene  encoding a  broadly neutralizing antibody  into monkeys infected with simian  HIV ; the monkeys' cells produced the  antibody , which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway. [ 230 ] [ 231 ]


In March, scientists, including an inventor of  CRISPR ,  Jennifer Doudna , urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations". [ 153 ] [ 154 ] [ 155 ] [ 156 ]


In December, scientists of major world academies called for a moratorium on inheritable  human genome  edits, including those related to  CRISPR-Cas9  technologies [ 232 ]  but that basic research including embryo gene editing should continue. [ 233 ]


Researchers successfully treated a boy with  epidermolysis bullosa  using skin grafts grown from his own skin cells, genetically altered to repair the mutation that caused his disease. [ 234 ]


In November, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T cells genetically engineered using  TALEN  to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of  acute lymphoblastic leukaemia  [ALL]). [ 235 ]  Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment. [ 236 ] [ 237 ]


In April the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  endorsed a gene therapy treatment called  Strimvelis [ 238 ] [ 239 ]  and the European Commission approved it in June. [ 240 ]  This treats children born with  adenosine deaminase deficiency  and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe. [ 241 ]


In October, Chinese scientists reported they had started a trial to genetically modify T cells from 10 adult patients with lung cancer and reinject the modified T cells back into their bodies to attack the cancer cells. The T cells had the  PD-1 protein  (which stops or slows the immune response) removed using CRISPR-Cas9. [ 242 ] [ 243 ]


A 2016  Cochrane systematic review  looking at data from four trials on  topical cystic fibrosis transmembrane conductance regulator  (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy. [ 244 ]


In February  Kite Pharma  announced results from a clinical trial of  CAR-T  cells in around a hundred people with advanced  non-Hodgkin lymphoma . [ 245 ]


In March, French scientists reported on clinical research of gene therapy to treat  sickle cell disease . [ 246 ]


In August, the FDA approved  tisagenlecleucel  for  acute lymphoblastic leukemia . [ 247 ]  Tisagenlecleucel is an  adoptive cell transfer  therapy for  B-cell  acute lymphoblastic leukemia;  T cells  from a person with cancer are removed,  genetically engineered  to make a specific  T-cell receptor  (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called  CD19  that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called  axicabtagene ciloleucel  was approved for non-Hodgkin lymphoma. [ 248 ]


In October,  biophysicist  and  biohacker   Josiah Zayner  claimed to have performed the very first in-vivo human genome editing in the form of a self-administered therapy. [ 249 ] [ 250 ]


On 13 November, medical scientists working with  Sangamo Therapeutics , headquartered in  Richmond, California , announced the first ever in-body  human gene editing therapy . [ 251 ] [ 252 ]  The treatment, designed to permanently insert a healthy version of the flawed gene that causes  Hunter syndrome , was given to 44-year-old Brian Madeux and is part of the world's first study to permanently edit  DNA  inside the human body. [ 253 ]  The success of the gene insertion was later confirmed. [ 254 ] [ 255 ]  Clinical trials by Sangamo involving gene editing using  zinc finger nuclease  (ZFN) are ongoing. [ 256 ]


In December the results of using an adeno-associated virus with blood clotting  factor VIII  to treat nine  haemophilia A  patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels. [ 257 ] [ 258 ]


In December, the FDA approved  voretigene neparvovec , the first  in vivo  gene therapy, for the treatment of blindness due to  Leber's congenital amaurosis . [ 259 ]  The price of this treatment is  US$850,000  for both eyes. [ 260 ] [ 261 ]


In May, the FDA approved  onasemnogene abeparvovec  (Zolgensma) for treating  spinal muscular atrophy  in children under two years of age. The list price of Zolgensma was set at  US$2.125 million  per dose, making it the most expensive drug ever. [ 262 ]


In May, the EMA approved  betibeglogene autotemcel  (Zynteglo) for treating  beta thalassemia  for people twelve years of age and older. [ 263 ] [ 264 ]


In July,  Allergan  and  Editas Medicine  announced phase I/II clinical trial of AGN-151587 for the treatment of  Leber congenital amaurosis  10. [ 265 ]  This is one of the first studies of a  CRISPR -based  in vivo   human gene editing therapy , where the editing takes place inside the human body. [ 266 ]  The first injection of the CRISPR-Cas System was confirmed in March 2020. [ 267 ]


