A team of scientists at the National Institutes of Health (NIH) used gene editing to fix the mutation that causes a form of the rare Tay-Sachs disease in mice, sparking hope that the approach could also work for human patients and other related disorders.
Late-onset Tay-Sachs disease (LOTS) is often caused by a single change, an adenine where a guanine should be, in the DNA of a gene that makes an enzyme critical for a cell’s ability to break down a common nervous system lipid. Using a DNA base editor packaged inside a viral vector, researchers were able to partially flip the errant adenine back to a guanine, restoring the missing enzyme’s activity and reducing toxic buildup of lipid.
A paper describing the results was published June 17, and the NIH shared news of the work in an Aug. 15 release.
Because the AAV vector used in the study is specific to mice, the team is now working to develop vectors or nanoparticles that can be used to get the therapy into the brains of human patients, Richard Proia, Ph.D., an investigator at the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases and leader of the study, told Fierce Biotech.
Proia has studied Tay-Sachs and related diseases for years, identifying the mutations that cause LOTS and developing an effective mouse model of the disease. He collaborates closely with Cynthia Tifft, M.D., Ph.D., a senior clinician at the NIH’s National Human Genome Research Institute (NHGRI) who treats about 25 patients with LOTS at the NIH Clinical Center, according to the release.
Tay-Sachs is caused by mutations in the gene that makes part of the enzyme hexosaminidase A. This enzyme breaks down large lipids called gangliosides; without it, ganglioside levels build up in cells to toxic levels. The more common, though still rare, form of the disease occurs in infants and is always fatal. Children with the disease usually only live a few years.
The infant form of Tay-Sachs is “the one that's screened for in groups that may be at risk for carrying the mutations,” such as Amish and Ashkenazi Jewish people, Proia said. “But it's now appreciated that there's a spectrum of the disease” that includes milder forms that emerge in adolescence or adulthood.
Patients with LOTS may have a normal life span but commonly experience symptoms like muscle weakness, loss of coordination, difficulty swallowing and mental health issues.
While using a similar base editing approach to treat the more severe infant form of the disease would be tricky, Proia said, different therapeutic approaches have recently made progress in combating the illness and related conditions.
Last week, a team led by the Horae Gene Therapy Center at the UMass Chan Medical School, also collaborating with Tifft, reported using a gene therapy to deliver functional copies of the hexosaminidase A genes to children with Tay-Sachs. The therapy was able to temporarily restore the enzyme’s activity in the phase 1/2 trial but lost effectiveness after 24 weeks.
And, earlier this month, a different team of researchers used a cell therapy approach called microglia replacement to treat mice with Sandhoff disease, a lysosomal storage disease similar to Tay-Sachs.
“For a rare disease, it's amazing to me that recently there’s such high-profile work,” Proia said. “That's nice to see.”
The new study by Proia and Tifft represents “the best of the intramural program at NIH,” Eric Green, M.D., Ph.D., former director of the NHGRI, told Fierce Biotech. “It’s like a mixing bowl” of “highly motivated, really talented physician-scientists.”
The NIH Clinical Center, in particular, Green said, is a gem that not enough people appreciate. Free to patients, the center focuses solely on clinical research and, as such, has built a strong capacity to treat rare diseases, which is why it doesn’t surprise Green that the center treats 25 of the 500 patients worldwide who have LOTS—a full 5% of all patients.
“They pay for everything, including patient travel,” Green said. “Because for a rare disease, you may not be able to gather enough patients just here in the United States, you need to use the world population. It's not just a national treasure; it's an international treasure.”