Genes as Medicine: Molecular Therapy Comes of Age

Ricki Lewis, PhD

November 13, 2012

SAN FRANCISCO — Gene therapy is edging closer to mainstream medicine.

The first trial of gene therapy, for adenosine deaminase (ADA) deficiency, was conducted in the United States in 1990. On November 2, 2012, the European Commission approved the first gene therapy (for the treatment of lipoprotein lipase deficiency).

In gene therapy, researchers use stem cells or viruses to deliver functional copies of genes to patients whose own copies of the gene are mutated and causing disease. Viral vectors include adeno-associated virus, gamma retrovirus, and lentivirus ("gutted" HIV). In nondividing cells, the virally delivered genes remain extrachromosomal; in dividing cells, they integrate into the host genome and replicate.

Here at the American Society of Human Genetics 62nd Annual Meeting, researchers presented the results of clinical trials in which gene therapy is being used to treat patients with hemophilia B, Leber's congenital amaurosis type 2, and primary immune deficiencies.

Hemophilia B

Katherine High, MD, professor of pediatrics at the Perelman School of Medicine in Philadelphia, Pennsylvania, explained that hemophilia B (factor IX deficiency) affects 1 in 5000 men. In affected patients, less than 1% have severe disease, 1% to 5% have moderate disease, and 5% have mild disease.

Hemophilia B is an ideal candidate for gene therapy because minor improvement has a clinical impact. "Even a modest increase in clotting factor, in the 1% to 5% range, greatly ameliorates symptoms and prevents life-threatening bleeds," Dr. High said.

Existing treatment with recombinant clotting factor requires repeated treatments and is so expensive that only 20% of the world's patients use it. Gene therapy could change that by providing a 1-time treatment. "The goal is to get away from the peaks and troughs of factor IX and to institute a steady level that would prevent bleeds, so that more people can have a normal quality of life," Dr. High said.

Gene therapy uses a subtype of adeno-associated virus, which targets hepatocytes, to intravenously deliver the factor IX gene. Several patients now produce enough factor IX to greatly reduce the need for clotting factor. "This transforms hemophilia B into a mild disease," Dr. High noted.

Leber's Congenital Amaurosis

The immune-privileged nature of the retina makes it an excellent target for gene therapy, according to Jean Bennett, PhD, MD, professor of ophthalmology at Children's Hospital of Philadelphia (CHOP). He explained that, so far, more than 230 patients with Leber's congenital amaurosis type 2 (LCA2) have received gene therapy in clinical trials.

In LCA2, lack of the functional RPE65 enzyme prevents the isomerization of 11-cis-retinal that enables rhodopsin in photoreceptors to signal the visual cortex. "Patients can see very bright lights and large objects, but their vision decreases as the photoreceptors degenerate," Dr. Bennett said.

In gene therapy for LCA2, an ophthalmologic surgeon subretinally injects the therapeutic gene near the region with the most damage. Researchers conducting a phase 1/2 trial at CHOP originally treated the worst eye of the patient; the second eye has since been treated in most patients.

Indicators of successful outcome include activity in the visual cortex on functional magnetic resonance imaging (MRI), standard ophthalmological tests, and patient observations.

After the procedure, functional MRI shows, strikingly, that "neurons in the visual cortex are still responsive after decades of severe impairment," Dr. Bennett said. Efficacy has persisted beyond 5 years. A phase 3 trial will begin in December, Dr. Bennett told Medscape Medical News.

Primary Immune Deficiencies

More than 200 mutant genes cause primary immune deficiencies. For the 90% of patients without a compatible bone marrow donor, gene therapy could be an option. By targeting autologous hematopoietic stem cells, researchers could, theoretically, treat any such disease.

Clinical trials of gene therapy are underway for severe combined immune deficiency (SCID)-X1, SCID-ADA, chronic granulomatous disease, and Wiskott–Aldrich syndrome. In all of the diseases, the altered cells appear to have a selective advantage over the pathogenic ones.

A group at the SanRaffaele Scientific Institute Telethon in Milan, Italy, has cured SCID-ADA and Wiskott–Aldrich syndrome with gene therapy, scientific director Maria-Grazia Roncarolo, MD, reported.

Like hemophilia B, a minor correction (10%) for SCID-ADA can have a significant clinical effect, but enzyme replacement is extremely expensive. After gene therapy for SCID-ADA, patients respond to vaccines and rarely contract infections, Dr. Roncarolo said.

Gene therapy for SCID-X1 has also been successful. The program had a rocky start when 5 boys developed leukemia because the gene vector was inserted into an oncogene. The researchers corrected the problem, and they have since treated 18 patients. "All are alive, with median follow-up 6 years, and 15 patients are completely out of any treatment," she said. Other groups have treated 22 other patients, all successfully. GlaxoSmithKline will sponsor a phase 3 trial.

Dr. Roncarolo reported promising results for 3 patients treated for Wiskott–Aldrich syndrome, which have yet to be published. "All 3 patients had severe recurrent infection and eczema and 2 had gastrointestinal bleeding. There was robust gene transfer, no autoantibodies, and improved immune function and platelet counts," she said.

Genes as Medicine

With the successes stacking up, all of the researchers anticipate that many other conditions will respond to gene therapy. "We are getting close to using genes as medicine," organizer Beverly Davidson, PhD, from the University of Iowa in Iowa City, concluded.

Dr. High reports being a consultant for Genzyme Corporation and Amsterdam Molecular Therapeutics. Dr. Bennett reports being a coauthor on a patent for retarding blindness but waived financial interest in 2002. The other researchers have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 62nd Annual Meeting: Session 23. Presented November 8, 2012.