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By Fiona Yau

Fiona Yau - finalThe development of unwanted immune response toward a protein is a complication that could compromise the safety and efficacy of a protein therapeutic or lead to a breakdown in self-tolerance that ultimately manifests in autoimmunity. A hallmark of autoimmune diseases such as multiple sclerosis (MS) is the breakdown of self-tolerance toward a self-protein and the loss of self and non-self recognition. Strategies to overcome autoimmunity by reversing the disease are crucial in order to provide an alternative treatment option for patients.

A strategy utilized for tolerance induction toward a protein is being developed in the lab of Sathy Balu-Iyer, Ph.D., at the University at Buffalo. This strategy uses phosphatidylserine (PS), a naturally occurring phospholipid present in cell membranes, in liposomes complexed with an antigen in order to induce tolerance. This approach exploits the ability of PS to convert an immunogen to a tolerogen by apoptotic mimicry. It is hypothesized that PS is able to induce tolerance toward an antigen by mimicking the exterior of an apoptotic cell in order to present the associated antigen as self. We have shown that administration of Factor VIII (FVIII) in the presence of PS in hemophilia A mice can reduce the immune response towards FVIII and induce tolerance toward FVIII even after PS treatment ended.

The work presented at the 2016 AAPS National Biotechnology Conference will extend this strategy from therapeutic proteins and into autoimmunity using MS as a model disease. MS is characterized as an inflammatory and demyelinating disease of the central nervous system resulting in the breakdown of self-tolerance and autoantibody production against myelin proteins. Current clinical options for treating MS include general immunosuppressants and disease-modifying agents such as interferon-β. Although the current clinical options have proven to be successful especially in patients with the relapsing-remitting MS, long-term safety profiles are not fully understood. General immunosuppressants could compromise the immune status of the patient. Finally, there is no currently approved disease-modifying treatment for patients diagnosed with primary-progressive MS. As a result, there is an urgent need to develop a safe and efficacious strategy to reduce and reverse the progression of the disease. This work seeks to address this need by exploiting the ability of PS to convert an immunogen to a tolerogen by redirecting the immune system back to an “immunologically tolerant” state.

Fiona Yau is pursuing a Ph.D. in pharmaceutical sciences at the University at Buffalo in Buffalo, NY, under the guidance of Sathy V. Balu-Iyer, Ph.D.