The science of gene therapy has been advancing very quickly over the past five years. The concept of using gene therapy to treat Tay-Sachs disease is to use molecular trucks (vectors) to transport one or more therapeutic genes into diseased cells in the brain. Once inside the cells those vectors will direct the production of large amounts of normal Hex A enzyme, which will be distributed throughout the entire brain. This will lead to elimination of lysosomal storage in the brain, and possibly reversal of deficits and resumption of normal neurological development.
Tay-Sachs disease is an excellent candidate for gene therapy because:
- Tay-Sachs is caused by mutations in a single gene (the Hex A gene). Therefore we only need to restore the activity of one enzyme, which can be accomplished by introducting one gene (hexA) or two genes (hexA and hexB simultaneously) since higher levels of HexA can be reached if both hex genes are introduced simultaneously into the target cells.
- Cells have the ability to take Hex A from outside the cell and absorb it. If we can create Hex A in the brain, the cells are adept at picking it up and using it.
The gene therapy work that is most interesting to us is that of the Tay-Sachs Gene Therapy Consortium is composed of researchers from six highly regarded academic institutions (Auburn University, Boston College, Cambridge University, NYU and Massachusetts General Hospital/Harvard Medical School). Their work as individual scientists has focused on lysosomal storage diseases (LSDs) affecting the brain. These researchers have combined their expertise with the goal of initiating a gene therapy clinical trial for Tay-Sachs disease (and Sandhoff disease) by June 2012 or sooner. The Consortium's first year of reasearch was funded entirely by private sources (include $300,00 from the CTSF) at a cost of $423,000. They are currently working on animal models, vector systems, delivery methods, and determine the best timing for intervention. This first year of research produced unbelievable success in small animal models and vector distribution throughout the brain. The second year of research (at a cost of $572,000) focus on large animal models. There are naturally occuring models in both cat and sheep populations. If we can save these animals the research should transfer to human clincial trials. In year 3 of 4 (depending on success with large animal models) the Consortium will be preparing a clinical trial protocol and seek approval from regulatory agencies in the US (FDA) and UK.
Here is how it might work. All the genes of a virus (adeno-associated virus) are removed and replaced with the HexA gene and other non-viral genetic elements necessary to direct production of the enzyme in infected cells. This is what is commonly known as a viral vector because of it is derived from a virus and it can shuttle (vector) genetic information into cells. The virus vectors carrying a normal HexA gene are then injected into the brain, and infected cells will start make large amounts of active HexA enzyme which is released into the brain. In essence the viral vectors turn brain cells into microfactories of normal enzyme in the brain. Diseases cells throughout the brain pick up this enzyme released from those manufacturing centers and use it to metabolize (recycle) GM2-ganglioside and eliminate this main product stored in their lysosomes. The concept is quite simple, and it has been demonstrated to be highly effective in treating mouse models of different lysosomal storage diseases, including GM2-gangliosidoses. Untreated GM2 mice (Sandhoff disease) die at 3-4 months of age. Members of the Consortium have shown that animals treated by the approach described above survive up to 2 years. Although treated animals still present movement abnormalities their lifespan has been increased by 8-fold!
Click play to start video
Translation of this approach into an effective treatment in humans has considerable challenges:
- Size - The human brain is ~2000-fold larger than the mouse brain.
- Complexity – The human brain anatomy is considerably different than the mouse.
- Delivery modality – Although it has been relatively easy to treat mice, the targets in the human brain will have to be carefully chosen to minimize risk and at the same time achieve global distribution of enzyme throughout the brain.
- Timing of treatment – Can severely affected patients resume normal development after treatment? Recent experiments in mouse models of LSDs indicate that the earlier the intervention is performed the better the outcome. This raises the question of when it may be too late to alter the course of disease?
We know gene therapy works in small animals. Now we need to safely upscale to larger animal models and ultimately human trials. The Tay-Sachs Gene Therapy Consortium has a three year plan to prove the theory and develop a clinical trial protocol. Our hope is the National Institute of Health (NIH) will aid in funding the research, the consortium has applied for grant monies. The three years needed to identify the best approach and optimize it will cost between $1.9 and $2.3 million. The first year cost of $423,000 has already been funded year, the year year cost of $572,000 is currently being funded. The need for an additional year at a cost of $361,000 will be dependent upon 2009's success in cat and sheep. Efficacy and toxicity studies will be required by the FDA at a cost of nearly $1 million.
One of the real benefits of gene therapy is that if we can prove that this therapeutic approach works in Tay-Sachs, the vectors can be packed with genes that would help other LSD diseases. From what will be learned during this pre-clinical and clinical studies we may be able develop treatments for many other neurological diseases including Parkinson's, Alzheimer's or multiple sclerosis (MS). Ongoing gene therapy trials in Parkinson’s patients have already shown hopeful results.
The skeptics might say introducing virus vectors into the brain is dangerous. Any injection in the brain is fraught with peril. The risk of brain damage or infection does exist. Early vector systems were unpredictable – how can we understand the long-term impact? The proposed studies will help find answers to these questions before a clinical trial is initiated. It is important to realize that risk can never be eliminated from any human enterprise, but it can be managed and reduced to acceptable levels. Inaction is not an alternative! Creativity, hard work, and responsible conduct of research will prevail and a cure for Tay-Sachs disease shall be developed.
To read the detailed Tay-Sachs Gene Therapy Consortium project description – click here.
Visit the Tay-Sachs Gene Therapy Consortium website at www.tsgtconsortium.com.
For additional information:
Article from February 14, 2008 Edition of Boston College Chronicle
www.ntsad.org Research Initiatives
www.ntsad.org Therapeutic Approach
www.pubmedcentral.nih.gov Gene Therapy
www.ornl.gov Gene Therapy
Overview of Gene Therapy