Blood-Filtering Procedure Removes Antibodies That Impede Gene Transfer

A research group supported in part by MDA has found that a blood-filtering strategy known as plasmapheresis looks promising as a way to help overcome one type of unwanted immune response to gene transfer therapy. Gene transfer therapy is the addition of therapeutic genes to treat disease, and it is often administered via transport vehicles made from viruses.

Louis Chicoine at Nationwide Children's Hospital and Ohio State University in Columbus, Ohio, and colleagues, reported the findings online Oct. 23, 2013, in the journal Molecular Therapy.

The findings are important because many people have pre-existing antibodies — immune system proteins — to the viral shells used to transport therapeutic genes to the body's tissues. These antibodies, which can come from natural infections, interfere with the effectiveness of the therapy.

Plasmapheresis can be used to treat autoimmune ("self"-immune) disorders, in which unwanted antibodies attack the body's own tissues. For example, myasthenia gravis (MG) is sometimes treated with plasmapheresis.)

Plasmapheresis improved gene transfer in monkeys with AAV antibodies

The investigators, which included MDA research grantee Jerry Mendell at Nationwide Children's Hospital, administered gene transfer therapy via a blood vessel to leg muscles of monkeys, using microdystrophin genes encased in transport vehicles made from adeno-associated viruses (AAVs).

Microdystrophin gene therapy is an experimental strategy for the treatment of Duchenne muscular dystrophy (DMD), a disease caused by the absence of the dystrophin protein in muscles. (The monkeys in these experiments, however, did not have dystrophin deficiency.)

Monkeys that had pre-existing antibodies to AAVs — probably from previous infections — received either no treatment, plasmapheresis, or treatment with drugs to suppress the immune system along with the microdystrophin gene transfer.

Monkeys with AAV antibodies treated with plasmapheresis showed high levels of gene transfer to the targeted muscle fibers, comparable to levels seen in monkeys with no pre-existing AAV antibodies.

However, monkeys treated with immunosuppressant drugs showed no increase in gene transfer compared to untreated animals.

The investigators concluded that plasmapheresis may be an effective strategy for reducing unwanted viral antibodies in patients receiving gene transfer therapy.

Study did not address other types of unwanted immune responses

It should be noted that this study did not address other types of unwanted immune responses to gene transfer — such as reactions against newly made dystrophin protein — that have been seen in various gene therapy studies. Other strategies, including immunosuppressant medications, may be needed to treat this kind of unwanted immune response. (Since the monkeys did not have dystrophin deficiency, it was not possible to assess immune responses to dystrophin resembling those that occur in DMD patients, who lack dystrophin.)

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