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By Fiona Yau

Unwanted immune response towards a therapeutic protein is a clinical complication that could compromise the safety and efficacy of the therapy. Patients born with Hemophilia A (HA) have the deficiency or dysfunction of the essential blood clotting protein, Factor VIII (FVIII), and recombinant FVIII is the first line of therapy for these patients. However, about 30% of severe HA patients develop neutralizing antibodies (Nabs) against FVIII, which abrogate the activity of the protein, rendering the therapy less efficacious and increasing the risk of bleeding tendencies. With the development of Nabs, patients are put on alternative treatment options including bypass therapies, or they undergo the immune tolerance induction (ITI) protocol where high doses of FVIII are administered. However, ITI therapies are often costly and met with varying success. As a result, safe and effective strategies to overcome unwanted immunogenicity is crucial in order to improve treatment options for patients.

A lipid-based strategy used to induce tolerance is being developed in the lab of Sathy Balu-Iyer, Ph.D., at the University at Buffalo. This strategy exploits the biological functions of phosphatidylserine (PS) during apoptotic events to induce immunological tolerance. PS is a naturally occurring phospholipid present in cell membranes and becomes externalized to the outer leaflet when a cell undergoes apoptosis. Therefore, it is hypothesized that PS is able to induce tolerance towards an antigen by mimicking the exterior of an apoptotic cell in order to present the complexed antigen as self. We have previously shown that subcutaneous administration of FVIII in HA mice can induce tolerance towards FVIII in HA mice, even after treatment with PS ended. This approach has also been seen to induce tolerance towards acid alpha glucosidase (GAA) in Pompe disease mice.

Through the work with FVIII and GAA in the laboratory, it has been identified that PS has the unique ability to convert an immunogen to a tolerogen. This work, which received an AAPS Innovation in Biotechnology award and will be presented at the 2017 AAPS National Biotechnology Conference, seeks to exploit the biological properties of PS in order to engineer a better tolerogenic nanoparticle to induce more effective tolerance towards FVIII. The identification of a specific PS species responsible for the PS-mediated effects we have observed is critical for the translation of this strategy. Moreover, the route of administration may be a critical component in determining the most effective tolerance induction strategy. The oral route of administration would provide an optimal delivery approach that could provide ease in translation of the strategy. Moreover, the gut immune system is highly evolved and has mechanisms in place that tightly regulate the tolerogenic balance in the gut. It is able to suppress unwanted inflammatory responses with the exposure of food antigens, yet is able to activate the necessary protective response if the body is exposed to any harmful pathogens. This work seeks to exploit this natural tolerogenic site to induce oral tolerance towards FVIII using a specific PS species to prevent the development of Nabs.

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.