Gene therapy

File:Gene therapy.jpg
Gene therapy using an adenovirus vector. A new gene is inserted into a cell using an adenovirus. If the treatment is successful, the new gene will make a functional protein to treat a disease.
Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease. The polymers are either expressed as proteins, interfere with protein expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies. The first gene therapy experiment approved by the US Food and Drug Administration (FDA) occurred in 1990, when Ashanti DeSilva was treated for ADA-SCID.[1] By January 2014, some 2,000 clinical trials had been conducted or approved.[2]

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of 2014, it was still largely an experimental technique.[3] These include treatment of retinal disease Leber's congenital amaurosis,[4][5][6][7] X-linked SCID,[8] ADA-SCID,[9][10] adrenoleukodystrophy,[11] chronic lymphocytic leukemia (CLL),[12] acute lymphocytic leukemia (ALL),[13] multiple myeloma,[14] haemophilia[10] and Parkinson's disease.[15] Between 2013 and April 2014, US companies invested over $600 million in the field.[16]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[17] In 2012 Glybera, a treatment for a rare inherited disorder, became the treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[3][18]


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.[19] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[18]

DNA must be administered, reach the damaged cells, enter the cell and express/disrupt a protein.[20] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[21][22] Naked DNA approaches have also been explored, especially in the context of vaccine development.[23]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then "edit" the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[24]

Other technologies employ antisense, small interfering RNA and other DNA. To the extent that these technologies do not alter DNA, but instead directly interact with molecules such as RNA, they are not considered "gene therapy" per se.[citation needed]

Cell types

Gene therapy may be classified into two types:

Somatic cell

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any of 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, thalassaemia and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[25]


In germline gene therapy (GGT), germ cells (sperm or eggs) 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[26] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[26] and higher risks versus SCGT.[27] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[26][28][29][30]


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


Main article: Viral vector

Viruses introduce their genetic material into the host cell as part of their replication cycle. Viral vectors exploit this behavior by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA.

A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex, vaccinia and adeno-associated virus.[2]


Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, initially non-viral methods produced lower levels of transfection and gene expression. Later technology remedied this deficiency.

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.


Some of the unsolved problems include:

  • 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 genome 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. The immune 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. The virus also may recover its ability to cause disease.
  • Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are affected by variations in multiple genes, which complicate gene therapy.
  • Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.[31]
  • Insertional mutagenesis – If the DNA is integrated in a sensitive spot in the genome, for example in a tumor suppressor gene, the therapy could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.[32][33] 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. CRISPR technology allows researchers to make much more precise genome changes at exact locations.[34]
  • Cost – Alipogene tiparvovec or Glybera, for example, at a cost of $1.6 million per patient, was reported in 2013 to be the world's most expensive drug.[35][36]


Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999.[37] One X-SCID patient died of leukemia in 2003.[1] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[38]


1970s and earlier

In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?"[39] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[40]


In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[41]


The first approved gene therapy in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[42] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The effects were temporary, but successful.[43]

Cancer therapy of glioblastoma multiforme, the most common human brain tumor, whose outcome is always fatal, was introduced in 1992/93y.[44] The strategy used a vector expressing antisense IGF-I RNA, showed promising results in clinical trials (approved by NIH n˚ 1602, and FDA in 1994). This strategy proved to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena. The median survival reached 21 months, and in some cases, three to four years.[45]

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.[46] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase-deficiency (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.[47]

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

Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.[48][49] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[50]



Sickle-cell disease can be treated in mice.[51] The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[52]

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.[53]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[54]


In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which, unlike viral vectors, are small enough to cross the blood–brain barrier.[55]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[56]

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.[17]


In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[57]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[58] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[59]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[60][61]


In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[62]


Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[63] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[4][5][6][7]


In September researchers were able to give trichromatic vision to squirrel monkeys.[64] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[65]



An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[66]

In September it was announced that an 18 year old male patient in France with beta-thalassemia major had been successfully treated.[67] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[68] The technique used a lentiviral vector to transduce the human ß-globin gene into purified blood and marrow cells obtained from the patient in June 2007.[69] 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.[69][70] Further clinical trials were planned.[71] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[70]


In 2007 and 2008, a man was cured of HIV by repeated Hematopoietic stem cell transplantation (see also Allogeneic stem cell transplantation, Allogeneic bone marrow transplantation, Allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[72] It required complete ablation of existing bone marrow, which is very debilitating.

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.[12] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[73]

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.[74][75]


The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[76] The study was expected to continue until 2015.[77]

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.[78] The recommendation was endorsed by the European Commission in November 2012[3][18][79][80] and commercial rollout began in late 2014.[81]

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.[14]


In March researchers reported that three of five subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[13]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[82] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2a protein in heart muscles, improving muscle function.[83] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[84]

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.[85] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases and cancer.[86] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[87][88]

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.[10] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[89] ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."[10]

Also in October researchers reported that they had treated six haemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[10][90]

Data from three trials on Topical cystic fibrosis transmembrane conductance regulator gene therapy were reported to not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections.[91]


In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight. Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of signt.[92][93]

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.[94][95]

Clinical trials of gene therapy for sickle cell disease were started in 2014[96][97] although one review failed to find any such trials.[98]


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.[99]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkey's 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 are underway.[100][101]

In March scientists, including an inventor of CRISPR, 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”.[102][103][104][105]

Also in 2015 Glybera was approved for the German market.[106]

Speculative uses

Speculated uses for gene therapy include:

Gene doping

Main article: Gene doping

Athletes might adopt gene therapy technologies to improve their performance.[107] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[108]

Human genetic engineering

Genetic engineering could be used to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold such rights, and that every child has the right to be born free of preventable diseases.[109][110][111] For adults, genetic engineering could be seen as another enhancement technique to add to diet, exercise, education, cosmetics and plastic surgery.[112][113] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[114]

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."[115]

As early in the history of biotechnology as 1990, the scientific community was opposed to attempts to modify the human germline using these new tools,[116] and such cautions continued as technology progressed.[117] With the advent of new techniques like CRISPR, in March 2015 scientists urged a worldwide ban on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[102][103][104][105] In April 2015, Chinese researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[118][119]


Regulations covering genetic modification are part of general guidelines about human-involved biomedical research.

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.[120]

United States

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering), must obey international and federal guidelines for the protection of human subjects.[121]

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.[122] 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.[123]

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.[124][125]

Popular culture

Gene therapy is the basis for the plotline of the film I Am Legend[126] and the TV show Will Gene Therapy Change the Human Race?[127]

See also


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Further reading


External links

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