Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy.Bone marrow transplantation andorgan 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 tomammaliancells began to be researched. Several methods to do so were tested, including injectinggenes 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 avirus could also be used as a vehicle, or vector, to deliver new genes into cells.
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 forADA-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]
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 engineeredvirus to deliver the DNA into achromosome.[36][37]Naked DNA approaches have also been explored, especially in the context ofvaccine development.[38]
Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding ofnuclease function has led to more direct DNA editing, using techniques such aszinc finger nucleases andCRISPR. 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 theInstitute 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 thedefinition 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 theCOVID-19 pandemic, some academics insisted that themRNA 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 asFull Fact,[48]Reuters,[49]PolitiFact,[50] andFactCheck.org[51] said that calling the vaccines a gene therapy was incorrect. Podcast hostJoe Rogan was criticized for calling mRNA vaccines gene therapy as was British politicianAndrew 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 differentnucleic acids to a cell.Gene augmentation adds a new protein coding gene to a cell. One form of gene augmentiation isgene replacement therapy, a treatment formonogenic 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 butgeneaddition, 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.
Insomatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than agamete,germ cell,gametocyte, or undifferentiatedstem cell. Any such modifications affect the individual patient only, and are not inherited byoffspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in thegenome or as an externalepisome orplasmid) is used to treat disease.[55] Over 600clinical trials utilizing SCGT are underway[when?] in the US. Most focus on severe genetic disorders, includingimmunodeficiencies,haemophilia,thalassaemia, andcystic 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]
Ingermline gene therapy (GGT),germ cells (sperm oregg 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 thereforeheritable 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]
Inin 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. Inex vivo gene therapies, such asCAR-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 ofmitotic cells. However,ex vivo gene therapies are better tolerated and less associated with severe immune responses.[63] The death ofJesse Gelsinger in a trial of anadenovirus-vectored treatment forornithine 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 andex vivo therapeutics are both seen as safe.[65]
A duplex of crRNA andtracrRNA acts as guide RNA to introduce a specifically located gene modification based on the RNA 5' upstream of the crRNA. Cas9 binds the tracrRNA and needs a DNA binding sequence (5'NGG3'), which is called protospacer adjacent motif (PAM). After binding, Cas9 introduces a DNA double strand break, which is then followed by gene modification via homologous recombination (HDR) or non-homologous end joining (NHEJ).
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.
The introduction ofCRISPR gene editing has opened new doors for its application and utilization in gene therapy, as instead of pure replacement of a gene, it enables correction of the particular genetic defect.[40] Solutions to medical hurdles, such as the eradication of latent human immunodeficiency virus (HIV) reservoirs and correction of the mutation that causes sickle cell disease, may be available as a therapeutic option in the future.[67][68][69]
Prosthetic gene therapy aims to enable cells of the body to take over functions they physiologically do not carry out. One example is the so-called vision restoration gene therapy, that aims to restore vision in patients with end-stage retinal diseases.[70][71] In end-stage retinal diseases, the photoreceptors, as the primary light sensitive cells of the retina are irreversibly lost. By the means of prosthetic gene therapy light sensitive proteins are delivered into the remaining cells of the retina, to render them light sensitive and thereby enable them to signal visual information towards the brain.
In vivo, gene editing systems usingCRISPR 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 multiplemethods. The two major classes arerecombinant viruses (sometimes called biologicalnanoparticles or viral vectors) andnaked DNA or DNA complexes (non-viral methods).[73]
Gene therapy using anadenovirus vector. In some cases, the adenovirus will insert the new gene into a cell. If the treatment is successful, the new gene will make a functionalprotein to treat a disease.
In order toreplicate,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 anon-integrative vectors, or to enter the host's nucleus becoming a permanent part of the host's nuclear DNA in infected cells.[54]: 50
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 theEbola vaccine, vaccines used in clinical trials forHIV andSARS-CoV-2, orcancer vaccines.[75]: 5
Lentiviral vectors based onlentivirus, aretrovirus, can modify a cell's nucleargenome 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 formetachromatic leukodystrophy which uses a lentiviral vector and was authorized 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 ofconcatemers mostly organized asepisomes.[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 causehepatocellular carcinoma, a form ofliver cancer.[78] Several AAV investigational agents have been explored in treatment ofwet age related macular degeneration by bothintravitreal 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 hostimmunogenicity. However, non-viral methods initially produced lower levels oftransfection andgene 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.
More recent approaches, such as those performed by companies such asLigandal, 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 asArbutus Biopharma andArcturus Therapeutics, offer non-viral, non-cell-targeted approaches that mainly exhibit liver trophism. In more recent years, startups such asSixfold Bio,GenEdit, andSpotlight 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.
