Mount Sinai preclinical program flags a potential drug strategy for MS

Mount Sinai's Icahn School of Medicine

Testing a theory that the molecule that transports proteins from the nucleus of a cell to the cytoplasm is altered in neurodegenerative diseases like multiple sclerosis, a group of investigators at the Icahn School of Medicine at Mount Sinai say that they have successfully completed an animal study that tested drugs that could block the molecule and perhaps repair nerve cell damage that occurs in MS.

That molecule is called XPO1, or CRM1. Using money from the NIH and the National Multiple Sclerosis initiative Fast-Forward, the researchers tested two chemicals--KPT-276 and KPT-350, from Karyopharm Therapeutics ($KPTI)--and found that it prevented the target protein from carrying "cargo" out of the nucleus of nerve cells in a mouse model. The shutdown helped prevent the structural damage of the key cells, which are damaged by MS when an autoinflammatory process attacks the myelin sheaths that protect nerve cells.

The compounds also stopped inflammatory cells from multiplying, according to a statement on the work, thereby reducing inflammation. Mice with hindlimb paralysis demonstrated signs of recovery in the study, though as with all mouse studies it should be noted that rodents can have amazing recoveries that never apply to humans. The results were published online in Nature Neuroscience on Feb. 23.

Newton, MA-based Karyopharm says that it appears likely that a number of factors spur neurodegenerative diseases like MS. And this preclinical study demonstrates the potential of one of its selective inhibitors of nuclear export, or SINE, drugs for MS. The biotech's lead drug is oral selinexor, which is being developed for hematological malignancies.

"The compounds identified in this study, when administered orally, both reduced the inflammation that is a hallmark of multiple sclerosis and protected against the nerve cell damage seen in mouse models of the disease," said Jeffery Haines, a postdoctoral fellow at Mount Sinai and the study's lead author. "The multiple sclerosis drugs currently on the market and being tested elsewhere seek to reduce the immune attack on cells, but none target neurodegeneration nor do they work to restore nerve cell function. The findings of this new study represent an exciting step in the process of advancing new oral treatment options."

"We had previously identified XPO1-mediated nuclear export as one of the first events preceding the occurrence of axonal damage in cultured neurons," Mount Sinai's Dr. Patrizia Casaccia says in a statement for the biotech. "In this study, we report the upregulation of XPO1 in MS lesions. SINE compounds are capable of reducing axonal damage in cultured neurons and to reduce the clinical progression in mouse models of MS."

- here's the release from Karyopharm
- here's the release from Mount Sinai
- read the research abstract

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