Exagamglogene autotemcel , a  CRISPR -based  human gene editing therapy , was used for  sickle cell  and  thalassemia  in clinical trials. [ 268 ]


In May, onasemnogene abeparvovec (Zolgensma) was approved by the European Union for the treatment of spinal muscular atrophy in people who either have clinical symptoms of SMA type 1 or who have no more than three copies of the  SMN2  gene , irrespective of body weight or age. [ 269 ]


In August,  Audentes Therapeutics  reported that three out of 17 children with  X-linked myotubular myopathy  participating the clinical trial of a AAV8-based gene therapy treatment AT132 have died. It was suggested that the treatment, whose dosage is based on body weight, exerts a disproportionately toxic effect on heavier patients, since the three patients who died were heavier than the others. [ 270 ] [ 271 ]  The trial has been put on clinical hold. [ 272 ]


On 15 October, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product  Libmeldy  (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene), a gene therapy for the treatment of children with the "late infantile" (LI) or "early juvenile" (EJ) forms of metachromatic leukodystrophy (MLD). [ 273 ]  The active substance of Libmeldy consists of the child's own stem cells which have been modified to contain working copies of the ARSA gene. [ 273 ]  When the modified cells are injected back into the patient as a one-time infusion, the cells are expected to start producing the ARSA enzyme that breaks down the build-up of sulfatides in the nerve cells and other cells of the patient's body. [ 274 ]  Libmeldy was approved for medical use in the EU in December 2020. [ 275 ]


On 15 October, Lysogene, a French biotechnological company, reported the death of a patient in who has received LYS-SAF302, an experimental gene therapy treatment for  mucopolysaccharidosis type IIIA  (Sanfilippo syndrome type A). [ 276 ]


In May, a new method using an altered version of  HIV  as a  lentivirus vector  was reported in the treatment of 50 children with  ADA-SCID  obtaining positive results in 48 of them, [ 277 ] [ 278 ] [ 279 ]  this method is expected to be safer than  retroviruses vectors  commonly used in previous studies of SCID where the development of  leukemia  was usually observed [ 280 ]  and had already been used in 2019, but in a smaller group with X-SCID. [ 281 ] [ 282 ] [ 283 ] [ 284 ]


In June a clinical trial on six patients affected with  transthyretin amyloidosis  reported a reduction the concentration of missfolded  transthretin  (TTR) protein in serum through  CRISPR -based inactivation of the  TTR  gene in liver cells observing mean reductions of 52% and 87% among the lower and higher dose groups.This was done in vivo without taking cells out of the patient to edit them and reinfuse them later. [ 285 ] [ 286 ] [ 287 ]


In July results of a small gene therapy  phase I  study was published reporting observation of dopamine restoration on seven patients between 4 and 9 years old affected by  aromatic L-amino acid decarboxylase deficiency  (AADC deficiency). [ 288 ] [ 289 ] [ 290 ]


In February, the first ever gene therapy for  Tay–Sachs disease  was announced, it uses an  adeno-associated virus  to deliver the correct instruction for the  HEXA  gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related  adverse events . [ 291 ] [ 292 ] [ 293 ]


In May,  eladocagene exuparvovec  is recommended for approval by the European Commission. [ 294 ] [ 295 ]


In July results of a gene therapy candidate for  haemophilia B  called FLT180 were announced, it works using an  adeno-associated virus  (AAV) to restore the clotting  factor IX  (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses. [ 296 ] [ 297 ] [ 298 ]


In December, a 13-year girl that had been diagnosed with  T-cell acute lymphoblastic leukaemia  was successfully treated at  Great Ormond Street Hospital  (GOSH) in the first documented use of therapeutic gene editing for this purpose, after undergoing six months of an experimental treatment, where all attempts of other treatments failed. The procedure included reprogramming a healthy T-cell to destroy the cancerous T-cells to first rid her of leukaemia, and then rebuilding her immune system using healthy immune cells. [ 299 ]  The GOSH team used  BASE editing  and had  previously  treated a case of  acute lymphoblastic leukaemia  in 2015 using  TALENs . [ 237 ]


In May 2023, the FDA approved  beremagene geperpavec  for the treatment of wounds in people with  dystrophic epidermolysis bullosa  (DEB) which is applied as a topical gel that delivers a herpes-simplex virus type 1 (HSV-1) vector encoding the collagen type VII alpha 1 chain ( COL7A1 ) gene that is dysfunctional on those affected by DEB . One trial found 65% of the Vyjuvek-treated wounds completely closed while only 26% of the placebo-treated at 24 weeks. [ 97 ]  It has been also reported its use as an eyedrop for a patient with DEB that had vision loss due to the widespread blistering with good results. [ 300 ]