In academic contexts, a number of laboratories are working on delivery ofPEGylated particles, which form serumprotein coronas and chiefly exhibitLDL receptor mediated uptake in cellsin vivo.[84]
There have been attempts to treatcancer using gene therapy. As of 2017, 65% of gene therapy trials were for cancer treatment.[74]: 7
In 2025, a consortium of researchers, in partnership with the National Science Foundation of Iran, conducted anin vitro study to develop a novelformulation of an anti-breast cancer medication that employs gene therapy and intelligentnanocarriers for the first time. This approach enabled researchers to inhibit the proliferation of over 90% of breast cancer cells by concurrently silencing two critical genes (Integrin β3 andIGF-1R) and initiating programmed cell death within 48 hours.[85]
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 causeantigens to be added to cancers causing an immune response, or hinderangiogenesis by expressing certain proteins.[86]: 5 An Adenovirus vector is used in the commercial productsGendicine andOncorine.[86]: 10 Another commercial product,Rexin G, uses a retrovirus-based vector and selectively binds to receptors that are more expressed in tumors.[86]: 10
One approach,suicide gene therapy, works by introducing genes encoding enzymes that will cause a cancer cell to die. Another approach is the useoncolytic viruses, such as Oncorine,[87]: 165 which are viruses that selectively reproduce in cancerous cells leaving other cells unaffected.[88]: 6 [89]: 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.[90]
Afamitresgene autoleucel, sold under the brand name Tecelra, is an autologous T cell immunotherapy used for the treatment ofsynovial sarcoma. It is a T cell receptor (TCR) gene therapy.[91] It is the first FDA-approved engineered cell therapy for a solid tumor.[92] It uses a self-inactivating lentiviral vector to express a T-cell receptor specific for MAGE-A4, a melanoma-associated antigen.[93]
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 assickle cell disease that are caused byautosomal recessive disorders for which a person's normalphenotype 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.[94][95] The risks and benefits related to gene therapy for sickle cell disease are not known.[95]
Off-target effects – The possibility of unwanted, likely harmful, changes to the genome present a large barrier to the widespread implementation of this technology.[126] Improvements to the specificity of gRNAs and Cas enzymes present viable solutions to this issue as well as the refinement of the delivery method of CRISPR.[127] It is likely that different diseases will benefit from different delivery methods.
Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the nucleargenome and the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.
Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible. Theimmune system's enhanced response to viruses that it has seen before reduces the effectiveness to repeated treatments.
Problems with viral vectors – Viral vectors carry the risks of toxicity, inflammatory responses, and gene control and targeting issues.
Some therapies may breach theWeismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.[128][unreliable source?]
Insertionalmutagenesis – If the DNA is integrated in a sensitive spot in the genome, for example in atumor suppressor gene, the therapy could induce atumor. This has occurred in clinical trials forX-linked severe combined immunodeficiency (X-SCID) patients, in whichhematopoietic stem cells were transduced with a corrective transgene using aretrovirus, and this led to the development ofT cell leukemia in 3 of 20 patients.[129][130] One possible solution is to add a functional tumor suppressor gene to the DNA to be integrated. This may be problematic since the longer the DNA is, the harder it is to integrate into cell genomes.[131]CRISPR technology allows researchers to make much more precise genome changes at exact locations.[132]
Cost –alipogene tiparvovec (Glybera), for example, at a cost of $1.6 million per patient, was reported in 2013, to be the world's most expensive drug.[133][134]
Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that ofJesse Gelsinger, who died in 1999, because of immune rejection response.[135][136] One X-SCID patient died of leukemia in 2003.[13] In 2007, arheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[137]
Regulations covering genetic modification are part of general guidelines about human-involved biomedical research.[138] There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.[138]
TheHelsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by theWorld 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 theHuman 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.[139]
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 theDepartment 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.[140]
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.[141]
An NIH advisory committee published a set of guidelines on gene manipulation.[142] 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.[143] 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.[142]
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 asclinical trials, must be reviewed and approved by the FDA and anInstitutional Review Board.[144][145]
Athletes may adopt gene therapy technologies to improve their performance.[146]Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping couldlevel 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.[147]
Genetic engineering could be used to cure diseases, but also to change physical appearance,metabolism, and evenimprove physical capabilities and mental faculties such asmemory andintelligence. Ethical claims about germline engineering include beliefs that everyfetus 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.[148][149][150] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[151][152] Another theorist[who?] claims that moral concerns limit but do not prohibit germline engineering.[153]
A 2020 issue of the journalBioethics was devoted to moral issues surrounding germline genetic engineering in people.[154]
Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. TheAmerican 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."[155]
As early in the history ofbiotechnology as 1990, there have been scientists opposed to attempts to modify the humangermline using these new tools,[156] and such concerns have continued as technology progressed.[157][158] With the advent of new techniques likeCRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit thehuman genome in a way that can be inherited.[159][160][161][162] In April 2015, researchers sparked controversy when theyreported results ofbasic research to edit theDNA of non-viablehuman embryos using CRISPR.[163][164] A committee of the AmericanNational Academy of Sciences andNational Academy of Medicine gave qualified support to human genome editing in 2017[165][166] once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."[167]
