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The RXR nuclear receptor agonist IRX4204 promotes myelin repair in vivo
Author(s): ,
M.E Sanders
Affiliations:
Io Therapeutics, Inc., Santa Ana, CA
,
R Avila
Affiliations:
Renovo Neural, Inc., Cleveland, OH, United States
,
B Trapp
Affiliations:
Renovo Neural, Inc., Cleveland, OH, United States
,
S Medicetty
Affiliations:
Renovo Neural, Inc., Cleveland, OH, United States
R Chandraratna
Affiliations:
Io Therapeutics, Inc., Santa Ana, CA
ECTRIMS Online Library. Sanders M. Sep 16, 2016; 147039; 193
Martin E. Sanders
Martin E. Sanders
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Abstract: 193

Type: Oral

Abstract Category: Therapy - disease modifying - Neurorepair

Objective: To determine if the RXR nuclear receptor agonist IRX4204 is effective in promoting myelin repair in vivo, in a cuprizone/rampamycin-induced model of chronic demyelination/remyelination in mice.

Background: IRX4204 is a potent and highly selective RXR agonist compound being developed for the treatment of MS. IRX4204 is effective in multiple models of EAE, and in in vivo models of neuroprotection. We have reported previously that IRX4204 promotes differentiation of oligodendrocyte precursor cells into myelin-producing oligodendrocytes in vitro, and that this activity is potentiated by thyroid hormone. Since RXR agonists are known to induce hypothyroidism in vivo, we studied the effects of treatment with IRX4204, combined with thyroid hormone supplementation, on in vivo myelin repair.

Methods: Mice were administered cuprizone to induce demyelination; and concurrently administered rapamycin to prevent remyelination, for twelve weeks. At twelve weeks, cuprizone and rapamycin administration were stopped, and the mice were treated with IRX4204 or vehicle control, with or without thyroid hormone supplementation, for six weeks, to observe potential effects on remyelination. Remyelination was assessed by quantitation of the density of PPD stained myelinated axons in white matter of the corpus callosum; and by PLP immunostaining in hippocampal and cortical grey matter.

Results: There was a statistically significant (p< 0.01), approximately 30% increase in the density of myelinated axons in the corpus callosum white matter of IRX4204 treated mice compared to vehicle controls. This effect was not augmented by thyroid hormone supplementation; however, the dose of thyroid hormone supplementation used in this experiment did not fully normalize circulating thyroid hormone levels in the IRX4204 treated mice to the levels observed in the vehicle group. There was no difference in the extent of PLP density in the gray matter of the hippocampus or cortex with IRX4204 or thyroid hormone treatments compared to vehicle controls.

Conclusion: These data add promotion of white matter myelin repair in vivo, to the previously reported immunomodulatory and neuroprotective mechanisms of action of IRX4204, as a potential treatment for MS.



Supported by the National Multiple Sclerosis Society Fast Forward Program.

Disclosure: Martin E. Sanders is Chief Executive Officer, a director, and shareholder of Io Therapeutics Inc., which sponsored the studies.

Robin Avila is an employee of Renovo Neural, Inc., which conducted the studies under contract with Io Therapeutics, Inc.

Bruce Trapp is a consultant, director, and shareholder of Renovo Neural, Inc.

Satish Medicetty is Chief Executive Officer, a director and a shareholder of Renovo Neural, Inc.

Rosh Chandraratna is President, Chief Scientific Officer, a director, and shareholder of Io Therapeutics, Inc.



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