BC Researchers Aid Effort to End Tay-Sachs Disease

Prof. Thomas Seyfried (Biology) with members of his Tay-Sachs research group: L-R, Karie Heinicke, Rena Baek and Linh Ta. (Photo by Lee Pellegrini)

By Ed Hayward

BC Chronicle, February 14, 2008

Researchers from Boston Col­lege, Massachusetts General Hospi­tal, Cambridge University (UK) and Auburn University have formed the Tay-Sachs Gene Therapy Consor­tium, with a goal of advancing to human clinical trials a unique gene therapy with the potential to halt the fatal genetic disorder.

Commonly found in children of Eastern European Jewish descent, Tay-Sachs typically claims its vic­tims before they reach age 5. There are variants that affect children of Irish and French-Canadian descent as well. While genetic screening has greatly reduced deaths from Tay-Sachs, approximately 20 individuals die from the disease annually.

By 2011, the consortium plans to have initiated a gene therapy clinical trial in Tay-Sachs disease patients.

“To bring the resources and ex­pertise of Boston College and these other world-class institutions to bear on this deadly disease means we may see the first successful attempt to control a neurodegenerative dis­ease,” says Prof. Thomas Seyfried (Biology), whose lab has made breakthrough discoveries regarding Tay-Sachs.

"This is a scientifically important project, but more important is the opportunity to use our scientific ex­pertise to dramatically improve the lives of others – particularly children – stricken by Tay-Sachs."

The disorder creates an enzyme deficiency that allows harmful quan­tities of a fatty substance, or lipid, to build up in the nerve cells of the brain, resulting in a relentless deterioration of mental and physical abilities. Consortium researchers say their therapy will battle the disease at the cellular level.

The proposed therapy would in­ject a viral vector carrying two hu­man genes – known as HexA (T-S) and HexB (SD) – which are defi­cient in Tay-Sachs. Infection of cells in the brain through two individual vectors has been shown in laboratory mice to spur production of normal enzyme at levels sufficient to correct the enzymatic deficiency through­out the entire brain of these subjects. Consortium researchers have suc­cessfully paired the two genes in a single vector, which they believe will result in increased therapeutic effi­ciency and lower production costs.

"We think we know how to do this, based on the experience in my lab, the experiences at Cambridge University, at Auburn and at BC," says principal investigator Miguel Sena-Esteves, an assistant professor in neurology at Massachusetts Gen­eral Hospital and Harvard Medical School. "This group was essentially working on this initiative with some loose connections or six degrees of separation. Ultimately, we decided we can work together because we all have complimentary expertise."

The consortium combines the expertise in lipid biochemistry of Seyfried’s lab, MGH leadership in building viral vectors and delivering gene therapy to the brain, Cam­bridge scientists who have produced long-term survival of laboratory mice afflicted with Tay-Sachs, and the Scott-Ritchey Research Center at Auburn University’s veterinary school, a leading center for small animal research.

Seyfried’s lab has been research­ing Tay-Sachs for 30 years. Three years ago, Seyfried reported success in mice of a drug that blocks the accumulation of the fatty substances in the brain. That drug was a small, artificial amino sugar molecule that blocked the initial steps of the dis­ease.

Infants can show signs of the disease as early as six months, cease meeting developmental milestones, and then begin to lose motor skills. Children affected by juvenile on­set show signs after age three and quickly begin to regress physically and mentally. For adults afflicted by late onset Tay-Sachs, symptoms are often confused with mental illness or other diagnoses.

The consortium has received sup­port from the Cameron and Hayden Lord Foundation, the Brighton-based National Tay-Sachs and Al­lied Diseases Association (NTSAD), The Cure Tay-Sachs Foundation, The Mathew Forbes Romer Foun­dation, and The Jewish Community Federation of San Francisco Endow­ment Fund. It is in the process of applying to the National Institutes of Health for funding for thera­pies that show promise of successful clinical trials.

For more information about the Tay-Sachs Gene Therapy Con­sortium see www.tsgtconsortium.com/. For more information about Seyfried’s lab, see www2.bc.edu/~seyfridt/index.html.