Despite being characterized over 100 years ago, to date there remains no treatment or cure for Tay-Sachs disease. Several therapeutic approaches are being researched and open label use (approved by FDA for other diseases but not Tay-Sachs) clinical trials are ongoing. Most common approaches include: enzyme replacement therapy (ERT) which delivers a healthy form of the defective enzyme, substrate reduction therapy (SRT) which reduces synthesis of the molecule that cannot be broken down, and chaperone therapy which uses a small pharmacological molecule that can interact with the mutant protein to restore its original conformation and function. ERT has become the standard of care for some LSDs, such as Type I Gaucher disease (5), in which there is no CNS disease. However, the inability of large proteins to cross the blood brain barrier (BBB) and enter the brain renders this therapy ineffective for neurologic LSDs such as Tay-Sachs disease.
A 2009 Research Initiative grant from NTSAD was administered to Dr. Joe Clarke to support an open-label Phase I/II clinical trial of pyrimethamine, a pharmacological chaperone, for the treatment of patients affected with Tay-Sachs or Sandhoff disease. This clinical trial evaluated the tolerability of pyrimethamine by patients and the effectiveness of the molecule in raising Hex A levels in blood in a small number of patients. The study found that Hex A level was increased up to 4-fold in people taking 50 mg or less of the medication each day. When the dose was increased to 75 mg per day or higher, most participants had significant side effects, including worsening problems with coordination. The full publication can be viewed here.
A clinical trial to evaluate the safety and efficacy of SRT using a drug called migulstat (brand name Zavesca) has also been conducted for Late Onset Tay-Sachs. Miglustat did not result in any measurable clinical benefit in the 20 late onset patients given 200 mg orally three times a day when compared to patients that did not take miglustat. Prominent side effects of the drug were weight loss and diarrhea (6), as this drug also effects the ability to digest complex carbohydrates. It remains unclear whether earlier treatment in more mildly affected patients would result in benefit. There are reports of benefits to individual patients with Tay-Sachs disease treated with miglustat (7, 8), and further studies are warranted if coupled with detailed natural history studies to allow better interpretation of the outcomes of the trial. The NTSAD Scientific Advisory Committee (SAC) subcommittee on experimental therapies recently reviewed the data regarding miglustat’s safety and potential efficacy.
The Tay-Sachs Gene Therapy Consortium, formed from a collaboration with NTSAD and researchers from the U.S. and the U.K., is focused on developing gene therapy approaches to all forms of Tay-Sachs disease. These studies are still in the pre-clinical phase and safety studies must be completed before clinical trials can be initiated.
NTSAD is committed to further characterizing Tay-Sachs disease through natural history studies and development of therapies for this and other LSDs.
References:
1. M. Fuller, P. J. Meikle, J. J. Hopwood, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, G. Sunder-Plassmann, Eds. (Oxford, 2006).
2. P. J. Meikle, J. J. Hopwood, A. E. Clague, W. F. Carey, Prevalence of lysosomal storage disorders. JAMA 281, 249-254 (1999); published online EpubJan 20 (joc80368 [pii]).
3. S. Sanderson, A. Green, M. A. Preece, H. Burton, The incidence of inherited metabolic disorders in the West Midlands, UK. Archives of disease in childhood 91, 896-899 (2006); published online EpubNov (10.1136/adc.2005.091637).
4. A. E. Bley, O. A. Giannikopoulos, D. Hayden, K. Kubilus, C. J. Tifft, F. S. Eichler, Natural history of infantile G(M2) gangliosidosis. Pediatrics 128, e1233-1241 (2011); published online EpubNov (10.1542/peds.2011-0078).
5. A. Zimran, D. Elstein, Management of Gaucher disease: enzyme replacement therapy. Pediatric endocrinology reviews : PER 12 Suppl 1, 82-87 (2014); published online EpubSep (
6. B. E. Shapiro, E. L. Logigian, E. H. Kolodny, G. M. Pastores, Late-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients. Muscle Nerve 38, 1012-1015 (2008); published online EpubAug (10.1002/mus.21061).
7. B. Bembi, F. Marchetti, V. I. Guerci, G. Ciana, R. Addobbati, D. Grasso, R. Barone, R. Cariati, L. Fernandez-Guillen, T. Butters, M. G. Pittis, Substrate reduction therapy in the infantile form of Tay-Sachs disease. Neurology 66, 278-280 (2006); published online EpubJan 24 (10.1212/01.wnl.0000194225.78917.de).
8. M. Masciullo, M. Santoro, A. Modoni, E. Ricci, J. Guitton, P. Tonali, G. Silvestri, Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up. J Inherit Metab Dis 33 Suppl 3, S355-361 (2010); published online EpubDec (10.1007/s10545-010-9186-3).