Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. Fascinatingly the therapeutic technique is moving from the conceptual stage to technology development to their application in patients for clinical trials for a variety of patient disorders. To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide.
The most notable advancements include:
Gene Therapy for Genetic Disorders
Severe Combined Immune Deficiency (ADA-SCID)
Adenosine deaminase (ADA) deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency (SCID). ADA-SCID is also known as the bubble boy disease. It occurs in fewer than one in 100,000 live births worldwide and those affected children must have a bone marrow transplantation from matched donors to acquire a functional immune system. As detailed in this report – Gene therapy for ADA-SCID: defining the factors for successful outcome - two clinical studies have shown the long-term success of hematopoietic autologous stem cell (HSC) gene therapy in correction of ADA-SCID. The therapeutic gene called ADA was introduced into the bone marrow cells of patients in the laboratory in Italy, followed by transplantation of the genetically corrected cells back to the same patients. The immune system was reconstituted in all six treated patients without noticeable side effects, who now live normal lives with their families without the need for further treatment.
Chronic Granulomatus Disorder (CGD) is a genetic disease in the immune system; a rare X-linked or autosomal recessive primary immune deficiency characterized by recurrent, life-threatening bacterial and fungal infections. Mortality rates are high with conventional treatment. However, haematopoietic stem cell transplantation (HSCT) offers cure. In a study last year which looked at the outcome of HSCT in 14 Swedish patients with CGD to that in 27 patients with CGD who were given conventional treatment; thirteen of the 14 transplanted patients are alive and well in the first treatment whilst seven of 13 who were treated conventionally died from complications of CGD at a mean age of 19 years, while the remaining patients suffered life-threatening infections.
Hemophilia
Patients born with Hemophilia are not able to induce blood clots and suffer from external and internal bleeding that can be life threatening. A landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent an infusion of an adeno-associated viral (AAV) vector expressing factor IX. These 6 subjects have now exhibited expression of FIX at levels ranging from 1% to 6% of normal for periods of > 2 years. The therapeutic effect however, was transient because the genetically corrected liver cells were recognized as foreign and rejected by the healthy immune system in the patients. This is the same problem faced by patients after organ transplantation, and curative outcome by gene therapy might be achievable with immune-suppression or alternative gene delivery strategies currently being tested in preclinical animal models of this disease.
However at the end of last year Researchers at the UNC School of Medicine and the Medical College of Wisconsin found that a new kind of gene therapy led to a dramatic decline in bleeding events in dogs with naturally occurring hemophilia A. Additionally the team figured out a potential way around the antibody response by using a plasmapheresis machine & a blood-enrichment technique, to isolate specific platelet precursor cells that have hemophilia A. The team then engineered those platelet precursor cells to incorporate a gene therapy vector that expresses factor VIII. The engineered platelet precursors back into the dogs and as the cells proliferated and produced new platelets, more and more were found to express factor VIII. It seemed that at least in dogs, nature took over and platelets were naturally discharge at sites of vascular injury.
Other genetic disorders
A number of clinical trials will soon be launched for various genetic disorders that include congenital blindness, lysosomal storage disease and muscular dystrophy, among others.
Gene Therapy for Acquired Diseases
Cancer
To date, only one immunotherapeutic that could be considered a vaccine, Dendreon’s Provenge, has gained U.S. marketing approval. But even with late-stage clinical trial failures accrue, multiple gene therapy strategies are still being developed to treat a wide variety of cancers, including suicide gene therapy, oncolytic virotherapy, anti-angiogenesis and therapeutic gene vaccines. These approaches are a direct result of unprecedented discoveries of genes and pathways involved in tumorigenesis revealing potential targets for gene and cellular therapies. With this knowledge in the literature, researchers are now studying novel approaches such as siRNA delivery to block a critical pro-growth pathway or delivery of a gene coding for a pro-apoptotic inducer can be realized. What gene therapy does allow is a tailored, targeted approach that has the potential to improve efficacy and minimize toxicity.
At the start of 2012, predictions had been that three immunotherapy products could reach the market in the 2014–2015 timeframe this included:
1. Biovest International’s BiovaxID, an autologous idiotype lymphoma cancer vaccine (Id-KLH/GM-CSF), projected to be approved in Canada and the EU in 2013–2014 and in the U.S. in 2017. In 2012, the FDA denied marketing approval for BioVaxID, requiring that the vaccine undergo another Phase III trial. However in January 2014, the company announced that the European Medicines Agency (EMA) accepted its marketing authorization application for BiovaxID, thus beginning the review process intended to secure approval for the treatment of non-Hodgkin’s follicular lymphoma in patients [who have achieved a first complete remission].
