The Resurgence of Gene and Cell Therapy
For those who have not been watching or involved, gene and cell therapy is experiencing a state of resurgence, driven by a series of positive achievements over the last three to four years. These are exciting times for those who kept the faith over the last two decades and pushed onward. There is buoyancy in the field and a demonstrable interest by large pharma and biotech companies. The enthusiasm about recent advances will be on display this week, May 18-21, at the 14th annual meeting of the American Society of Gene and Cell Therapy at the Seattle Convention Center.
After 15 to 20 years of trials, clinical results are powering a resurgence of enthusiasm, right on the standard biotechnology clinical developmental timelines. Trials in patients, mostly young children, having debilitating inherited immune deficiencies are showing remarkable reconstitution of immune systems. Success rates are at least equivalent to bone marrow transplantation, the only other possible treatment for these diseases. Currently, the gene delivery systems are being modified to decrease the risk of clonal expansion leading to leukemia in some cases that is an undesirable side effect. Several groups tested gene therapy for an inherited eye disease caused by a mutant gene leading to retinal degeneration and blindness. A viral vector placed under the retina gave substantial gains in retinal sensitivity and improvement in visual mobility. These advances in patients with rare, inherited genetic diseases provide proof of concept for gene therapy.
Gene and cell therapies are also directed at complex multigenic and acquired diseases, such as cancer. Thus, oncolytic viruses replicate in cancer cells to destroy them and may induce immune responses against them, to give a double whammy. Oncolytic viruses have progressed into advanced phase II and phase III trials. Of course, over the last year we have seen approval for marketing of the first cell therapy, sipuleucel-T (Provenge), for prostate cancer developed here in Seattle by Dendreon. Other cell therapies, particularly those in which T-cells are specifically modified to enhance their ability to recognized and destroy cancer cells, are making substantial strides. Heart failure is being targeted and a viral vector (AAV) and a non-viral plasmid DNA delivered by interventional catheterization, are advancing in clinical trials. In Parkinson’s disease patients, direct injection into the brain shows evidence for sustained gene expression for up to two years and, in at least one Phase II trial, statistical evidence for improvement.
Development of new technologies such as stem cells, small RNAs and gene-targeting continues apace. Testing of stem cells has now advanced into clinical trials. The ability to modify T-cells or hematopoietic stem cells is being coupled with gene-targeting technology, like zinc finger nucleases. This represents the next step in gene therapy by disabling a gene to remove a dominant mutant or to engender infection resistance, such as HIV by deletion of the HIV receptor on CD4 cells.
Hemophilia B can be treated with the protein clotting factor, Factor IX, but may require bi-weekly injection at an annual cost of $100,000 to $200,000. Preliminary results from an ongoing trial suggest single administration of a gene therapy, delivered by peripheral intravenous injection, may lead to sustained therapeutic levels of Factor IX, without the need for protein prophylaxis. This suggests a pharmacoeconomic rationale for gene therapy; reduced health care cost, space for reimbursement, perhaps eventual availability in the developing world.
These advances are leading to more positive media commentary and are attracting attention from large Pharma and biotech companies. Last year a GlaxoSmithKline initiative on rare diseases drove their collaboration with the Telethon Institute in Milan, Italy to advance gene therapy into Phase III testing for rare diseases including immune deficiencies. This year, Amgen acquired Woburn, MA-based Biovex because of their oncolytic virus for glioma that showed impressive results in Phase II testing and is now advancing in Phase III trials. This week, Shire announced a new initiative in gene therapy and stem cells for rare diseases.
A few years ago, public interest and support for gene and cell therapy waned, in connection with negative publicity from a few severe adverse events. Investors came to view the field as moribund. The sentiment was exacerbated by the perceived risk, long product development timelines and liquidity concerns. They lost heart. Consequently, a severe adverse event was inflicted on this segment of the biotech industry.
With the exciting results accruing in the clinic and the strong interest from Big Pharma and biotech players, hopefully investors will not be far behind. Meanwhile, the old adage that “success builds success” is still true. To drive this field forward we need continued translation to clinical success and this is a primary mission and vision of the ASGCT.