Gene Therapy Animal Study Offers Hope For Some Neurodegenerative Diseases

September 15, 1998

A study co-authored by UC San Francisco researchers offers the first evidence that a gene therapy technique involving ribozymes, molecules that disrupt protein production, can be used to slow neurodegeneration in an animal model, signalling a possible approach for overcoming one of the monumental hurdles of gene therapy.

In the study, reported in the August issue of Nature Medicine, researchers demonstrated that ribozymes could be used to reduce the production of a faulty gene product that leads to the degeneration of light-sensitive rod cells in the eye. The degeneration occurs in association with autosomal dominant retinitis pigmentosa, an untreatable condition of progressive blindness.

Importantly, the approach could potentially also be used to treat other diseases resulting from a destructive protein, including some forms of glaucoma, Huntington's disease, amyotrophic lateral sclerosis (ALS) and Warfan's syndrome, according to the senior author of the study, Matthew M. LaVail, PhD, a professor of anatomy and ophthalmology at UCSF.

The finding represents an important breakthrough in the still fledgling field of gene therapy, which has been particularly challenged by disorders caused by abnormal, or mutant, proteins, so-called autosomal dominant diseases, said LaVail.

Most gene therapy approaches have focused on diseases that occur when the two copies of a particular gene fail to produce, or fail to produce sufficient quantity of, a healthy protein. The challenge in developing treatments for these so-called autosomal recessive diseases, such as cystic fibrosis, has involved trying to introduce healthy genes directly into the pertinent cells to replace and compensate for the missing proteins. This challenge has been daunting enough. Some successes have been achieved in animal models with recessive diseases, but only in recent months have such approaches even begun to demonstrate small successes in clinical trials, according to LaVail.

But researchers have been virtually foiled in their attempts to create a gene therapy technique for diseases in which one of the two copies of a gene produces a protein that is actually destructive, as is the case with autosomal dominant diseases.

"That's what makes this study particularly exciting," said LaVail. "The research community has been really stumped when it comes to developing gene therapy techniques that will destroy faulty gene products to a clinically relevant degree. Scientists have thought that ribozymes would prove to be an effective approach, and our study establishes that they are."

In the study, conducted in rats, the DNA containing the code for specifically designed ribozymes was carried via a harmless adeno-associated virus vector. The researchers injected the DNA-containing vectors immediately adjacent to the rod cells of the eyes. Once the vectors infected the rod cells, the DNA synthesized the ribozymes, short strands of RNA, which were "turned on" by a promoter molecule that is active only in rod cells.

The ribozymes, one shaped like a hairpin, the other like a hammerhead, then sought out and destroyed the faulty messenger RNA carrying the mutated gene's code for building the destructive protein.

The results were significant: After two to three months, 30 to 40 percent more rod cells remained in eyes that had been injected with either of the ribozymes than in eyes receiving placebo injections.

"We've demonstrated the effectiveness of these approaches by direct measurement of the reduction of the mutant RNA in the retina, in studies of the eye's anatomy and in the ability of the eye to show better electrical function following therapy," said LaVail.

Phase I clinical trials of the therapy could begin within several years if subsequent studies prove the method safe and effective.

The co-authors of the study included Alfred S. Lewin, Kimberly A. Drenser and William W. Hauswirth of the University of Florida College of Medicine, Shimpei Nishikawa, MD, PhD, a visiting postdoctoral fellow at UCSF, Douglas Yasumura, MA, a specialist at UCSF, and John G. Flannery, of UC Berkeley.

The study was funded by grants from the National Eye Institute, The Foundation Fighting Blindness, Research to Prevent Blindness, That Man Might See, Inc., and the March of Dimes Foundation.

University of California - San Francisco

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