2. Vical’s Allovectin-7 [plasmid-based immunotherapeutic that expresses the HLA-B7 and β2 microglobulin genes, forming a major histocompatibility class I complex] in melanoma had failed to meet key endpoints (statistically significant improvement at time intervals when compared with first-line chemotherapy) in a Phase III trial in patients with stage III/IV metastatic melanoma and lead to the company dropping the product.
3. GlaxoSmithKline’s MAGE A3 [incorporating recombinant MAGE-A3 protein and a novel immunostimulant, AS15 (a combination of QS-21 Stimulon adjuvant, monophosphoryl lipid A, and CpG7909, a TLR-9 agonist] failed its first co-primary endpoint (last September) in a Phase III study for melanoma, failing to produce better results than a placebo in enhancing disease-free survival. The company says it will carry on with the study to determine whether the second primary endpoint—testing the immunotherapy in a genetically defined subpopulation—will provide better efficacy, with data expected in 2015.
Looking back down the pipeline, the industry will be watching these trials closely:
- Introgen’s Phase III trial of Ad.p53 for head and neck cancer. The adenovirally-mediated p53 gene therapy is aimed at encoding the p53 protein which is one of the most intricate elements in the apoptotc (cell death) signalling cascade – a mutation in which leads to a decreased ability of a cell to apoptose & results in tumour growth.
- Aduro Biotech announced safety and efficacy data from its Phase II clinical trial of a two-vaccine approach, suggesting that 93 pancreatic cancer patients demonstrated a statistically significant survival benefit in patients receiving the combination of GVAX Pancreas and CRS-207 cancer vaccines compared to GVAX Pancreas vaccine alone.
- Virtual drug developer Madison Vaccines Inc. (MVI) says it raised $8 million to further its efforts to advance its MVI-816 DNA vaccine for prostate cancer beyond basic research and has completed Phase I in early-stage patients. The trial demonstrated that MVI-816 was safe and that the product induced antigen-specific CD8+ cytotoxic T-cell immunological responses and prostatic acid phosphatase (PSA) doubling times in more than 30% of patients.
- Agenus announced last September (2013) that an analysis from a Phase II trial in patients with newly diagnosed glioblastoma multiforme (GBM) treated with the company’s Prophage Series G-100 (HSPPC-96), a vaccine [autologous therapies derived from cells extracted from the patient’s tumor] used in combination with the current standard of care (radiation and temozolomide), showed an almost 18-month median progression-free survival, representing a 160% increase versus current standard of care alone.
- Bavarian Nodric’s showed promising clinical evidence from it’s phase 1 trial combining PROSTVAC plus ipilimumab (previously published in The Lancet Oncology) and announced a few days ago at the American Association for Cancer Research (AACR) Annual Meeting in San Diego
- NewLink launched a first in human Phase 1 clinical trial of HyperAcute Renal immunotherapy in patients with metastatic renal cell cancer. HyperAcute Renal Immunotherapy is comprised of two allogeneic renal cell cancer cell lines engineered to express the murine alpha(1,3)GT gene.
Neurodegenerative Diseases
Recent progress in gene therapy has allowed for novel treatments of neurodegenerative diseases such as Parkinson’s Disease and Huntington’s Disease, for which exciting treatment results have been obtained in appropriate animal models of the corresponding human diseases. In January a study in 15 Parkinson patients (all in advanced stages) at Imperial College London using a treatment called ProSavin, a modified virus to deliver three genes into the striatum [a part of the brain that controls movement], described a 30 per cent improvement in movement tests with no serious adverse effects. The gen therapy is designed to boost the production of dopamine, a chemical that becomes deficient in patients with Parkinson’s, and is seen as superior to current treatments that only boost the neuroendocrine transmitter temporarily.
AIDS
Gene therapy is being used to mimic a rare but natural mutation that makes about 1% of the population resistant to the most common strains of HIV. The mutation results in a lack of CCR5 which is a cell surface receptor used by HIV to get inside our immune cells. By editing cells harvested in patients and then infusing them back into the patient (10 billion at a time). A clinical trial involving 10 patients showed that 4 showed lasting long time effects and their antiretroviral therapy taken off. One patient’s HIV levels fell so low that they could no longer be detected and a follow up investigation showed that he had already inherited a rare resistance mutation from one of his parents, thus giving his immune system an advantage.
Other acquired diseases
The same gene therapeutic techniques are being studied in the treatment of Influenza, cardiovascular disease and gene therapy , among others. Some of these have entered, or will soon be entering, into early phase clinical trials.