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Estradiol Analog May Boost Remyelination in MS


















Image Source: SCIENCEMAG

An analog of estradiol appears to be able to promote remyelination in a mouse model of multiple sclerosis, according to early work presented here.

Using the cuprizone model of MS in mice, animals treated with NDC-1308 had 18% more remyelination in cortical regions (P<0.01) and 44% more remyelination in hippocampal regions (P<0.0001) than control mice, according to Steven Nye, PhD, and James Yarger, PhD, of the biopharmaceutical company Endece.

They also found improved functionality in drug-treated animals as measured by a significant improvement in grip strength over controls, they reported during a poster session at the Society for Neuroscience meeting here.

"This compound induces progenitor cells, and they differentiate into mature myelinating cells that can repair damage to the myelin sheath," Nye told MedPage Today. "Our drug appears to turn on the pathway that helps them differentiate."

The hunt has been on for compounds that can repair the demyelination, a hallmark feature of MS. One of the leading candidates is Biogen's anti-LINGO-1 monoclonal antibody, which has demonstrated evidence of remyelination in acute optic neuritis.

All of the therapies that are currently approved to treat MS impact immune mechanisms of the disease only, not remyelination – so researchers are hard at work on developing remyelinating therapeutics.

Nye explained that several years ago their team discovered several pathways that were important for progenitor cells converting into myelinating cells, and developed NDC-1308, an analog of estradiol – but one with distinct biological activity -- that may activate intracellular pathways for oligodendrocyte progenitor cell (OPC) differentiation.

Earlier work had shown that the compound could induce mouse OPCs to differentiate into mature myelinating oligodendrocytes in vitro and boosted remyelination of axons in vivo.

Their next step, in the present study, was to test the compound in the cuprizone model of MS, in which white and gray matter regions of the mouse brain are demyelinated. Animals were treated with 68 mg/kg of the investigational drug or with placebo for 6 weeks.

Over that time, they saw that the drug rapidly crosses the blood-brain barrier and is absorbed into central nervous system (CNS) tissues at levels exceeding that required for OPC differentiation in vitro.

It is also eliminated from the CNS after 24 hours, which could be an indication of safety, they said.

Nye and Yarger also found that the drug increased remyelination by 18% in cortical regions of the brain (P<0.01) and by 44% in hippocampal regions (P<0.0001).

And after only 3 weeks, they saw functional improvement as measured by a 36% increase in grip strength compared with control animals.

In terms of other measures of safety, they found that animal behaviors and clinical chemistries were normal, and the OPC population remained in tact.
It was also well tolerated, and they didn't see any potential side effects of an estradiol compound, such as breast growth in men or breast cancer in women.
"Estrogenic effects can be problematic, but we don't see any of those," Nye told MedPage Today.

Researchers who were not involved in the study told MedPage Today that the results could be promising – they applauded the demonstration of safety and of crossing the blood-brain barrier.

"They even checked in a large animal, a dog, that NDC-1308 crosses the blood-brain barrier," Anne Boullerne, PhD, of the University of Illinois at Chicago, told MedPage Today. "Vascularization and blood flow is quite different between humans and small animals like mice. Dogs are closer to humans."

But they did express some caution about the use of the cuprizone model instead of the Experimental Autoimmune Encephalomyelitis (EAE) model of MS.

"The cuprizone model ... does not recapitulate the complicated situation in MS where demyelination is accompanied by inflammation," Samia Khoury, MD, of American University of Beirut, told MedPage Today.

Boullerne said the cuprizone model data are "convincing for remyelination and functionality. But cuprizone is not an adequate model for MS since there is no astroglial scar or overt inflammation to overcome."

"They should test their molecule in a demyelinating EAE model," she added.
Nye and Yarger said Endece is currently moving NDC-1308 into phase I trials.

Story Source: The above story is based on materials provided by MEDPAGETODAY
Note: Materials may be edited for content and length


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