Neuromyelitis optica (NMO), a rare autoimmune disorder often mistaken for multiple sclerosis, is similar in that it is characterized by myelin destruction in the optic nerves and spinal cord. In contrast to multiple sclerosis, as reported by the Transverse Myelitis Association, NMO does not initially affect the brain, NMO patients experience more robust attacks, and aquaporin-4 reactive T-cells (ARTCs) appear to be the culprit of NMO pathology (rather than myelin-reactive T-cells). Without either FDA-approved therapies specifically indicated to treat NMO or fully efficient off-label treatments, Opexa Therapeutics is looking to help patients through immunotherapy and recently presented data at the American Academy of Neurology (AAN) meeting in Washington, DC.
Dr. Lauren W. Collison, Director of Immunology at Opexa, presented the study, “Immune Profiling of NMO Patients Receiving B-cell Depleting Therapy,” at AAN. The goal of the study was to describe the phenotype of immune cells circulating in 10 NMO patients who were treated with B-cell depleting therapy and compare their leukocyte profiles to those of 30 healthy individuals in an attempt to understand the therapy’s mechanism of action.
The NMO patients showed an increase in activated CD4+ and CD8+ T-cells and a decrease in certain populations of T-regulatory cells. Also, half of the NMO patients continued to show the existence of a certain type of B-cell, despite their treatment with B-cell depleting therapy. Importantly, these results demonstrated the presence of harmful activated T-cells, which Opexa believes are responsible for continued neuroinflammation and disease progression. It appears that B-cells are not the only culprit in NMO.
Previous reports also identify that off-label Rituximab treatment may not help all NMO patients. “A 5-Year Follow-up of Rituximab Treatment in Patients With Neuromyelitis Optica Spectrum Disorder,” which was published in JAMA Neurology, found that 87% of patients had a markedly reduced annualized relapse rate, and 60% were relapse free. The reason for the discrepancy in efficacy may be the pathology of the disease.
“Reports have suggested the basis of NMO progression is B-cells,” said Neil Warma, President and CEO of Opexa, in an exclusive interview with Multiple Sclerosis News Today. “We believe T-cells lead or control the entire destructive process.” According to information compiled by Opexa, pathogenic ARTCs induce B-cell production of anti-aquaporin-4 antibodies. These antibodies bind to aquaporin-4 channels on astrocytes, leading to neuroinflammation, oligodendrocyte injury, demyelination, and loss of neurons in the optic nerves.
“[In the study presented at AAN], patients receiving B-cell depleting therapy continued to show inflammation,” commented Warma. “T-cells are likely the root cause for this persistent and harmful inflammation.” Accordingly, Opexa is developing a personalized treatment for NMO patients that focuses on T-cells. OPX-212, Opexa’s development candidate for NMO, uses ImmPath technology developed by Opexa. The proposed therapy, which is still in preclinical development, would begin with a patient’s blood sample. ARTCs would be isolated and expanded from the patient’s blood, attenuated by irradiation, and sent to the patient’s physician’s office. The patient would then receive a subcutaneous injection of the deactivated T-cells, which could lead to a heightened immune response that reduces the number of or regulates the activity of circulating ARTCs. With fewer or less active pathogenic ARTCs, B-cells would not be stimulated to produce anti-aquaporin-4 antibody, and the destructive cycle would be prevented. OPX-212 is currently in refinement for future clinical trials with NMO patients and has not yet been tested in humans, although Opexa may look to submit an investigational new drug application for human studies.
If successful, OPX-212 would be a unique, personalized treatment for NMO patients. According to “Current and Future Treatment Approaches for Neuromyelitis Optica,” which was published in Therapeutic Advances in Neurological Disorders, T-cell-targeted therapies have not been well studied in the literature. By understanding the mechanisms of action for efficacious NMO treatments and focusing on the affected cells, Opexa is one of the first to propose T-cell specific therapies for NMO.