Tolerant MS vaccine shows efficacy in relapsing-remitting multiple sclerosis model

Recently, Pasithea Therapeutics announced positive results from a proof-of-concept preclinical study of PAS002, its tolerant vaccine under development in a multiple sclerosis (MS) program.1 The results of the study showed that the glial cell adhesion molecule (GlialCAM) present in the white matter of the brain is attacked in MS.2

The results suggest that there was an established recurrent paralysis in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). From 3 groups, a proprietary DNA cassette was designed to encode GlialCAM and injected to potentially block acute disease and its relapse. DNA molecules were designed to protect against paralytic disease by tolerating the immune system, functioning as a “reverse vaccine”.2

Pasithea President Lawrence Steinman, MD, PhD, Zimmerman Professor of Neurology & Neurological Sciences, and Pediatrics, Stanford University, said in a statement that, based on the study results, “this technology has the potential to tolerate GlialCAM, a myelin molecule that has molecular similarity to the Epstein Barr virus that triggers MS.2

Viral triggers in MS have long been investigated, but evidence of their functional relevance is scarce.3 Recently, the results of another study published in early 2022 by Ascherio et al suggested that one such virus, Epstein-Barr virus (EBV) has a causal relationship with MS.4

Pasithea’s study aimed to demonstrate high-affinity molecular mimicry between the transcription factor EBV, EBV nuclear antigen 1 (EBNA1) and the central nervous system protein GlialCAM and to provide in vivo structural and functional evidence of its relevance.2 Pasithea CEO Tiago Reis Marques, MD, PhD said in a statement, “We believe these results demonstrate the promise and validity of our tolerance approach, which builds on recent data on the biological mechanism linking EBV infection to the development of MS.”2

Conducted at Hooke Laboratories, the study had a standard duration of 32 days and patient samples were taken from Stanford University and the University of Heidelberg. Patients were tested for antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein and showed negative results.1 All included patients had an increased white blood cell count in the cerebrospinal fluid (CSF) (≥ 10 µl–1 cells), and blood-contaminated CSF samples were excluded by visual and microscopic inspection. Paired peripheral blood and CSF specimens were obtained at clinical onset (clinically isolated syndrome) or at acute relapse.

Primary study outcomes included treatment with a DNA-tolerant “reverse vaccine” that delayed the onset of paralysis compared to vehicle (P 1 The data showed that the modified DNA plasmids provide a high level of efficacy in reducing disease severity and incidence of relapses when administered prophylactically in the EAE model, a recurrent model -remitting MS widely used.

Study author Tobias V. Lanz MD, Physician-Scientist, Stanford University School of Medicine, and colleagues wrote that the study “demonstrated the presence of EBV EBNA1 and GlialCAM antibodies to cross-reacted in 20% to 25% of MS patients and showed that immunization of EAE mice with this EBNA1 epitope exacerbated autoimmune demyelination.2 They showed that immunization of EAE mice generated a robust B-cell response against GlialCAM and worsened EAE. The authors concluded that their “finding of activated plasmablasts (PB) in CSF that express unusually high levels of HLA-DR suggest that these B cells present antigens and exchange inflammatory signals with follicular helper T cells.”

REFERENCES
1. Pasithea Therapeutics announces the results of a preclinical study demonstrating the efficacy of a tolerant vaccine in the relapsing-remitting model of multiple sclerosis. Press release. Pasithea Therapeutics. August 11, 2022. Accessed September 9, 2022. https://www.globenewswire.com/news-release/2022/08/11/2496725/0/en/Pasithea-Therapeutics-Announces-Results-of-Preclinical-Study – Demonstrating-Tolerizing-Vaccine-Efficacy-in-Relapse-Remitting-Model-of-Multiple-Sclerosis.html
2. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanding B cells in multiple sclerosis bind to EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7
3. Tengvall K, Huang J, Hellstrom C, et al. Molecular mimicry between anoctamine 2 and Epstein-Barr virus nuclear antigen 1 is associated with the risk of multiple sclerosis. Proc Natl Acad Sci US A. 2019;116(34):16955-16960. doi:10.1073/pnas.1902623116
4. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals a high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222

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