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Gene therapy is medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. (2025). 9789814675819, World Scientific. ISBN 9789814675819
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. 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. 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 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. 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.
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) 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.
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.U.S. Congress, Office of Technology Assessment (1984). 9781428923713, DIANE Publishing. . ISBN 9781428923713 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. (2025). 9780470756379, John Wiley & Sons. ISBN 9780470756379
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.
The first somatic treatment that produced a permanent genetic change was initiated in 1993. 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.
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 gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.
Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although , it was still largely an experimental technique. These include treatment of retinal diseases Leber's congenital amaurosis and choroideremia, X-linked SCID, ADA-SCID, adrenoleukodystrophy, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), multiple myeloma, haemophilia, and Parkinson's disease. Between 2013 and April 2014, US companies invested over $600 million in the field.
The first commercial gene therapy, Gendicine, was approved in China in 2003, for the treatment of certain cancers. 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. 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.
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. 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.
DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein. Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome. Naked DNA approaches have also been explored, especially in the context of vaccine development.
Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nucleases 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. these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.
Genome editing is a potential approach to alter the human genome to treat genetic diseases, viral diseases, and cancer. these approaches are being studied in clinical trials.
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.
During the COVID-19 pandemic, some academics insisted that the 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. Fact-checking, such as Full Fact, Reuters, PolitiFact, and FactCheck.org 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.
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. Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, Thalassemia, 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.
In germline gene therapy (GGT), (sperm or ) 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 prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations and higher risks versus SCGT. The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).
In vivo gene therapy is seen as simpler, since it does not require the harvesting of Mitosis cells. However, ex vivo gene therapies are better tolerated and less associated with severe immune responses. The death of Jesse Gelsinger in a trial of an Adenoviridae-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. , in vivo and ex vivo therapeutics are both seen as safe.
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.
A number of viruses have been used for human gene therapy, including viruses such as lentivirus, , herpes simplex, vaccinia virus, and adeno-associated virus.
Adenoviridae (Ad) temporarily modify a cell's genetic expression with genetic material that is not integrated into the host cell's DNA. As of 2017, such vectors were used in 20% of trials for gene therapy. 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 .
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. Retroviruses were used in 18% of trials before 2018. Libmeldy is an ex vivo stem cell treatment for metachromatic leukodystrophy which uses a lentiviral vector and was authorized by the European medical agency in 2020.
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 mostly organized as . 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. 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. 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.
Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of , lipoplexes, dendrimers, and inorganic nanoparticles. These therapeutics can be administered directly or through scaffold enrichment.
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 . 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 and chiefly exhibit LDL receptor mediated uptake in cells in vivo.
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 to be added to cancers causing an immune response, or hinder angiogenesis by expressing certain proteins. An Adenovirus vector is used in the commercial products Gendicine and Oncorine. Another commercial product, Rexin G, uses a retrovirus-based vector and selectively binds to receptors that are more expressed in tumors.
One approach, Suicide gene, works by introducing genes encoding enzymes that will cause a cancer cell to die. Another approach is the use , such as Oncorine, which are viruses that selectively reproduce in cancerous cells leaving other cells unaffected.
mRNA vaccine 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.
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. It is the first FDA-approved engineered cell therapy for a solid tumor. It uses a self-inactivating lentiviral vector to express a T-cell receptor specific for MAGE-A4, a melanoma-associated antigen.
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. The risks and benefits related to gene therapy for sickle cell disease are not known.
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. 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.
| +List of approved gene therapies for the treatment of disease !INN !Brand name !Type !Manufacturer !Target !US Food and Drug Administration (FDA) approved !European Medicines Agency (EMA) authorized | ||||||
| afamitresgene autoleucel | Tecelra | Ex vitro | Adaptimmune | synovial sarcoma | August 2024 | |
| alipogene tiparvovec | Glybera | In vivo | Chiesi Farmaceutici | lipoprotein lipase deficiency | Withdrawn | |
| atidarsagene autotemcel | Libmeldy, Lenmeldy (Arylsulfatase A gene encoding autologous CD34+ cells) | Ex vitro | Orchard Therapeutics | metachromatic leukodystrophy | March 2024 | December 2020 |
| Strimvelis | Strimvelis | adenosine deaminase deficiency (ADA-SCID) | May 2016 | |||
| axicabtagene ciloleucel | Yescarta | Ex vitro | Kite Pharma | large B-cell lymphoma | October 2017 | August 2018 |
| beremagene geperpavec | Vyjuvek | In vivo | Krystal Biotech | dystrophic epidermolysis bullosa (DEB) | May 2023 | |
| betibeglogene autotemcel | Zynteglo | beta thalassemia | August 2022 | May 2019 | ||
| brexucabtagene autoleucel | Tecartus | Ex vitro | Kite Pharma | mantle cell lymphoma and acute lymphoblastic leukemia | July 2020 | December 2020 |
| cambiogenplasmid | Neovasculgen | vascular endothelial growth factor peripheral artery disease | ||||
| delandistrogene moxeparvovec | Elevidys | In vivo | Catalent | Duchenne muscular dystrophy | June 2023 | |
| eladocagene exuparvovec | Kebilidi, Upstaza | In vivo | PTC Therapeutics | aromatic L‑amino acid decarboxylase (AADC) deficiency | November 2024 | July 2022 Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. |
| elivaldogene autotemcel | Skysona | cerebral adrenoleukodystrophy | July 2021 | |||
| exagamglogene autotemcel | Casgevy | Ex vivo | Vertex Pharmaceuticals | sickle cell disease | December 2023 | |
| gendicine | head and neck squamous cell carcinoma | |||||
| idecabtagene vicleucel | Abecma | Ex vivo | Celgene | multiple myeloma | March 2021 | |
| lisocabtagene maraleucel | Breyanzi | Ex vivo | Juno Therapeutics | B-cell lymphoma | February 2021 | |
| lovotibeglogene autotemcel | Lyfgenia | Ex vivo | Bluebird Bio | sickle cell disease | December 2023 | |
| nadofaragene firadenovec | Adstiladrin | Ferring Pharmaceuticals | high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) | Yes | ||
| obecabtagene autoleucel | Aucatzyl | Autolus Therapeutics | acute lymphoblastic leukemia | November 2024 | ||
| onasemnogene abeparvovec | Zolgensma | In vivo | Novartis Gene Therapies | spinal muscular atrophy type I | May 2019 | March 2020 |
| prademagene zamikeracel | Zevaskyn | recessive dystrophic epidermolysis bullosa | April 2025 | |||
| revakinagene taroretcel | Encelto | Neurotech Pharmaceuticals | macular telangiectasia type 2 | March 2025 | ||
| talimogene laherparepvec | Imlygic | In vivo | Amgen | melanoma | October 2015 | December 2015 |
| tisagenlecleucel | Kymriah | B cell lymphoblastic leukemia | August 2018 | |||
| valoctocogene roxaparvovec | Roctavian | BioMarin International Limited | hemophilia A | August 2022 | ||
| voretigene neparvovec | Luxturna | In vivo | Spark Therapeutics | biallelic RPE65 mutation associated Leber congenital amaurosis | December 2017 | November 2018 |
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.