In 1972, Friedmann and Roblin authored a paper inScience titled "Gene therapy for human genetic disease?".[168] Rogers (1970) was cited for proposing thatexogenous good DNA be used to replace the defective DNA in those with genetic defects.[169]
The first approved gene therapy clinical research in the US took place in September 1990, at theNational Institutes of Health (NIH), under the direction ofWilliam French Anderson.[171] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her withadenosine 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.[172]
Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[173] The treatment ofglioblastoma 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,[174] 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 theVita-Salute San Raffaele University, performed the first gene therapy procedure usinghematopoietic stem cells as vectors to deliver genes intended to correcthereditary diseases.[175] 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.[176]
In 1993, Andrew Gobea was born with SCID following prenatalgenetic screening. Blood was removed from his mother'splacenta andumbilical cord immediately after birth, to acquire stem cells. Theallele that codes foradenosine 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 yearsT cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[177]
Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.[179][180] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[181]
The modified gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602)[174] 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.[182] The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production offetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use ofhydroxyurea 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.[183]
A new gene therapy approach repaired errors inmessenger RNA derived from defective genes. This technique has the potential to treatthalassaemia,cystic fibrosis and some cancers.[184]
Researchers createdliposomes 25 nanometers across that can carry therapeutic DNA through pores in thenuclear membrane.[185]
Short pieces ofdouble-stranded RNA (short, interfering RNAs orsiRNAs) 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.[187]
In March, researchers announced the successful use of gene therapy to treat two adult patients for X-linkedchronic granulomatous disease, a disease which affectsmyeloid cells and damages theimmune system. The study is the first to show that gene therapy can treat the myeloid system.[188]
In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene.[189] Similar toorgan 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 asmicroRNAs. 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 metastaticmelanoma in two patients usingkiller T cells genetically retargeted to attack the cancer cells.[190]
In November, researchers reported on the use of VRX496, a gene-basedimmunotherapy for the treatment ofHIV that uses alentiviralvector to deliver anantisense gene against theHIV envelope. In aphase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least twoantiretroviral regimens were treated. A single intravenous infusion ofautologousCD4 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 HIVantigens and otherpathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[191][192]
In May 2007, researchers announced the first gene therapy trial for inheritedretinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[193]
Leber's congenital amaurosis is an inherited blinding disease caused by mutations in theRPE65 gene. The results of a small clinical trial in children were published in April.[17] Delivery of recombinantadeno-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]
An April paper reported that gene therapy addressedachromatopsia (color blindness) in dogs by targetingcone 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.[196]
In September it was announced that an 18-year-old male patient in France withbeta thalassemia major had been successfully treated.[197] Beta thalassemia major is an inheritedblood disease in whichbeta haemoglobin is missing and patients are dependent on regular lifelongblood transfusions.[198] The technique used a lentiviral vector to transduce the human β-globin gene into purified blood andmarrow cells obtained from the patient in June 2007.[199] 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.[199][200] Further clinical trials were planned.[201]Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[200]
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).[202][203]
In August two of three subjects of a pilot study were confirmed to have been cured fromchronic lymphocytic leukemia (CLL). The therapy used genetically modifiedT cells to attack cells that expressed theCD19 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.[206]
The FDA approved Phase I clinical trials onthalassemia major patients in the US for 10 participants in July.[211] The study was expected to continue until 2015.[201]
In July 2012, theEuropean Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment usedAlipogene tiparvovec (Glybera) to compensate forlipoprotein lipase deficiency, which can cause severepancreatitis.[212] The recommendation was endorsed by theEuropean Commission in November 2012,[16][33][213][214] and commercial rollout began in late 2014.[215] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[216] revised to $1 million in 2015,[217] making it the most expensive medicine in the world at the time.[218] 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.[219]
In December 2012, it was reported that 10 of 13 patients withmultiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineeredT cells to target proteinsNY-ESO-1 andLAGE-1, which exist only on cancerous myeloma cells.[28]
In March researchers reported that three of five adult subjects who hadacute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modifiedT cells which attacked cells withCD19 genes on their surface, i.e. allB 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[220] at several hospitals to combatheart disease. The therapy was designed to increase the levels ofSERCA2, a protein in heart muscles, improving muscle function.[221] The U.S.Food and Drug Administration (FDA) granted this abreakthrough therapy designation to accelerate the trial and approval process.[222] In 2016, it was reported that no improvement was found from the CUPID 2 trial.[223]
