The challenges of the lysosomal storage disorder
Tay-Sachs disease is a progressive neurological lysosomal storage disorder resulting from deficiencies in the ability of HexA to catabolize GM2 ganglioside. The excessive neuronal accumulation of GM2 ganglioside is accompanied by progressive neurological deterioration affecting motor, cerebral and spinocerebellar functions. These diseases are rare genetic conditions (<1000 people in the US and Canada) for which there is no effective treatment.
Tay-Sachs is categorized by onset and severity into three clinical-subtypes: Classic Infantile, Juvenile and Late-Onset (also called Adult-Onset). Onset and disease progression is a reflection of lysosomal HexA concentrations and activity.
Classic Infantile Tay-Sachs is caused by a null mutation in HexA, the gene that encodes one of the two evolutionarily related HexA subunits. The complete absence of HexA in Classic Infantile Tay-Sachs is associated with the most severe form of the disease. Disease progression is characterized by a rapid and relentless deterioration of mental and physical abilities until death typically by age 3 or 4.
Late-Onset Tay-Sachs (LOTS) is caused by a reduction as opposed to complete loss in HexA activity. Pharmacological chaperones may represent a relevant form of therapy provided that some amount of HexA is minimally present as it is with Juvenile Tay-Sachs and LOTS.
Initial symptoms of Juvenile and LOTS may include clumsiness, mood alterations, and muscle weakness. As affected individuals age, they may exhibit tremors, muscle twitching, slurred speech, and an inability to coordinate voluntary movements. Approximately 40% of LOTS patients experience significant depression or bipolar disorder. It is believed that progress with a safe and effective treatment for LOTS will facilitate the development of a therapeutic for Juvenile Tay-Sachs.
ExSAR is developing a treatment for Late-Onset Tay-Sachs (LOTS) — EXR-101
EXR-101 is a small molecule pharmacological chaperone that binds to and stabilizes HexosaminidaseA (HexA). EXR-101 is a drug that has already been approved by the FDA for the treatment of another indication, can be administered orally and has shown remarkable efficacy in cell lines derived from LOTS patient fibroblasts. Accordingly, the nonclinical characteristics (such as pharmacological, toxicological and pharmacokinetic/metabolism characteristics) of EXR-101 have been thoroughly examined. In the preclinical assessment of the efficacy of EXR-101 in the treatment of Tay-Sachs and Sandhoff diseases, a number of cell culture studies using cell lines originating from various patients with Adult Tay-Sachs or Sandhoff disease have been performed.* These studies showed that EXR-101 is a competitive inhibitor of HexA enzyme, a prerequisite to being a PC. Although a competitive inhibitor, EXR-101 actually increases the enzymatic activity of HexA mutant from Adult Tay-Sachs or Sandhoff disease. The effects of EXR-101 on HexA enzyme is selective, as reflected by EXR-101 increasing the activities of HexA enzyme, but not other lysosomal enzymes, in cell lines originally extracted from patients with Adult Tay-Sachs or Sandhoff diseases. EXR-101 is an effective PC for a variety of HexA enzyme mutations (including the most frequent missense mutation associated with Adult Tay-Sachs disease), although is not effective with all mutations in HexA enzyme.
The FDA granted EXR-101 IND authorization in April 2007, and in addition, ExSAR has applied for orphan drug designation with the FDA. Click here for additional information on ExSAR’s development plan and for a snapshot of our therapeutic product pipeline.
* Maegawa GHB, Tropak M, Buttner J, Stockley T, Kok F, Clarke JTR, et al. Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem. 2007;282(12):9150-9161.