Tolerable MS vaccine displays efficacy in a relapsing-remitting MS model

Recently, Pasithea Therapeutics announced positive results from a preclinical proof-of-concept study of PAS002, and its tolerability vaccine is being developed in a multiple sclerosis (MS) program.1 Study results show that glial cell adhesion molecule (GlialCAM) found in the white matter of the brain is under attack in MS.2

The results indicate the presence of relapsing paralysis established in a mouse model of experimental autoimmune encephalomyelitis (EAE). From 3 sets, a special DNA cassette was designed to encode and inject GlialCAM to prevent acute disease and its relapse. The DNA molecules are designed to protect against paralysis by tolerating the immune system, acting like a “reverse vaccine.”2

“This technology has the potential to tolerate GlialCAM, a myelin molecule that has a molecular similarity to Epstein-Barr virus,” Pasithea President, Lawrence Steinman, MD, PhD, Zimmerman Professor of Neurology, Neurosciences and Pediatrics, Stanford University, said in a statement based on the study results. that causes multiple sclerosis.”2

Viral triggers of MS have been a subject of investigation for a long time, but evidence of their functional significance is scarce.3 Recently, results of another study published in early 2022 by Ascherio et al indicated that one of these viruses, Epstein-Barr virus (EBV) has a causal relationship with MS.4

The Pasithea study aimed to demonstrate high-affinity molecular mimicry of the EBV nuclear antigen 1 (EBNA1) transcription factor and CNS protein GlialCAM and to provide structural and endogenous functional clues to their importance.2 Pasithea CEO Tiago Reis Marques, MD, said in a statement: “We believe these findings demonstrate the promise and validity of our tolerability approach, which is based on recent data on the biological mechanism linking EBV infection with the development of disease. MS.”2

The study was conducted at Hook Laboratories, the standard study duration was 32 days, and patient samples were collected from Stanford University and Heidelberg University. The patients were screened for antibodies against aquaporin-4 and oligodendrocyte myelin glycoprotein and showed negative results.1 All included patients had an increased CSF white blood cell count (10 μl-1 cells), and CSF samples contaminated with blood were excluded by visual and microscopic examination. Paired peripheral blood and cerebrospinal fluid samples were obtained at the time of clinical onset (a clinically isolated syndrome) or during acute relapse.

Main findings from the study, included treatment with a DNA tolerant reverse transcriptase vaccine that delayed the onset of paralysis when compared to vehicle (P < .001); decrease in disease severity, as compared to vehicle (P = .002); decrease in relapse severity, when compared to vehicle (P < .001); Treatment with the DNA vaccine prevented the disease in about 50% of the mice, compared to the vehicle (P = .004).1 The data demonstrated that engineered DNA plasmids provide a high level of efficacy in reducing disease severity and incidence of relapse when administered prophylactically in the EAE, the relapse and remittance model of MS.

Study author Tobias V. Lanz MD, Physician, Stanford University School of Medicine, and colleagues write that the study “showed the presence of EBV-reactive antibodies EBNA1 and GlialCAM in 20% to 25% of MS patients and showed that immunization of EAE mice with the EBNA1 epitope exacerbated Demyelination of autoimmunity”.2 They showed that immunization of EAE mice generated a robust B-cell response against GlialCAM and exacerbated EAE. The authors conclude that “their detection of highly activated plasmablasts (PBs) in cerebrospinal fluid expressing exceptionally high levels of HLA-DR indicates that these B cells present antigens and exchange inflammatory signals with follicular helper T cells.”

the reviewer
1. Pasithea Therapeutics announces results of a preclinical study demonstrating the tolerability of a vaccine in a relapsing-remitting model of multiple sclerosis. New release. Pasithea Therapeutics. August 11, 2022. Accessed September 9, 2022. https://www.globenewswire.com/news-release/2022/08/11/2496725/0/en/Pasithea-Therapeutics-Announce-Results-of-Preclinical- Study-prove-tolerance-vaccine-efficacy-in-relapse-transfer-model-multiple sclerosis.html
2. Lanz TV, Brewer RC, Ho PP, et al. The relatively dilated B cells in EBV bind EBNA1 and GlialCAM. temper 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 nuclear antigen 1 is associated with multiple sclerosis risk. Proc Natel 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 the Epstein-Barr virus associated with multiple sclerosis. Sciences. 2022; 375 (6578): 296-301. doi: 10.1126/science.abj8222