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 hadmetachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[224] The other children hadWiskott–Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[225] Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising.[226][227]
In October researchers reported that two children born withadenosine 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.[228] 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 producingclotting factor.[24][229]
In January researchers reported that sixchoroideremia patients had been treated with adeno-associated virus with a copy ofREP1. Over a six-month to two-year period all had improved their sight.[66][230] 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.[231][232]
In FebruaryLentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment ofbeta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[235]
In March researchers delivered arecombinant gene encoding abroadly neutralizing antibody into monkeys infected with simianHIV; the monkeys' cells produced theantibody, 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.[236][237]
In March, scientists, including an inventor ofCRISPR,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".[159][160][161][162]
In December, scientists of major world academies called for a moratorium on inheritablehuman genome edits, including those related toCRISPR-Cas9 technologies[238] but that basic research including embryo gene editing should continue.[239]
Researchers successfully treated a boy withepidermolysis bullosa using skin grafts grown from his own skin cells, genetically altered to repair the mutation that caused his disease.[240]
In November, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T cells genetically engineered usingTALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form ofacute lymphoblastic leukaemia [ALL]).[241] Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.[242][243]
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 thePD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[248][249]
A 2016Cochrane systematic review looking at data from four trials ontopical 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.[250]
In March, French scientists reported on clinical research of gene therapy to treatsickle cell disease.[252]
In August, the FDA approvedtisagenlecleucel foracute lymphoblastic leukemia.[253] Tisagenlecleucel is anadoptive cell transfer therapy forB-cell acute lymphoblastic leukemia;T cells from a person with cancer are removed,genetically engineered to make a specificT-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 calledCD19 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 calledaxicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[254]
On 13 November, medical scientists working withSangamo Therapeutics, headquartered inRichmond, California, announced the first ever in-bodyhuman gene editing therapy.[257][258] The treatment, designed to permanently insert a healthy version of the flawed gene that causesHunter syndrome, was given to 44-year-old Brian Madeux and is part of the world's first study to permanently editDNA inside the human body.[259] The success of the gene insertion was later confirmed.[260][261] Clinical trials by Sangamo involving gene editing usingzinc finger nuclease (ZFN) are ongoing.[262]
In December the results of using an adeno-associated virus with blood clottingfactor VIII to treat ninehaemophilia 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.[263][264]
In May, the FDA approvedonasemnogene abeparvovec (Zolgensma) for treatingspinal muscular atrophy in children under two years of age. The list price of Zolgensma was set atUS$2.125 million per dose, making it the most expensive drug ever.[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 theSMN2 gene, irrespective of body weight or age.[275]
In August,Audentes Therapeutics reported that three out of 17 children withX-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.[276][277] The trial has been put on clinical hold.[278]
On 15 October, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal productLibmeldy (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).[279] 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.[279] 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.[280] Libmeldy was approved for medical use in the EU in December 2020.[281]
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 formucopolysaccharidosis type IIIA (Sanfilippo syndrome type A).[282]
In May, a new method using an altered version ofHIV as alentivirus vector was reported in the treatment of 50 children withADA-SCID obtaining positive results in 48 of them,[283][284][285] this method is expected to be safer thanretroviruses vectors commonly used in previous studies of SCID where the development ofleukemia was usually observed[286] and had already been used in 2019, but in a smaller group with X-SCID.[287][288][289][290]
In June a clinical trial on six patients affected withtransthyretin amyloidosis reported a reduction the concentration of missfoldedtransthretin (TTR) protein in serum throughCRISPR-based inactivation of theTTR 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.[291][292][293]
In February, the first ever gene therapy forTay–Sachs disease was announced, it uses anadeno-associated virus to deliver the correct instruction for theHEXA 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-relatedadverse events.[297][298][299]
In July results of a gene therapy candidate forhaemophilia B called FLT180 were announced, it works using anadeno-associated virus (AAV) to restore the clottingfactor 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.[302][303][304]
In December, a 13-year girl that had been diagnosed withT-cell acute lymphoblastic leukaemia was successfully treated atGreat 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.[305] The GOSH team usedBASE editing and hadpreviously treated a case ofacute lymphoblastic leukaemia in 2015 usingTALENs.[243]
In May 2023, the FDA approvedberemagene geperpavec for the treatment of wounds in people withdystrophic 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.[100] 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.[306]
In June 2023, the FDA gave anaccelerated approval toElevidys forDuchenne 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 (138kDa) into the muscle cells to act in place of the normaldystrophin (427 kDa) that is found mutated in this disease.[105]
In July 2023, it was reported that it had been developed a new method to affect genetic expressions through direct current.[307]
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