To put it very succinctly, gene therapy has been and is being explored for many conditions that can be directly attributed to specific genetic mutations
that cause excess, insufficient or dysfunctional protein expression. Rather than treating downstream symptoms like most conventional therapies do, gene therapy is meant to correct the “cause” ie the genetic mutation that “drives” the disease.
The concept of gene therapy was first described / introduced in the 1960s. In 1972, Friedman and Roblin published a paper in Science: “Gene therapy for human genetic disease”, in which they urged caution before commencing human gene therapy studies.
The first attempt to use gene therapy came in 19751 when Rogers and his colleagues attempted to introduce Shope papilloma virus – which they believed encoded for arginase, in sisters who suffered from a urea cycle deficiency. The treatment was unsuccessful, but the rationale was thought to be sound.
Several different types of viral vectors have been used in gene therapy research, including retrovirus, lentivirus, adenovirus, adenoassociated virus (AAV), herpesvirus, pox virus, human foamy virus, and more.2
Nevertheless many therapies and approaches are on the horizon and with increasing understanding of real life application from in-market candidates experience, gene therapy can be considered to bring in a new era of disease treatment by manipulating the very “cause” or source of the condition rather than addressing the downstream “consequences”.
Adeno-associated viruses were discovered >50 years ago in the laboratories of Bob Atchison at Pittsburgh and Wallace Rowe at NIH. Both groups recognized that small particles, which were initially thought to be subunit contaminants of adenovirus preparations, were actually a genus of the parvoviruses, now known as dependoviruses. AAV offered some unique advantages as an experimental system due to their lack of pathogenicity and being replication-defective3. This paved the way for the use of AAV as a gene therapy vector. More than 100 serotypes of AAV have been isolated to date, that vary in tissue tropism, transduction efficiency and immunogenic profile.
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 Martin Cline on 10 July 19804 when he transfected the bone marrow of two patients with severe beta-thalassemia with a recombinant human globin gene with a selectable marker. 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 and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.
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 Ashi DeSilva was treated for ADA-SCID5.
In spite of the major setback in 1999, with trial patient Jessie Gelsinger6 7 dying of a severe immune reaction after being administered an adenovirus vector as part of clinical study, gene therapy made progress in the next decade, and the first successful treatment was achieved in Haemophilia B with AAV mediated gene transfer8. In 2012 EMA approved the first gene therapy, Alipogene Tiparvovec, for the treatment of lipoprotein lipase deficiency in severe or multiple pancreatitis attacks9. The advances in gene therapy developed pace after this and in 2017 a trial using AAV2 based vector carrying RPE65 gene for RPE65 deficient inherited retinal dystrophy showed substantial and significant improvements in light perception in treated patients compared to
Current approaches to Gene therapy include Gene transfer, Gene silencing, Gene editing and Cell elimination. In addition, cell therapy (administration of living whole cells that fulfill a particular function into humans for the treatment of disease) can be combined with ex vivo gene therapy.
In spite of advances and successes many significant hurdles remain in this area, like improved methods of gene transfer and editing, as well as better expression of the transduced genes. Reducing the immunogenic potential and cytokine response is also a major challenge. Additionally, manufacturing and regulatory considerations also continue to be important limiting factors.
At the moment there is a significant number of diseases which are thought to be candidates for gene therapy. These include aggressive malignancies like Glioblastoma Multiforme, hepatocellular carcinoma, pancreatic adenocarcinoma, metabolic diseases like lysosomal storage disorders, genetic rare disease like Batten disease which is associated with very poor outcomes, as well as more commonly known conditions like myocardial infarction and haemophilia. More than 50 clinical candidates are in development that harness recombinant AAV technologies. Clinical trials are also being started for gene editing technologies.
Decades of research in gene therapy has increased our understanding in the basic biology of the genetic diseases, various methods of gene delivery and editing, their potential strengths and limitations and also probable adverse events and their management. Challenges do remain in the scientific and safety domains of improving gene transfer and gene-editing efficiencies, addressing immune responses and cytokine release syndrome and off-target effects in gene editing. Nevertheless many therapies and approaches are on the horizon and with increasing understanding of real life application from in-market candidates experience, gene therapy can be considered to bring in a new era of disease treatment by manipulating the very “cause” or source of the condition rather than addressing the downstream “consequences”Of course, regulatory conditions, manufacturing sustainability and efficiency, and cost effectiveness remain important considerations.
A list of some of the conditions being considered candidates for gene therapy:11
Acute LHON Granulomatous Disease,
Chronic, X-linked Danon Disease
Adenosine Deaminase Deficiency
Limb Girdle Muscular Dystrophy
Type 2C Gammasarcoglycanopathy
Neovascular Agerelated Macular Degeneration
Wet Age-related Macular Degeneration
Non-small Cell Lung Cancer Stage 1
X-Linked Retinitis Pigmentosa
X-Linked Chronic Granulomatous Disease
AIDS-related Non Hodgkin Lymphoma
AIDS-related Plasmablastic Lymphoma
AIDS-related Primary Effusion Lymphoma
Aromatic L-amino Acid Decarboxylase (AADC) Deficiency
Lysosomal Storage Disease
Homozygous Familial Hypercholesterolemia
Wiskott-Aldrich Syndrome (WAS)
Early Onset Alzheimer Disease
Severe Combined Immunodeficiency Syndrome
Sickle Cell Disease
Acute Myeloid Leukaemia
Chronic Myeloid Leukaemia
Chronic Granulomatous Disease
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1 Wirth T et al. Gene. 2013; 525:162-169
2 [Yin 2014/p541/col1/para2] | [Nayerossadat 2012/p3/col1/para2]
3 BJ Carter,Molecular Therapy, Volume 10, ISSUE 6, P981-989, December 01, 2004
4 U.S. Congress, Office of Technology Assessment (December 1984, Sun M (October 1982))
5 Sheridan C (February 2011). “Gene therapy finds its niche”. Nature Biotechnology. 29 (2): 121–8
6 Lehrman S et al. Nature. 1999;401:517-518
7 Wirth T et al. Gene. 2013;525:162-169
8 Nathwani AC et al. N Engl J Med. 2011;365:2357-2365
9 European Medicines Agency. July 20, 2012 Accessed 1st October 2019
10 Russell S et al. Lancet. 2017;390:849-860