Method for immune tolerance induction in patients receiving enzyme replacement therapy for a variety of metabolic disorders

Unmet Need

Genetically based metabolic disorders affect 1 in 2500 births globally and many of these disorders result in an enzyme deficiency. In most cases, a single enzyme is not produced by the body at all, in not enough quantities to keep a patient healthy, or it is produced in a form that doesn’t work. Depending on the specific enzyme that is missing, toxic by-products can build up inside cells, causing nerve damage, developmental delay, kidney and heart disease, severe disabilities, or premature death. Enzyme replacement therapy (ERT) is a common medical treatment for these cases, in which the patient receives purified human, animal, or recombinant enzyme preparations to replace a missing or deficient enzyme through intravenous infusions. While ERT can allow patients to live relatively normal lives, sometimes the enzyme being provided to the patient is recognized as foreign by the patient’s immune system, causing anaphylaxis, severe hypersensitive reactions, or reducing the therapeutic effect of the treatment during their infusion due to elevated enzyme specific antibody titers. Therefore, there is a need for a method to prevent the development of or remove existing pathogenic antibodies in patients receiving ERT for metabolic diseases where this therapy is the standard of care.

Technology

Duke inventors have developed a method for inducing tolerance for patients receiving ERT for a variety of metabolic diseases. This is intended to be used in conjunction with ERT to induce tolerance or to remove existing antibodies against the functional enzyme being infused. Specifically, Duke inventors discovered a method of inducing tolerance using in combination or alone rituximab, methotrexate, intravenous gamma globulin, or bortezomib. This has been demonstrated to prevent antibody production in patients that did not produce any of their own enzyme and those that produced some but not enough (or a deficient version) of it. Further, this has been demonstrated to reduce antibody titers in patients with pre-existing antibodies against the enzyme. This immune tolerance induction method can be used for the treatment with ERT of metabolic diseases including Fabry Disease, Gaucher Disease, GSDs types I-VIII, IX, XI, XII, and XIII, cardiac glycogenesis due to AMP-activated protein kinase gamma subunit 2 deficiency, MPS diseases including MPS I (Hurler, Hurler-Scheie, or Scheie Syndrome), MPS II (Hunter Disease), and MPS VI (Maroteaux-Lamy syndrome), Pompe Disease, or Wolman disease.

Advantages

• Can be used in conjunction with ERT therapy with options for oral, subcutaneous, or intravenous administration

• Can be used to tolerize patients that do not produce any enzyme

• Can be used on patients that have established antibodies

• Prevents the formation of antibodies in naïve patients