In June 2023, the FDA gave an  accelerated approval  to  Elevidys  for  Duchenne muscular dystrophy  (DMD) only for boys 4 to 5 years old as they are more likely to benefit from the therapy which consists of one-time intravenous infusion of a virus (AAV rh74 vector) that delivers a functioning "microdystrophin" gene (138  kDa ) into the muscle cells to act in place of the normal  dystrophin  (427 kDa) that is found mutated in this disease. [ 102 ]


In July 2023, it was reported that it had been developed a new method to affect genetic expressions through direct current. [ 301 ]


In December 2023, two gene therapies were approved for  sickle cell disease ,  exagamglogene autotemcel [ 105 ]  and  lovotibeglogene autotemcel . [ 108 ]


In November 2024, FDA granted accelerated approval for  eladocagene exuparvovec -tneq (Kebilidi,  PTC Therapeutics ), a direct-to-brain gene therapy for  aromatic  L -amino acid decarboxylase deficiency . [ 302 ]  It uses a recombinant  adeno-associated virus  serotype 2 (rAAV2) to deliver a functioning  DOPA decarboxylase  (DDC) gene directly into the  putamen , increasing the AADC enzyme and restoring  dopamine  production. It is administered through a  stereotactic  surgical procedure. [ 103 ]


Genetic admixture  occurs when previously  isolated  populations interbreed resulting in a population that is descended from multiple sources. It can occur between species, such as with  hybrids , or within species, such as when geographically distant individuals migrate to new regions. It results in  gene pool  that is a mix of the source populations. [ 1 ] [ 2 ] [ 3 ]


Climatic cycles facilitate genetic admixture in cold periods and genetic diversification in warm periods. [ 4 ]
Natural  flooding  can cause genetic admixture within populations of migrating fish species. [ 5 ]
Genetic admixture may have an important role for the success of populations that colonise a new area and  interbreed  with individuals of native populations. [ 6 ]


Admixture mapping is a method of  gene mapping  that uses a  population  of mixed ancestry (an admixed population) to find the genetic  loci  that contribute to differences in diseases or other  phenotypes  found between the different ancestral populations. The method is best applied to populations with recent admixture from two populations that were previously genetically isolated. The method attempts to correlate the degree of ancestry near a genetic locus with the phenotype or disease of interest. Genetic markers that differ in frequency between the ancestral populations are needed across the genome. [ 7 ]


Admixture mapping is based on the assumption that differences in disease rates or phenotypes are due in part to differences in the frequencies of disease-causing or phenotype-causing genetic variants between populations. In an admixed population, these causal variants occur more frequently on chromosomal segments inherited from one or another ancestral population. The first admixture scans were published in 2005 and since then genetic contributors to a variety of disease and trait differences have been mapped. [ 8 ]  By 2010, high-density mapping panels had been constructed for African Americans, Latino/Hispanics, and  Uyghurs .


Genetic counseling  is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This field is considered necessary for the implementation of  genomic medicine . [ 1 ] [ 2 ]  The process integrates:


The practice of advising people about inherited traits began around the turn of the 20th century, shortly after  William Bateson  suggested that the new medical and biological study of  heredity  be called "genetics". [ 3 ]  Heredity became intertwined with social reforms when the field of modern  eugenics  took form. Although initially well-intentioned, ultimately the movement had disastrous consequences; many states in the United States had laws mandating the sterilization of certain individuals, others were not allowed to immigrate and by the 1930s these ideas were accepted by many other countries including in Germany where  euthanasia for the "genetically defective"  was legalized in 1939. [ 3 ]   This part of the history of genetics is at the heart of the now  "non directive"  approach to genetic counseling. [ 4 ]


