Tolerization for treating neurodegenerative and psychiatric diseases

Abstract

Neurodegenerative and psychiatric diseases (NPDs) are associated with chronic or flaring brain inflammation and infiltrations of cytotoxic lymphocytes in the inflamed brain parts, causing mild to severe or even lethal brain damage. NPDs thus show features of autoimmune diseases (De Haan P et al., Frontiers in Psychiatry 8: 46, 2017). An autoimmune disease can be effectively treated by tolerization, in which the immune response to the primary self-components that are targeted by the adaptive immune system e.g. the primary self-antigens, pSAgs of the disease is reversed into an immune tolerance response. We at Amarna have developed a replication-defective gene delivery platform named SVec that based on its safety, non-immunogenicity and tolerogenicity properties is highly effective in inducing immune tolerance to pSAgs of autoimmune diseases. For one of the major NPDs, multiple sclerosis (MS) we have recently demonstrated that SVec-mediated expression of myelin oligodendrocyte glycoprotein (MOG), the pSAg of the disease, in liver cells of mice protects the tolerized animals from developing the disease. SVec is therefore excellently suited for developing effective tolerization therapies for patients with autoimmune diseases including NPDs.In order to design effective tolerization treatments for other NPDs, the pSAgs of the disease need to be identified. A pSAg of an autoimmune disease is predominantly or exclusively expressed in the affected tissue and all patients have a cellular immune response to the pSAg. Induction of an immune response to the pSAg in an animal results in the development of the disease. In order to identify pSAgs of autoimmune diseases traditionally, animals were immunized with the pSAg protein or peptides derived thereof in the presence of complete Freund's adjuvant (CFA) to enhance the immune response to the pSAg. This method, however, is highly labour-intensive, time-consuming and costly. We developed a replication-competent Alphaviral replicon vector system named AlphaSelect to reliably and cost-effectively test candidate pSAgs for their capacity to induce autoimmune disease symptoms in animals (De Haan P et al., Human Vaccines & Immunotherapeutics 17: 14-21, 2020). Recombinant AlphaSelect vectors encoding candidate pSAgs of amyotrophic lateral sclerosis (ALS) have been made and tested in animals to induce the characteristic disease symptoms. Here we report on the results of the initial immunization studies and on the feasibility of this approach to reach our long term ambition of developing effective tolerization therapies not only for NPDs, but also for other autoimmune diseases such as obesity, diabetes mellitus, atherosclerotic cardiovascular disease, arthritis, inflammatory bowel diseases and chronic obstructive pulmonary disease.