Deconstructing the Pharmacological Contribution of Sphingosine-1 Phosphate Receptors to Mouse Models of Multiple Sclerosis Using the Species Selectivity of Ozanimod, a Dual Modulator of Human Sphingosine 1-Phosphate Receptor Subtypes 1 and 5.

Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P1) and 5 (S1P5), is approved for the treatment of relapsing multiple sclerosis (MS) in multiple countries. Ozanimod profiling revealed a species difference in its potency for S1P5 in mouse, rat, and canine compared with that for human and monkey. Site-directed mutagenesis identified amino acid alanine at position 120 to be responsible for loss of activity for mouse, rat, and canine S1P5, and mutation back to threonine as in human/monkey S1P5 restored activity. Radioligand binding analysis performed with mouse S1P5 confirmed the potency loss is a consequence of a loss of affinity of ozanimod for mouse S1P5 and was restored with mutation of alanine 120 to threonine. Study of ozanimod in preclinical mouse models of MS can now determine the S1P receptor(s) responsible for observed efficacies with receptor engagement as measured using pharmacokinetic exposures of free drug. Hence, in the experimental autoimmune encephalomyelitis model, ozanimod exposures sufficient to engage S1P1, but not S1P5, resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light. In the demyelinating cuprizone model, ozanimod prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination after intoxication. Since free drug levels in this model only engaged S1P1, we concluded that S1P1 activation is neuroprotective but does not appear to affect remyelination. SIGNIFICANCE STATEMENT: Ozanimod, a selective modulator of human sphingisone 1-phosphate receptor subtypes 1 and 5 (S1P1/5), displays reduced potency for rodent and dog S1P5 compared with human, which results from mutation of threonine to alanine at position 120. Ozanimod can thus be used as a selective S1P1 agonist in mouse models of multiple sclerosis to define efficacies driven by S1P1 but not S1P5. Based on readouts for experimental autoimmune encephalomyelitis and cuprizone intoxication, S1P1 modulation is neuroprotective, but S1P5 activity may be required for remyelination.

Dementia Awareness Campaign in the Latino Community: A Novel Community Engagement Pilot Training Program with Promotoras.

OBJECTIVES: To create a curriculum about Alzheimer's disease and dementia, and to train Promotoras affiliated with a local community education and health advocacy organization, in order to raise awareness and knowledge of what dementia is, and how it can be recognized, in persons of Hispanic/Latino descent. METHODS: Community based participatory research (CPBR) model was used to create materials, implement training, and engage/empower Promotoras to educate the local community. RESULTS: Pre-post findings indicated a positive learning experience for the Promotoras and willingness to share new dementia information with their community. One year post-evaluative survey with a subset showed outreach to an average of 15-25 community members, indicating positive reception of this new information. CONCLUSIONS: CPBR model is a successful education and outreach tool with Latino communities. Our Dementia Awareness Campaign was a success with the first 20 Promotoras trained; at present we plan to train additional groups in nearby communities with significant Hispanic/Latino populations. CLINICAL IMPLICATIONS: In order to get Latinos to seek early detection, we need to first educate them about dementia, win trust, and encourage treatment-seeking. Early intervention, diagnosis, and prevention will benefit from educational campaigns using the CBPR model.