Sheldon Clark Reed  coined the term genetic counseling in 1947 and published the book  Counseling in Medical Genetics  in 1955. [ 5 ]  Most of the early genetic counseling clinics were run by non-medical scientists or by those who were not experienced clinicians. [ 6 ]  With the growth in knowledge of genetic disorders and the appearance of medical genetics as a distinct specialty in the 1960s, genetic counseling progressively became medicalized, representing one of the key components of clinical genetics. [ 7 ]  It was not, though, until later that the importance of a firm psychological basis was recognized and became an essential part of genetic counseling, the writings of Seymour Kessler making a particular contribution to this. [ 8 ]  The first master's degree genetic counseling program in the United States was founded in 1969 at  Sarah Lawrence College  in Bronxville, New York. [ 9 ]  In 1979, the  National Society of Genetic Counselors (NSGC)  was founded and led by the first president, Audrey Heimler. [ 10 ]


Diagnostic testing  occurs when an individual is showing signs or symptoms associated with a specific condition.  Genetic testing  can be used to arrive at a definitive diagnosis in order to provide better prognosis as well as medical management or treatment options. Testing can reveal conditions can be mild or asymptomatic with early treatment, as opposed to debilitating without treatment (such as  phenylketonuria ). Genetic tests are available for a number of genetic conditions, including but not limited to:  Down syndrome ,  sickle cell disease ,  Tay–Sachs disease ,  muscular dystrophy . Establishing a genetic diagnosis can provide information to other at-risk individuals in the family.  [ citation needed ]


Any reproductive risks (e.g. a chance to have a child with the same diagnosis) can also be explored after a diagnosis. Many disorders cannot occur unless both the mother and father pass on their genes, such as  cystic fibrosis ; this is known as  autosomal recessive  inheritance. Other  autosomal dominant  diseases can be inherited from one parent, such as  Huntington disease  and  DiGeorge syndrome . Yet other genetic disorders are caused by an error or mutation occurring during the cell division process (e.g.  aneuploidy ) and are usually not inherited. [ citation needed ]


Screening tests  are often used prior to diagnostic testing, designed to separate people according to a fixed characteristic or property, with the intention of detecting early evidence of disease. For example, if a screening test during a pregnancy (such as  maternal blood screening  or  ultrasound ) reveals a risk of a health issue or genetic condition, patients are encouraged to receive genetic counseling to learn additional information regarding the suspected condition. A discussion of the management, therapy and treatments available for the conditions may take place; the next step may differ depending on the severity of the condition and range from during pregnancy to after delivery. Patients may decline additional screening and testing, elect to proceed to diagnostic testing, or pursue further screening tests to refine the risk during the pregnancy. [ citation needed ]


Presymptomatic or predictive testing  occurs when an individual knows of a specific diagnosis (typically adult onset) in their family and has other affected relatives, but they themselves do not manifest any clinical findings at the time when they seek testing. The decision about whether or not to proceed with presymptomatic testing should entail a thoughtful approach and consideration of various medical, reproductive, social, insurance, and financial factors, with no "right" or "wrong" answer. Availability of treatment and medical management options for each specific diagnosis, as well as the genetics and inheritance pattern of the particular condition should be reviewed as inherited conditions can have reduced  penetrance . [ citation needed ]


Insurance and legal issues should also be discussed during genetic counseling. There are laws in the United States such as  GINA  (Genetic Information Non-discrimination Act) and  ACA  that provide certain protections against discrimination for individuals with genetic diagnoses. [ citation needed ]


There are different approaches to genetic counseling. The reciprocal-engagement model of genetic counseling practice includes tenets, goals, strategies, and behaviors for addressing patients' genetic concerns. [ 11 ]  Some counselors favor a psycho-educational approach while others incorporate more psycho-therapeutic techniques. Genetic counseling is psycho-educational as patients "learn how genetics contributes to their health risks and then process what this means and how it feels." [ 12 ]


Whether the process of genetic counseling is a form of  psychotherapy  is up for debate. The relationship between the client and counselor is similar as are the goals of the sessions. As a psychotherapist aims to help his client improve his wellbeing, a genetic counselor also helps his client to address a "situational health threat that similarly threatens client wellbeing". Due to the lack of studies which compare genetic counseling to the practice of psychotherapy, it is hard to say with certainty whether genetic counseling can be "conceptualized as a short-term, applied, specific type of psychotherapy". However, there few existing studies suggest that genetic counseling falls "significantly short of psychotherapeutic counseling" because genetic counseling sessions primarily consist of the distribution of information without much emphasis placed on explaining any long-term impacts to the client. [ 13 ] [ 14 ]


