Remyelination to Neuroprotection at the AAN

Neuroprotective and oligodendrocyte precursor cell differentiation promoting activities of the RXR nuclear receptor agonist IRX4204 are potentiated by thyroid hormone 

Authors: Martin Sanders, MD; Robin Avila, PhD; Bruce Trapp, PhD; Satish Medicetty, PhD; Rosh Chandraratna, PhD 

Objective: (1) determine if the RXR nuclear receptor agonist IRX4204 is effective in an in vivo neuroprotection (NP) model; (2) evaluate the effects of combination treatment with thyroid hormone and IRX4204 in this model; (3) determine if adding thyroid hormone increases the previously reported stimulatory effect of IRX4204 on in vitro differentiation of oligodendrocyte precursor cells (OPC) into oligodendrocytes (OL). 

Background: IRX4204 is a potent, highly selective RXR agonist compound being developed for treatment of multiple sclerosis (MS) and other neurologic diseases. Central hypothyroidism is a documented side effect of treatment with RXR agonists, including IRX4204. Since thyroid hormone is critical for CNS functions, we studied the effects of combination treatment with IRX4204 and thyroid hormone in an in vivo model of NP, and on OPC differentiation in vitro. 

Design/Methods: Mice were administered cuprizone to induce demyelination; and rapamycin to prevent remyelination. NP was assessed by quantitation of SMI-32 immunostained axonal ovoids (transected axons) in the corpus callosum. Quantitation of OPC differentiation was performed by high-content screening of OPCs, which express PLP-EGFP when differentiated into OL; and by MBP immunostaining. 

Results: Combination treatment with thyroid hormone and IRX4204 in the NP model resulted in reduction in axonal transection compared to vehicle, and approximately three-fold greater, statistically significant reduction compared to IRX4204 alone (-38.3% vs -13.6%). Addition of thyroid hormone with IRX4204 to OPC cultures resulted in statistically significant additive increase in myelin producing OL versus IRX4204 alone. 

Conclusions: IRX4204 demonstrated neuroprotective effects in vivo; and OPC differentiation promoting effects in vitro; both of which were potentiated by thyroid hormone. RXR agonists should be co-administered with thyroid hormone, not only to maintain euthyroid status, but also to obtain improved efficacy in MS and other neurologic diseases patients treated with these agents. 

Study Supported By: Supported by The National Multiple Sclerosis Society Fast Forward Program

Researchers at Cambridge and Edinburgh discovered that RXR agonists could promote remyelination. Whilst they struggled to get a trial in MS off the ground using a generic compound, and pharma companies with such drugs weren't interested in MS, Cambridge has apparently been funded by NHS England, and they will use Bexarotene an anti-cancer drug. RXR is a ubititous molecule expressed all over the place and so you must expect side-effects and this does induce rashes and itchiness, low white cell count and notably thyroid problems due to down regulation of thyroid hormones. Even if it is positive will bexarotene go anywhere?. It will be hard without company support. So in contrast to the UK, try a generic and fail to get it approved approach, our US colleagues aim to devlop a new drug. IRX4204 is also an XRX antagonist that has been used in human cancer treatment. It is highly brain penetrant, and promoted differentiation of OPCs into oligodendrocytes. They realise there is a problem with the thyroid hormone depression so in this animal study they add IRX4204 and supplement with thyroid hormone and find improved efficacy in saving nerves. This is yet more evidence that having demyelinated nerves leaves them vulnerable to death. Promote remyelination and it should be neuroprotective which is what is found here.

However it is not only demyelination that occurs ans as we have been anticipating the is immunosuppressive. You can see the poster presentated at the AAN (click)

This means it does every thing which could mean that trials could be uninterpretable if they are not done carefully.