New treatment uses reverse vaccination to teach immune system not to attack life-saving drugs

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Newswise – BUFFALO, NY – For nearly a third of patients with hemophilia A and almost all patients with Pompe disease, their own immune system is their biggest barrier to treatment. When they are given essential proteins and enzymes, their bodies perceive the treatments as a threat and an attack.

However, researchers at the University of Buffalo have come up with a new treatment that uses reverse vaccination to pre-expose the body to drugs and boost immune tolerance. The new treatment combines essential proteins and enzymes with lysophosphatidylserine (Lyso-PS), a fatty acid that helps the immune system tolerate foreign substances, reducing the side effects of drugs.

Unlike traditional vaccination, which uses pre-exposure to train the immune system to deal with potential threats, reverse vaccination uses exposure to train the immune system to ignore foreign substances. The treatment could be applied to a wide range of drug therapies, autoimmune disorders and allergies, says lead investigator Sathy Balu-Iyer, PhD, professor of pharmaceutical sciences and associate dean for research at UB School of Pharmacy and Pharmaceutical Sciences.

The results were published this month in Scientific reports. Balu-Iyer recently received funding continue the preclinical research of the Empire Discovery Institute, which will license the technology and advance the treatment in the market.

“The safety and efficacy of several life-saving therapeutic drugs are compromised by anti-drug antibodies. Once the antibodies develop, the clinical options available to patients become expensive and, in many cases, ineffective, ”said Balu-Iyer.

“Instead of trying to reverse anti-drug antibodies, which is very difficult, clinical treatments that prevent antibody development may be a more effective strategy,” says Nhan Hanh Nguyen, lead author and graduate science student pharmaceuticals at UB. “Our approach is based on the reasoning that pre-exposure of a protein in the presence of Lyso-PS teaches the immune system not to trigger a response.”

Hemophilia A is a genetic bleeding disorder caused by the lack of factor VIII in the blood clotting protein. Patients with the disease are at serious risk of bleeding after injury or surgery. Recombinant factor VIII is the first line of defense in treatment, however, the body may associate factor VIII with other threats and produce antibodies that destroy it. One-third of patients experience these side effects, and once the antibodies develop, the cost of clinical treatments can exceed $ 700,000 per year.

For Pompe disease, a rare genetic disorder in which the body lacks the enzyme needed to break down complex sugars for energy, more than 90% of patients develop antibodies against the treatments. Without the enzyme, alpha acid glucosidase (GAA), sugar builds up in muscles and organs, causing weakness and shortening of life expectancy. Attempts to suppress the immune system put patients at risk of secondary infection.

Results published in August in the Journal of Thrombosis and Hemostasis found that four weeks of co-administration of Lyso-PS with factor VIII significantly reduced antibody development without affecting the effectiveness of the protein.

The new research designed and tested a Lyso-PS nanoparticle with the ideal size and surface characteristics for cell uptake, binding, and survival in the digestive tract.

The study found that the designed Lyso-PS nanoparticle prevented the development of antibodies against factor VIII in 75% of subjects and significantly reduced the levels of antibodies against GAA.

The treatment was effective when given intravenously as well as orally, the latter of which may allow for easier consumption and better treatment compliance by patients, Balu-Iyer explains.

Other investigators in the September study include Fiona Glassman, PhD, senior clinical pharmacologist at CSL Behring, and Robert Dingman, PhD, at Regeneron Pharmaceuticals, both former students of the Balu-Iyer lab; Gautam Shenoy, PhD, research fellow at the Jacobs School of Medicine and Biomedical Sciences at UB; Elizabeth Wohlfert, PhD, assistant professor of microbiology and immunology at the Jacobs School; Jason Kay, associate professor of oral biology at the UB School of Dental Medicine; and Richard Bankert, VMD, PhD, professor of microbiology and immunology at the Jacobs School.


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