The goals of genetic counseling are to increase understanding of  genetic diseases , discuss disease management options and explain the risks and benefits of testing. [ 15 ]  Counseling sessions focus on giving vital, unbiased information and non-directive assistance in the patient's decision-making process. Seymour Kessler, in 1979, first categorized sessions in five phases: an intake phase, an initial contact phase, the encounter phase, the summary phase, and a follow-up phase. [ 16 ]  The intake and follow-up phases occur outside of the actual counseling session. The initial contact phase is when the counselor and families meet and build rapport. The encounter phase includes dialogue between the counselor and the client about the nature of screening and diagnostic tests. The summary phase provides all the options and decisions available for the next step. If patients wish to go ahead with testing, an appointment is organized and the genetic counselor acts as the person to communicate the results. Result delivery can happen both in person or via phone. Often counselors will call out results to avoid patients having to come back in as results can take weeks to be processed. If further counseling is needed in a more personal setting, or it is determined that additional family members should be tested, a secondary appointment can be made. [ citation needed ]


Genetic counselors provide supportive counseling to families, serve as patient advocates and refer individuals and families to community or state support services. They serve as educators and resource people for other health care professionals and for the general public. Many engage in research activities related to the field of medical genetics and genetic counseling. When communicating increased risk, counselors anticipate the likely distress and prepare patients for the results. Counselors help clients cope with and adapt to the emotional, psychological, medical, social, and economic consequences of the test results. [ citation needed ]


Each individual considers their family needs, social setting, cultural background, and religious beliefs when interpreting their risk. [ 17 ]  Clients must evaluate their reasoning to continue with testing at all. Counselors are present to put all the possibilities in perspective and encourage clients to take time to think about their decision. When a risk is found, counselors frequently reassure parents that they were not responsible for the result. An informed choice without pressure or coercion is made when all relevant information has been given and understood. [ citation needed ]


After counseling for other hereditary conditions, the patient may be presented with the option of having genetic testing. In some circumstances no genetic testing is indicated, other times it may be useful to begin the testing process with an affected family member. The genetic counselor also reviews the advantages and disadvantages of genetic testing with the patient. [ citation needed ]


The most commonly measured genetic counseling outcomes included knowledge, anxiety or distress, satisfaction, perceived risk, genetic testing (intentions or receipt), health behaviors, and decisional conflict. Results suggest that genetic counseling can lead to increased knowledge, perceived personal control, positive health behaviors, and improved risk perception accuracy as well as decreases in anxiety, cancer-related worry, and decisional conflict. [ 18 ]


Adult or general genetics clinics serve patients who are diagnosed with genetic conditions that begin to show signs or symptoms in adulthood. Many genetic conditions have varying ages of onset, ranging from an infantile form to an adult form. Genetic counseling can facilitate the decision-making process by providing the patient/family with education about the genetic condition as well as the medical management options available to individuals at risk of developing the condition. Having the genetic information of other members of the family opens the door to asking important questions about the pattern of inheritance of specific disease‐causing mutations. Whilst there is a wealth of literature that describes how families communicate information surrounding single genes, there is very little which explores the experience of communication about family genomes. [ 19 ]  Adult-onset disorders may overlap multiple specialties. [ 20 ]


Genetic counseling is an integral part of the process for patients utilizing  preimplantation genetic testing  (PGT), formerly called preimplantation genetic diagnosis. [ 21 ]  There are three types of PGT and all require  in vitro fertilization  (IVF) using  assisted reproductive technology  (ART). [ 22 ]  PGT-M, for monogenic disorders, involves testing embryos for a specific condition before it is implanted into the mother. This technique is currently being done for disorders with childhood onset, such as Cystic Fibrosis, Tay-Sachs and Muscular Dystrophy, as well as adult-onset conditions, including Huntington's Disease, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome. PGT-SR, for structural rearrangements, involves testing embryos to establish a pregnancy unaffected by a structural chromosomal abnormality (translocation). PGT-A, for aneuploidy, was formerly called preimplantation genetic screening, and involved testing embryos to identify any de novo aneuploidy. The indications to carry out PGT-A are: previous aneuploidy in the couple,  implantation failure ,  recurrent miscarriage , severe male factor or advanced maternal age. Finally, PGT seems to be: safe for the embryo, trustable in the diagnosis, more efficient from the reproductive point of view and cost-effective. [ citation needed ]


Genetic counseling can also involve medical evaluation and clinical work-up for couples with infertility or recurrent pregnancy loss, as these histories can be associated with parental chromosome aberrations (such as  inversions  or  translocations ) and other genetic conditions. [ citation needed ]


