NDC-1308 potently enhances remyelination in experimental models of multiple sclerosis(04/10/13)

Scientists from ENDECE Neural presented preclinical data today showing that the company’s lead compound, NDC-1308, addresses one of the root causes of multiple sclerosis (MS) by significantly inducing remyelination in nerves that have been damaged by MS. In an oral presentation at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Copenhagen, Denmark, the ENDECE Neural researchers also reported a dramatic upregulation of genes in signaling pathways involved in myelin sheath production.

NDC-1308 works by inducing differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes, cells that synthesize and maintain the myelin sheath that covers nerves in the brain and spinal cord, the researchers noted. By contrast, the female hormones estradiol and estriol do not exert that effect.

“Repair of the myelin sheath, called remyelination, has long been an elusive goal in the treatment of multiple sclerosis,” explained Steven Nye, Ph.D., Vice President of Discovery at ENDECE Neural. “The synthesis of NDC-1308, an estradiol analog, was inspired by observations that pregnant women typically do not experience the symptoms of MS during the third trimester. In our experiments, NDC-1308 induces remyelination in animal models of demyelination, compared to estradiol and estriol which appear to be neuroprotective but do not induce OPC differentiation.”

In his presentation, Dr. Nye described how he and his colleagues synthesized more than 40 proprietary estradiol analogs in which the core structure of estradiol had been modified, and assessed how subsets of those modifications changed the hormone’s biological activity. The researchers identified NDC-1308 as the most potent of several proprietary analogs having the ability to directly induce differentiation of OPCs into mature oligodendrocytes. NDC-1308 derives its novel biological activity from the addition of a specific alkoxyalklyl moiety to the C-6 position on the estradiol B-ring.

Dr. Nye reported the following findings:

- A 20% increase in remyelination (compared to vehicle control) of hippocampal regions of the brain (P<0.01) was associated with a 2-week course of NDC-1308 (50 mg/Kg once daily) in a mouse model of demyelination, in which the neurotoxicant cuprizone was used to remove the myelin sheath from the axons (nerve fibers) of mice.

- NDC-1308 caused a dramatic upregulation of key genes (5- to 75-fold) in signaling pathways involved in OPC differentiation and myelin sheath production.

- NDC-1308 significantly induced OPCs to differentiate into mature oligodendrocytes (P<0.05).

- NDC-1308 (3 µM/day for 4 days) enhanced remyelination in demyelinated rat brain slices visualized by staining for myelin basic protein, which was consistent with the mouse cuprizone data.

Prophylactic administration of NDC-1308 (10 mg/kg/day for 10 days) delayed the onset of MS symptoms and reduced the severity of MS in a mouse model of experimental allergic encephalitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG), suggesting that the compound may play a dual remyelination/anti-inflammatory role in treating MS. “Despite its structural similarity to estradiol and estriol, NDC-1308 differs from those two female hormones by virtue of its potent induction of remyelination, as demonstrated in animal models of MS,” commented James G. Yarger, Ph.D., chief executive officer and co-founder of ENDECE Neural. “Unlike estradiol and estriol, NDC-1308 induces OPC differentiation and maturation of oligodendrocytes. We envision administration of NDC-1308 either alone or in combination with current therapeutics that target the immune response and/or inflammation associated with MS. NDC-1308 may thus fill an unmet medical need for a remyelinating therapy in MS, one that may help improve the lives of patients living with this devastating neurological disease.”

About NDC-1308

NDC-1308 is a novel chemical entity designed to address one of the root causes of MS, and is being developed for potential use either alone or in combination with other MS therapeutics that slow the progression of the disease. By controlling key genes in pathways leading to myelin synthesis, NDC-1308 appears to induce restoration of the lost myelin sheath that is believed to cause the devastating symptoms of MS. NDC-1308 is a small molecule that readily crosses the blood-brain barrier, allowing it to reach the tissues in the brain and spinal cord where promoting myelin production is needed. ENDECE Neural discovered NDC-1308, and owns the intellectual property surrounding the compound.

Source: Rock Hill Herald Online © Rock Hill Herald Online (04/10/13)