Parkinson's
Fox Foundation grant funds major gene therapy advance for treatment of Parkinson's disease
By Michael J. Fox Foundation and University of Pittsburgh Medical Center
Jan 6, 2006 - 3:28:00 AM

An innovative gene therapy approach pioneered by Pennsylvania-based RheoGene Inc. will be further refined and tested in preliminary clinical trials within four years, thanks to a $4.2 million grant from the Michael J. Fox Foundation for Parkinson's Research (MJFF).
A wholly owned affiliate of the University of Pittsburgh Medical Center (UPMC), RheoGene Inc. has developed technology to manage gene expression, a key component of gene-based therapies. RheoGene's therapeutic system uses a patented small-molecule mediator that can turn genes "on" or "off" as well as adjust the level of gene activity similar to the way a rheostat regulates electric current.

"This project has the potential to revolutionize the clinical application of gene therapy � not only for the millions of people with Parkinson's disease, but for countless numbers afflicted by other health ailments as well," said Deborah W. Brooks, MJFF president and CEO. "It is a natural fit with the foundation's commitment to drive innovative technology that will have a significant impact on patients' lives."

Parkinson's disease gradually destroys brain cells that produce dopamine, a chemical messenger crucial for the cellular communication that controls muscle movement. As dopamine levels drop, symptoms increase. These include tremors in the arms, legs and face; periodically stiff or frozen limbs; slow movement; and impaired balance and coordination. In the United States, at least 500,000 � and perhaps as many as 1.5 million � people are thought to have Parkinson's disease, with 50,000 new cases being diagnosed each year, according to the National Institute of Neurological Disorders and Stroke, a division of the National Institutes of Health. Because risk increases with age, these rates will increase as the population ages.

Current treatment options focus on replacing lost dopamine with the drug levodopa (L-dopa), which converts to dopamine in the brain, or brain surgery to control tremors. These treatments generally work temporarily but cannot stop the disease's inevitable progression to disability.

Although research continues on gene-based treatments for a variety of ills, much of the strategy's early promise remains to be realized because of risks associated with failure to regulate gene expression � or turn it off entirely � if there are worrisome side effects. A RheoGene-led team will work to further the technology, called the RheoSwitch Therapeutic System (RTS), for safe and effective use to control the intensity and timing of gene expression. This will be accomplished using a specially developed Activator Drug that is administered orally to act as an "on switch." When the drug is no longer taken, gene expression stops. Preclinical testing in animal models has indicated that RTS can work as envisioned by researchers.

"We are pleased that the Fox Foundation has recognized that RheoGene's technology has important implications for advancing cell and gene therapies into the clinic," said Thomas Tillett, chief executive officer of RheoGene. "RTS has the potential to provide a critical efficacy and safety mechanism for a wide range of gene-based therapeutics."

The MJFF-funded project will begin with a dual focus. One gene target that researchers will evaluate produces glial cell derived neurotrophic factor (GDNF), a naturally occurring protein that protects and stimulates regeneration of brain cells that secrete dopamine, the same cells that are progressively lost in Parkinson's disease. The other gene target of interest produces aromatic L-amino acid decarboxylase (AADC), an enzyme involved in dopamine synthesis. Both avenues are especially exciting because neurotrophic factors, also known as trophic or growth factors, support critical neuron function and survival.

The team is being led by coordinating principal investigator Dean Cress, Ph.D., a biochemist and co-founder of RheoGene and J. Mark Braughler, Ph.D., head of RheoGene's clinical applications office and laboratory in Pittsburgh. The team includes two experts in gene therapy for Parkinson's disease: Krystof Bankiewicz, M.D., Ph.D., professor of neurological surgery at the University of California, San Francisco and Martha C. Bohn, Ph.D., professor of pediatrics and molecular and biological chemistry at Northwestern University Feinberg School of Medicine, Chicago.

Gene therapy for Parkinson's disease is the first target of the RheoGene-led team's first area of focus. Future research will concentrate on applications to cancers and diabetes.

"RheoGene has been able to reach this stage in its development of RTS and other technologies because of the strategic investment � both financial and intellectual � made by our partners at UPMC," said Mr. Tillett. "We look forward to continuing to leverage the relationships available to us through our association with the medical center's researchers to deliver hope to many patients using our gene therapy technologies."



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