A rapidly expanding field in genetic counseling is cardiovascular genetics. More than 1 in 200 people have an inherited  cardiovascular disease . Hereditary cardiac conditions range from common diseases, such as high cholesterol and coronary artery disease, to rare diseases like  Long QT Syndrome ,  hypertrophic cardiomyopathy , and  vascular diseases .  Genetic counselors who specialize in cardiovascular disease have developed skills specific to the management of and counseling for genetic cardiovascular disorders and practice in both the pediatric and adult setting. Cardiovascular genetic counselors are also integral in local and national efforts to prevent sudden cardiac death, which is the leading cause of sudden death in young people. This is done by identifying patients with known or suspected heritable cardiovascular diseases and promoting cascade family screening or testing of at-risk relatives. [ citation needed ]


Common referral reasons include:


Guidelines on cardiovascular genetics are published by multiple professional societies. [ 23 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ]


Cancer genetic counselors see individuals with a personal diagnosis or family history of cancer or symptoms of an inherited cancer syndrome. [ 29 ]  Genetic counselors take a family history and assess for hereditary risk, or risk that can be passed down from generation to generation. If indicated, they can coordinate genetic testing, typically via blood or saliva sample, to evaluate for hereditary cancer risk.  Personalized medical management and cancer screening recommendations can be provided based on results of genetic testing or the family history of cancer. While most cancers are sporadic (not inherited), some are more likely to have a hereditary factor, particularly when occurring at young ages or when clustering in families. These include common cancers such as breast, ovarian, colon and uterine cancers, as well as rare tumor types. [ 30 ]  General referral indications can include, but are not limited to:


Genetic counselors specializing in neurogenetics are involved in the care of individuals who have or are at risk to develop conditions affecting the central nervous system (brain and spinal cord) or peripheral nervous system (the nerves that leave the spinal cord and go to other places in the body, such as the feet and hands, skeletal  muscles, and internal organs). Effects of these conditions can lead to various impairments some examples of which include cognitive decline, intellectual disability, seizures, uncontrolled movements (e.g. ataxia, chorea), muscle weakness, paralysis, or atrophy.  [ citation needed ] Examples of neurogenetic disorders include:


Pediatric genetic counseling can be indicated for newborns, infants, children and their families. General referral indications [ 54 ]  can include:


Prenatal genetics involves services for women either during or prior to a pregnancy. [ citation needed ]


General indications for referral to genetic counseling in the preconception or prenatal setting may include, but are not limited to: [ 55 ]


Prenatal genetic counseling may help with the decision-making process by walking patients through examples of what some people might do in similar situations, and their rationale for choosing that option. Decisions made by patients are affected by factors including timing, accuracy of information provided by tests, and risk and benefits of the tests. This discussion enables patients to place the information and circumstances into the context of their own lives, and in the context of their own values. [ 72 ]  They may choose to undergo noninvasive screening (e.g.  ultrasound ,  triple screen ,  cell-free fetal DNA  screening) or invasive diagnostic testing ( amniocentesis  or  chorionic villus sampling ). Invasive diagnostic tests possess a small risk of  miscarriage  (1–2%) but provide more definitive results. Testing is offered to provide a definitive answer regarding the presence of a certain genetic condition or chromosomal abnormality. Prenatal genetic counseling also comes with ethical concerns both as the parents and as the counselor. It is important to consider all factors that go into the counseling, race, ethnic background, family history, and other significant issues that may arise. [ 73 ]


Psychiatric genetic counseling is a sub-specialty within genetic counseling focused on helping people living with a  psychiatric disorder  and/or their family members understand both the genetic and environmental factors that contributed to their illness and address associated emotions such as guilt or self-blame. [ 74 ]  Genetic counselors also discuss strategies to promote recovery and protect  mental health  and address any questions on chances for recurrence in other family members. While currently there is no single gene solely responsible for causing a psychiatric disorder, there is strong evidence from family,  twin studies , and  genome-wide-association studies  that both multiple genes and environment interact together. [ 75 ]  Like other areas of genetic counseling, patients at all different stages of life (pediatric, adult, prenatal) [ 76 ] [ 77 ]  can have psychiatric genetic counseling. Since the etiology of psychiatric disorders is complex and not fully understood, the utility of genetic testing is not as clear as it is in Mendelian or single gene disorders. [ 78 ]  Research has shown that individuals who receive psychiatric genetic counseling have significant increases in feelings of empowerment and  self-efficacy  after genetic counseling. [ 79 ]


