Gene therapies for Usher syndrome moving toward clinical trials

John Flannery, Ph.D., University of California, Berkeley, and David Williams, Ph.D., University of California, San Diego presented updates on their FFB-funded work on emerging gene therapies for Usher syndrome.

Flannery began his discussion by giving participants a general overview of Usher syndrome. He explained that there are three types of Usher syndrome, and each is characterized by different degrees and progressions of vision and hearing loss, as well as problems with balance. Also, each type is divided into subtypes based on the disease-causing gene.

People with Usher syndrome type 1 (Usher 1) are born with profound hearing loss, balance problems, and they experience vision loss during their first decade of life. Usher 1 is divided into six subtypes.

People with Usher syndrome type 2 (Usher 2) are born with moderate hearing loss and no balance problems. Vision loss begins in their first or second decade of life. Usher 2 is divided into three subtypes.

People with Usher syndrome type 3 (Usher 3) have progressive hearing loss and about half have balance problems. The amount and progress of vision loss in people with Usher 3 varies on an individual basis. Usher 3 has one subtype.

Flannery and his colleagues recently developed a mouse model for Usher 3, which is essential to developing potential treatments, and moving them into clinical trials. The mice with Usher 3 developed hearing-related problems early on, but have yet to show retinal symptoms. Flannery is hopeful that the mice will show retinal symptoms, so that gene therapy can be evaluated for vision. He noted that visual symptoms in people with Usher 3 can also progress slowly.

In 2006, Flannery and his team plan on investigating a gene replacement therapy study in the Usher 3 mice. The therapy, he said, is “patterned after the Leber congenital amaurosis (LCA) trials,” and will be delivered in two separate treatments — one to the retina and one to the cochlea (the inner ear). Both involve delivery of the same gene: clarin-1. Flannery said they will first deliver the treatment to the cochlea in mice, because the mice are showing hearing-related symptoms first.

Eeva-Marja Sankila, Ph.D., University of Helsinki, and her colleagues will be conducting the preclinical investigation of gene therapy for the cochlea.

An adeno-associated virus (AAV2) will be used to deliver the healthy, replacement gene to cells in the cochlea and retina. The virus, also known as a vector, is being designed by William W. Hauswirth, Ph.D., University of Florida. Hauswirth is also an investigator on an upcoming gene therapy trial for LCA.

Flannery concluded his presentation with a short discussion about his forthcoming work on a therapy he characterizes as lying somewhere between gene therapy and a retinal prosthesis. He explained that after photoreceptors die in people with retinal degenerative diseases, other neurons in the retina still survive. Flannery is collaborating with his bioengineering and neurobiology colleagues at the University of California, Berkeley to use gene therapy to turn those surviving neurons into light-sensing cells, which may restore vision.

For the second half of the discussion on Usher syndrome, Williams gave an update on his progress in developing a gene therapy for Usher 1B. The Usher 1B subtype, he said, accounts for about half of all cases of Usher 1.

Williams explained that mutations in a gene called myosin VIIa are the cause of Usher 1B, and that myosin VIIa belongs to a family of proteins known as motor proteins. These proteins are like “trucks on the freeway carrying cargo.” In the retinal pigment epithelium (RPE) — a layer of cells that provides nutrition and waste disposal for the retina — the absence of myosin VIIa degrades the waste disposal process and also the recycling of retinoids, which is critical for the visual cycle.

Williams showed the audience slides and video of how gene therapy leads to restoration of myosin VIIa production in the retinas of mice, and how the protein helps maintain the health and vitality of the retina.

One of the challenges in developing myosin VIIa gene therapy was designing a viral vector that could deliver the relatively large gene to the retina; the AAV vector used in LCA gene therapy studies would not be suitable. Instead, a lentivirus-based vector was used for gene delivery.

The success realized by Williams and his colleagues in the mouse studies of gene therapy for Usher 1B has moved them much closer to human clinical trials. FFB provided good support for enabling the team to reach this important milestone.

A few more goals and refinements remain to be completed before human studies can begin. One such goal is improving the vector, so that the replacement gene leads to the production of the right amount of protein — too much or too little protein will cause problems.

The investigators also want to conduct more efficacy and toxicology studies of the treatment.

Finally, the team will need to produce the vector for the human study, and identify individuals with Usher 1B for participation in a clinical trial.

Williams concluded by saying that he has submitted a large collaborative grant proposal to the National Eye Institute to move this Usher 1B work forward.

Audio 11:18

David Williams, Ph.D., University of California, San Diego

Audio 16:47