Gene Therapy Inches Forward Amid Formidable Challenges

by Brenda Patoine

May, 2008

An Interview with Xandra O. Breakefield, Ph.D.
Professor and Geneticist, Molecular Neurogenetics Unit
Neuroscience Program, Harvard Medical School
Massachusetts General Hospital

2007 marked the 10th anniversary of the American Society for Gene Therapy, on whose scientific board you sit. Despite the maturation of the field, there have been no “home runs” in terms of clinical results. What in your view is/are the biggest challenge(s) facing the field today?

A: As with any new medical technology there is a huge learning curve in translating exciting ideas for gene therapy into safe, effective treatments. However, there is renewed excitement in the field, especially for gene therapy in the nervous system, based on more than ten years of scientific research and clinical trials.

The nervous system, in fact, appears to offer a number of advantages as a platform for gene therapy. For one, compared to the periphery, the central nervous system has a reduced immune response to delivery vectors and genetically altered, or “transgene,” products that might be considered for gene therapy in the brain. Second, some disease applications may only need focal gene delivery to a particular brain region, which can be achieved with current technology; this is the case with Parkinson’s disease. Third, because only a few cells in the brain are dividing, there is less chance of tumor formation. Lastly, given that the brain is a fairly contained domain, transgenes introduced there have less access to germ (reproductive) cells and thus less potential for contaminating the gene pool.

There are a number of ongoing clinical trials investigating promising strategies for Parkinson’s disease, brain tumors, pain, Alzheimer’s disease, and lysosomal storage diseases, which have shown little-to-no serious adverse events. challenges include achieving efficient gene delivery, whether targeted or global (depending on the application), and translating findings into large brains, since most studies are initially carried out in mouse models. The length of transgene expression for most vectors is a few years in experimental models, but this may need to be extended in human uses. Also, for some transgene products, the ability to regulate the expression of the transplanted gene over time will be important to reducing non-specific side effects; the current technology still has problems related to leakiness of transgene expression and the propensity for regulatory proteins to provoke an immune reaction.

Q: Gene therapy research tends to make the most headlines when something goes wrong, as happened in 2007 with the death of a woman who was receiving an experimental gene therapy for rheumatoid arthritis. How do such cases impact the advancement of the field?

A: Such tragic cases always raise great concern in the gene therapy field, regulatory agencies, and the general population. They are reported promptly and investigated thoroughly. This increases the clinical and scientific knowledge base, which informs future trials.

In the 2007 case, the gene therapy procedure itself was not deemed responsible for the death of the woman. But in other cases a link was found, including links between leukemia and the treatment of X-linked SCID by ex vivo gene replacement using retrovirus vectors. As with all experimental medical procedures, the gene therapy community strives to improve safety and to consider risk versus potential benefit. More and more emphasis is focused on making sure that the patient is fully informed when consenting to procedures. Although it may appear that the field is slowed down by these events, in fact, they must be understood at the fullest level to improve safety in future trials.

Q: You have pioneered gene therapy applications for the nervous system. What unique challenges does the brain pose for gene delivery, compared to other body systems?

A: The brain represents very intricate machinery housed in a “closed box.” Therefore the gene-delivery procedure itself, including any inflammatory or immune responses to the transgene product or vector, can be toxic in its own right. Achieving delivery to large areas of the brain has been a challenge, but the use of vectors based on adeno-associated viruses (small, stable viruses that are not known to cause disease in humans) and a technique known as convention-enhanced delivery, for example, seem to be extending the therapeutic domain.

One goal of research in this area is to make the delivery procedure as non-invasive as possible and to reduce the number of therapeutic interventions in the brain. The adult brain, and even more so the young brain, represents a dynamic environment in which there is potential for detrimental effects due to, for example, growth factor-induced neuronal sprouting, imbalances in neurotransmitter pathways, or transformation of stem cells.

Q: Effective gene therapy involves not only getting the right gene product to accomplish the clinical goal, but getting it to the right place at the right time and “dose” and being able to shut it down if necessary. Do we know enough yet about any of these factors to know which approach is the best?

A: Most diseases of the nervous system, although they may affect one region more strongly than another, are in fact pervasive, and different regions of the brain may need different types of therapeutic intervention. In many cases, including Parkinson’s disease and brain tumors, we know the primary target region and can deliver transgenes to it. At the current time we cannot control the “dose,” so interventions use proteins that are proven not to be toxic in experimental systems if they are over-expressed.

It is the consensus in the field that some gene therapy approaches for devastating diseases seem logical and “safe” in the sense of not aggravating the disease. In situations where there is appropriate preclinical data, where trials are constructed to maximize scientific findings within regulatory guidelines, and where there is no effective alternate therapy, there is an impetus—from the scientific and medical community as well as patients and family members—to explore this new technology in order to try to achieve better treatment.

Q: Your lab is using neural precursor cells to deliver a “suicide” protein called TRAIL to invasive brain tumor cells. Why have you chosen this approach and what have you found so far?

A: We have found in experimental brain tumor models that normal brain cells, including neural precursor cells, are quite resistant to the apoptotic effects of TRAIL, whereas many glioma cell types are killed. Neural precursor cells have a natural tendency to migrate to tumor foci. Therefore we genetically modified them to release TRAIL in order to have them home in on invasive tumor foci and kill tumor cells, even those that are some distance from the site of delivery.

Since most glioblastoma patients die after removal of the main tumor mass from new foci within centimeters of the previous mass, these migratory, armed stem cells provide a means to extend the therapeutic zone. Our next steps, in collaboration with Dr. Rona Carroll, include obtaining mesenchymal stem cells from the bone marrow of brain tumor patients, genetically modifying them to release therapeutic gene products, and then implanting them into the tumor resection cavity in subsequent neurosurgical procedures. The hope is that the transplanted, modified cells will move out to and kill invasive tumor foci.