Psychiatric genetic counselors can help "dispel mistaken notions about psychiatric disorders, calm needless anxiety, and help those at risk to draw up a rational plan of action based on the best available information". [ 80 ]


In 2023, it was estimated there were over 10,000 genetic counsellors globally, practicing in over 45 countries. [ 81 ]  This is a marked increase over the 2018 data, which showed less than 7000 genetic counselors in at least 28 countries. [ 82 ]  The increased numbers of genetic counsellors over the period 2018-2023 is mostly accounted for by growth in the number of genetic counsellors in the US. [ 81 ]


Genetic counseling in China (mainland) has been primarily provided by pediatricians or obstetricians for prenatal or birth defect diagnoses. Most genetic tests can only be performed in academic institutions as research tests or in commercial direct-to-consumer companies for non-clinical use. [ 83 ]


In China, genetic counseling is steered by the  Chinese Board of Genetic Counseling (CBGC) , [ 84 ]  a not-for-profit organization. CBGC is composed of senior experts engaged in genetic education and research. CBGC is committed to establishing standardized procedures of genetic counseling, training qualified genetic counselors, improving health for all, and reducing the incidence of birth defects. CBGC was established in 2015 and is the major professional organization for genetic counselors in mainland China, providing training through short term online and in-person lectures, educational conferences, and certification for trainees. [ citation needed ]


Genetics education in China began in the 1980s when selected medical schools began offering genetics courses that focused predominantly on molecular genetics and had limited clinical content. [ 83 ] [ 85 ]  At present, there are no official master's level graduate programs in genetic counseling or clinical genetics in China, and there is great variability in the duration and content of genetics curricula among medical schools and professional organizations. [ citation needed ]


The  Chinese Ministry of Health  has not yet recognized genetic counselors as an independent health care occupation. There are no official statistics for the number of health care professionals (e.g., physicians, nurses, and lab technicians) who are providing genetic counseling services in China. [ citation needed ]  As of 2023, it was estimated that there were 4000-6000 genetic counsellors in China, however in China certification to work as a genetic counsellor is given after completing a very short training course (1-2 week equivalent). As such, genetic counsellors in China cannot be held to the same standard as those who are trained in other countries. [ 81 ]


Genetic Counselling is a developing field in South Africa. [ 86 ]  As of 2023, there are about 30 registered genetic counsellors practicing in the country, up from around 20 in 2018. [ 81 ]  South African genetic counsellors work at academic institutions, in the private health sector and more recently, private genetic laboratories. As of 2023, approximately two thirds of all genetic counsellors working in South Africa are employed in the private healthcare sector. [ 81 ]  Some qualified genetic counsellors are employed outside of the country or in other professions, owing to funding limitations that have severely impacted employment opportunities. [ 81 ]


The first genetic counselling programme in South Africa started in 1989 at the  University of the Witwatersrand  in Johannesburg. [ 87 ]  A second programme started in 2004 at the  University of Cape Town . [ 88 ]  These are the only two programmes offering Masters level genetic counselling training in South Africa. Currently these courses are running at full capacity. This is a two-year degree and includes a research component. The majority of students enter the Masters programme with a science background but those with a psychology background are also considered. [ citation needed ]


The  Health Professions Council of South Africa  (HPCSA) [ 89 ]  requires two years of internship. Often the first year forms part of the master's degree in Genetic Counselling and a further 12-month internship thereafter. Genetic Counsellors are required by law to register with the HPCSA in order to practice as genetic counsellors. At the end of the training period, registrants submit a portfolio to the HPCSA for assessment. If successful, the intern will be registered with the HPCSA and will be able to practice as a genetic counsellor in South Africa. [ citation needed ]


There is a professional organisation for Genetic Counsellors in South Africa,  Genetic Counselling South Africa (GC-SA) , which provides information and guidance to the HPCSA and others regarding professional issues. [ 90 ]  The GCSA is a focus group of the South African Society of Human Genetics (SASHG). [ 91 ]


The  University of Ghana's  two-year genetic counselling Master's degree began accepting enrolments in 2022. The program, which was made to address an Africa-wide shortage of genetic counsellors, and to facilitate related research, was developed in close collaboration with the two courses in South Africa. Upon graduation, the graduates in Ghana will register with the Psychological Council of Ghana or another regulatory body to enable them to practice in the country. [ 81 ]