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.
An NIH advisory committee published a set of guidelines on gene manipulation. 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. 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.
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.
A 2020 issue of the journal Bioethics was devoted to moral issues surrounding germline genetic engineering in people.
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."
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, and such concerns have continued as technology progressed. 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. In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR. A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017 once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."
Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993). 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, 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. 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.
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 (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.
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.
Jesse Gelsinger's death in 1999 impeded gene therapy research in the US. As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.
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.
Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.
Short pieces of double-stranded RNA (short, interfering RNAs or ) 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.
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.
In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene. Similar to , 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 . 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.
In November, researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentivirus viral 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 and other . This was the first evaluation of a lentiviral vector administered in a US human clinical trial.
In September it was announced that an 18-year-old male patient in France with beta thalassemia major had been successfully treated. Beta thalassemia major is an inherited blood disease in which HBB is missing and patients are dependent on regular lifelong blood transfusions. The technique used a lentiviral vector to transduce the human β-globin gene into purified blood and Bone marrow cells obtained from the patient in June 2007. 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. Further clinical trials were planned. Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.
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).
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. In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.
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.
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. Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.
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. The recommendation was endorsed by the European Commission in November 2012, and commercial rollout began in late 2014. Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012, revised to $1 million in 2015, making it the most expensive medicine in the world at the time. , only the patients treated in clinical trials and a patient who paid the full price for treatment have received the drug.
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.
Following encouraging Phase I trials, in April, researchers announced they were starting Phase II clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function. The U.S. Food and Drug Administration (FDA) granted this a breakthrough therapy designation to accelerate the trial and approval process. In 2016, it was reported that no improvement was found from the CUPID 2 trial.
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. The other children had Wiskott–Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer. Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising.
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. In 2014, a further 18 children with ADA-SCID were cured by gene therapy. ADA-SCID children have no functioning immune system and are sometimes known as "bubble children".
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.
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.
Clinical trials of gene therapy for sickle cell disease were started in 2014.
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.
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.
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".
In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies but that basic research including embryo gene editing should continue.
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). Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.
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.
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.
In March, French scientists reported on clinical research of gene therapy to treat sickle cell disease.
In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia. 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.
In October, Biophysics and biohacker Josiah Zayner claimed to have performed the very first in-vivo human genome editing in the form of a self-administered therapy.
On 13 November, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first ever in-body human gene editing therapy. 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. The success of the gene insertion was later confirmed. Clinical trials by Sangamo involving gene editing using zinc finger nuclease (ZFN) are ongoing.
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.
In December, the FDA approved voretigene neparvovec, the first in vivo gene therapy, for the treatment of blindness due to Leber's congenital amaurosis. The price of this treatment is for both eyes.
In May, the EMA approved betibeglogene autotemcel (Zynteglo) for treating beta thalassemia for people twelve years of age and older. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
In July, Allergan and Editas Medicine announced phase I/II clinical trial of AGN-151587 for the treatment of Leber congenital amaurosis 10. 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. The first injection of the CRISPR-Cas System was confirmed in March 2020.
Exagamglogene autotemcel, a CRISPR-based human gene editing therapy, was used for sickle cell and thalassemia in clinical trials.
In August, Astellas Pharma 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. The trial has been put on clinical hold.
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). Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. 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. 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. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Libmeldy was approved for medical use in the EU in December 2020.
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).
In June a clinical trial on six patients affected with transthyretin amyloidosis reported a reduction the concentration of missfolded Transthyretin (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.
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).
In May, eladocagene exuparvovec is recommended for approval by the European Commission.
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.
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. The GOSH team used BASE editing and had previously treated a case of acute lymphoblastic leukaemia in 2015 using TALENs.
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.
In July 2023, it was reported that it had been developed a new method to affect genetic expressions through direct current.
In December 2023, two gene therapies were approved for sickle cell disease, exagamglogene autotemcel and lovotibeglogene autotemcel.
2024
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. 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.
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