The Discovery of Tay-Sachs Disease in Sheep
Tay-Sachs disease has been discovered in a rare breed of sheep known as Jacob sheep. Their discovery is due to the persistence of Fred and Joan Horak, Texas farmers who noticed, in 1999, among their flock of Jacob sheep, two lambs that had developed signs of a nervous system disorder while still very young. Veterinary studies convinced them that the sheep had a lipid storage disease, but no enzyme deficiency could be found.
Fred and Joan realized that they had encountered an inherited disease and because they kept good records on their flock, they knew the parental origin of the affected sheep. They could have removed these animals from their breeding stock, but instead kept the gene around so that perhaps someday it would be better understood.
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It took more than a decade to solve the mystery. Dr. Brian Porter, a veterinary pathologist at Texas A&M, referred the Horaks to Dr. Edwin Kolodny at New York University Medical Center, a member of the Tay-Sachs Gene Therapy (TSGT) Consortium. Dr. Kolodny's lab began putting the pieces of the puzzle together and discovered that the Jacob sheep had Tay-Sachs disease.
Fred and Joan Horak were elated that a cause had finally been found to explain why their lambs had died, and the TSGT Consortium quickly realized the potential of Jacob sheep as a large animal model for gene therapy trials. The Horaks agreed to enlarge their flock in favor of carriers in the hope that a few affected lambs could be produced. In the breeding 2009 season, four lambs were born with Tay-Sachs disease. By three months of age, three of these lambs were already showing neurological signs.
The Horaks then donated the affected animals and others from the flock to NTSAD and the veterinary school at Auburn University where Dr. Douglas Martin and Dr. Miguel Sena-Esteves quickly mobilized to start gene therapy experiments in these sheep. The initial results have been promising, although more animals will be needed to perform further gene therapy studies. Fred and Joan are prepared to do their part. To recognize all that they have done to help advance research, the Horaks received the Above and Beyond Award at the 2010 NTSAD Annual Family Conference.
In 2017, NTSAD awarded a grant to study the methods of delivering gene therapy to Jacob sheep, a rare breed of the animal with a naturally occurring form of Tay-Sachs. The project, which received a grant of $80,000, was led by principal investigator Heather Gray-Edwards, PhD, Assistant Professor of Radiology at UMass Medical School, and a member of the Horae Gene Therapy Center. While other gene therapy studies using intravenous (IV) administration in sheep with Tay-Sachs disease have been conducted, this was the first time the efficacy of adeno-associated viral (AAV) gene therapy after the cerebrospinal fluid (CSF) delivery had been attempted in sheep. (CSF is the fluid surrounding the brain and spinal cord.)
The research showed that using CSF administration of AAV gene therapy is superior to IV administration finding all animals alive and well after more than two years of age at the conclusion of the study. Today, the sheep continue to live near-normal lives at the Farm at the Cummings School of Veterinary Medicine at Tufts University. The sheep are able walk through the pastures and barn, rise to their feet unassisted, and eat normally. One ewe even had a lamb. Throughout the course of the grant, Dr. Gray-Edwards and her team established biomarkers in the animals reflecting those used in humans (ex. MRIs, CSF, etc.), helping to determine efficacy in future clinical trials. The success of the project has directly led to early-stage planning of a possible AAV clinical trial for Late Onset of Tay-Sachs and Sandhoff disease in patients.