As of 2023, around 960 genetic counsellors practice in 19 European nations: Austria, Belgium, Cyprus, Denmark, France, Germany, Greece, Iceland, Ireland, Italy, Malta, Netherlands, Norway, Portugal, Romania, Spain, Sweden, Switzerland and the UK. [ 81 ]  As of 2023, there were about 960 genetic counselors practicing in Europe, a number that has only increased very slightly since 2018. [ 81 ] [ 92 ]  Formal GC registration occurs through two different programs: in the United Kingdom (via the GCRB as described below) and the European Union via the European Board of Medical Genetics (EBMG). Genetic counselors are not currently recognized as a profession in several European countries including Austria, Belgium, Germany, and Portugal. This is likely due to legal restrictions in these countries, which classify genetic counseling as a medical discipline, and therefore must be conducted by physicians. [ 93 ]


As of 2023, there were 12 active training programs across Europe: Austria, Belgium, France (three programs), Italy, Norway, Portugal, Spain, Sweden, and the United Kingdom (two programs). All are Master's degrees except for the graduate diploma program in Belgium, which trains students who already have a degree in healthcare. Since 2018, genetic counsellor training in The Netherlands has ceased due to legal problems relating to the private practice of genetic counsellors. However, genetic counselling training remains part of the Master's of Physician Assistant and Advanced Nurse Practice degrees. The program in Romania remained inactive as of 2023, and one of the programs in France is expected to close. [ 81 ]


Due to the limited Master's level Genetic Counseling programs located in Europe, the EBMG organization recognizes practicing genetic counselors that trained in Australia, Canada, South Africa and the US. These counselors must possess current registration or certification from their home country and must work full time in Europe for one year to apply for registration with EBMG. [ 93 ]


The majority of Genetic Counsellors in the UK work in the  National Health Service  (NHS) [ 94 ]  in one of the 33 Regional Clinical Genetics Services (some renamed Genomic Medicine Centres in England), Scotland, Wales or Northern Ireland. Others work in specialist roles in the NHS, education, policy or research. A minority work in the private sector.


Training
The first two-year MSc in Genetic Counselling program established in the UK was from the  University of Manchester  in 1992, followed by  Cardiff University  in Wales in 2000. 2016 saw major changes in the way genetic counsellors are trained in England. A 3-year training programme funded by Health Education England, the Scientist Training Programme (STP) uses a combination of work-based training in Genomic Medicine Centres and a part-time MSc in genetics (Genomic Counselling) from the University of Manchester. Recruitment is performed nationally through the National School of Healthcare Science (NSHCS). A 3-year part-time MSc in Genetic and Genomic Counselling is also now delivered by Cardiff University, through blended learning, with most of the teaching delivered online, alongside some short face-to-face teaching blocks in Wales. A 2-year MSc Genetic and Genomic Counselling program began at the  University of Glasgow  in Scotland in 2016. Prerequisites for acceptance on all the programmes include a degree in a relevant science or a nursing or midwifery qualification, and experience in a caring role. [ citation needed ]


Credentialing/certification/licensure
Genetic counselling training programmes are accredited by the UK Genetic Counsellor Registration Board (GCRB) and the European Board of Medical Genetics (EBMG). Genetic counsellors in the UK are regulated through the GCRB, although currently GCRB registration is voluntary. The GCRB registry was accredited in 2016 by the Professional Standards Authority under its Accredited Registers programme. Over 200 genetic counsellors are currently registered through the GCRB. Genetic Counsellors trained through the STP programme are expected to be eligible to apply for statutory regulation through the Health Care Professions Council and it is planned that soon there will be equivalence arrangements with the GCRB to ensure statutory regulation for GCRB registered genetic counsellors. In order to be eligible for GCRB credentialing, one of two sets of requirements must be met: completion of a 2-year Master's of Science degree and 2 years of experience as a genetic counselor, or completion of a 3-year combined Master's program and work-based training. In addition, a portfolio including a 50 case logbook, evidence of supervision, case studies, essays, and recorded counseling sessions is required. [ 92 ]


In order to be eligible for EBMG credentialing, a Master's of Science in genetic counseling is required, along with a portfolio including a logbook of 50 cases, case studies, references, and reflective essays. Both the EBMG and the GCRB also offer an alternative route to credentialing in which the applicant completes a nursing degree. [ 92 ]