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Tolerizing MS Vaccine Displays Efficacy in Model of Relapsing-Remitting Multiple Sclerosis

Results from a study provide a link between the association of multiple sclerosis and Epstein-Barr virus which could pave the way in the future for the development of new MS therapies.

Recently, Pasithea Therapeutics announced positive results from a preclinical proof of concept study of PAS002, its tolerizing vaccine being developed in a program for multiple sclerosis (MS).1 The study’s findings showed that the glial cell adhesion molecule (GlialCAM) found in the brain’s white matter is attacked in MS.2 

The findings suggest that there was a relapsing paralysis established in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). From 3 groups, a proprietary DNA cassette was engineered to encode GlialCAM and injected to potentially block acute disease and its relapse. The DNA molecules were designed to protect against paralytic disease by tolerizing the immune system, working like an ‘inverse vaccine.’2 

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

Viral triggers of MS have been the subject of investigation, for a long time but evidence for their functional relevance is scarce.3 Recently, findings 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 EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein GlialCAM and provide structural and in vivo functional evidence for its relevance.2 The CEO of Pasithea, Tiago Reis Marques, MD, PhD, said in a statement, "we believe these results demonstrate the promise and validity of our tolerizing approach, which is built on recent data on the biological mechanism linking infection with EBV with the development of MS.”2

Conducted at Hooke Laboratories, the study had a standard duration of 32 days, and the patient samples were collected 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 increased cerebrospinal fluid (CSF) white blood cell counts (≥10 cells µl–1), and blood-contaminated CSF samples were excluded by visual and microscopy inspection. Paired peripheral blood and CSF samples were obtained at the time of clinical onset (clinically isolated syndrome) or during an acute relapse.

The main findings from the study, included treatment with a DNA tolerizing ‘inverse vaccine’ delayed the onset of paralysis when compared to vehicle (P <.001); reduction in disease severity, when compared to vehicle (P =.002); reduction in relapse severity, when compared to vehicle (P <.001); treatment with DNA vaccine prevented disease in approximately 50% of the mice, when compared to vehicle (P =.004).1 The data showed that the engineered DNA plasmids provide a high level of efficacy in reducing disease severity and incidence of relapse when administered prophylactically in the EAE model, a widely used relapsing-remitting model of MS.

Study author Tobias V. Lanz MD, physician scientist, Stanford University School of Medicine, and colleagues wrote that the study, “demonstrated the presence of cross-reactive EBV EBNA1 and GlialCAM antibodies in 20% to 25% of patients with MS 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 aggravated EAE. The authors concluded that their “finding of activated high plasmablast (PBs) in the CSF that express exceptionally high levels of HLA-DR suggest that these B cells present antigens and exchange inflammatory signals with T follicular helper cells.”

REFERENCES
1. Pasithea Therapeutics Announces Results of Preclinical Study Demonstrating Tolerizing Vaccine Efficacy in Relapsing-Remitting Model of Multiple Sclerosis. News 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-Relapsing-Remitting-Model-of-Multiple-Sclerosis.html
2. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7
3. Tengvall K, Huang J, Hellström C, et al. Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc Natl Acad Sci U S A. 2019;116(34):16955-16960. doi:10.1073/pnas.1902623116
4. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222