Tricking the immune system into tolerating a therapeutic protein

Patients with inherited protein deficiencies such as hemophilia or lysosomal storage disorders are currently treated by frequent intravenous injections of a manufactured functional form of the missing protein. Gene therapies are being developed as alternatives. In either case, however, the immune system may reject therapy because it may not tolerate this “new” protein, creating a major complication.

One example is treatment of Pompe disease (glycogen storage disease type II), an inherited, progressive and often fatal lysosomal storage disorder caused by deficiency of the enzyme acid a-glucosidase (GAA). GAA deficiency causes glycogen to accumulate in skeletal, cardiac, and diaphragm muscles, disrupting their function. Patients who develop the disease as infants experience symptoms within the first year of life and often die early in life. More than 80 percent of patients suffering from infantile Pompe disease develop antibodies against infused GAA, which makes replacement therapy ineffective.

In an article in Molecular Therapy, researchers describe the transfer of a GAA gene to the thymus, an organ that is part of the immune system. Mice with Pompe disease that received this therapy became tolerant to the therapeutic GAA protein.

Only low doses of the genetic drug were required for this effect. This is one of several novel approaches, which may enable doctors to prevent immune responses that would otherwise block treatment of certain genetic diseases.