SFN: Parkinson's Disease Gene Transfer Called Safe


By Michael Smith, Senior Staff Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
October 18, 2006



ATLANTA, Oct. 18 -- An investigational gene therapy for Parkinson's disease appears to be "amazingly safe" after a year of follow-up, a researcher said here.
Action Points

* Advise patients who ask that this study shows that an experimental gene therapy for Parkinson's Disease is safe and may be effective.

* Note that the research is preliminary and will need to be confirmed in larger clinical trials.

* This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.

Preliminary efficacy results from a small phase I study show an overall 25% improvement in symptom scores, reported Matthew During, M.D., Ph.D., of Ohio State University, and colleagues, at the Society for Neuroscience meeting.

"We don't want to over-interpret, but we are very encouraged," Dr. During said after he presented his data.

He cautioned that the small size of the study -- just a dozen patients -- was not powerful enough to draw firm conclusions about the efficacy of the gene therapy.

The open-label, dose-escalating phase I study was intended to probe the safety of the procedure. So far, clinicians have infused an adeno-associated virus, transfected with the gene for glutamic acid decarboxylase, into the subthalamic nucleus of 12 patients with moderate to severe Parkinson's.

The theory, Dr. During said, is that the transfected gene would turn down the excessive activity of the subthalamic nucleus by increasing the region's ability to convert glutamate into GABA, the primary inhibitory neurotransmitter.

Because of fears over the safety of gene therapy, the researchers were required to treat only one hemisphere in each patient's brain, Dr. During said. Patients underwent stereotactic surgery and received one of three doses -- 3.5, 10.5, and 35 billion of the viral particles.

"Every single patient was discharged within 48 hours without fever," Dr. During said, and over the follow-up, "there was not a single adverse event related to the surgery or the gene transfer."

None of the patients had an immune reaction to the virus, as measured by antibody titers, Dr. During said, and MRI showed no brain injuries as a result of the surgery.

While the safety issue was the main endpoint of the study, the researchers also tracked changes in symptoms, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS), and changes in glucose metabolism, as measured by PET.

From baseline, Dr. During said, the whole patient group had a 25% improvement in UPDRS scores, which was significant at P<0.005, but nine patients -- all of the mid- and high-dose group and one person in the low-dose group -- had a 37% improvement overall.

The five best responders had improvements ranging from 40% to 65%, "which is quite remarkable considering we only treated half of the brain," Dr. During said.

The patients also had "highly significant" changes in glucose metabolism on the operated sides of their brains, compared with the other side, and those changes were highly correlated with improvements in UPDRS scores, he said.

Dr. During, formerly of Cornell in New York, is a founder of Neurologix, Inc., which is developing the gene therapy for Parkinson's, and he remains a consultant to the company and a member of its scientific advisory board.

Gene Therapy Trials Show Promise Against Parkinson's
Two studies benefit patients without adverse effects, but more tests are needed to be sure.
By Thomas H. Maugh II, Times Staff Writer
October 18, 2006

The first studies of human gene therapy for Parkinson's disease have shown that the technique is safe and can reduce symptoms for patients, two groups of researchers have reported.

All of the 24 patients who received therapy in the two separate trials received some benefit and none had any significant side effects, researchers reported at neuroscience meetings Tuesday and last week.

Gene therapy has a tarnished reputation because of problems encountered in trials involving other diseases, said Katie Hood, deputy chief executive officer of the Michael J. Fox Foundation for Parkinson's Research.

The Food and Drug Administration temporarily halted gene therapy trials in 1999 after an 18-year-old being treated for a mild genetic disorder died after a violent reaction to the procedure. Trials were halted in 2005 after three French children being treated for inherited immunodeficiency disease developed leukemia and one of them died.

"It's very encouraging that two companies were able to show benefits with no significant adverse effects," Hood said. "Safety is obviously the first hurdle."

Experts and the researchers themselves, however, cautioned patients against investing too much hope in the findings because Parkinson's studies are notorious for showing placebo effects.

Only when the techniques are tested in controlled trials, now in the planning stages, will researchers be able to determine whether the benefits are real and lasting.

Parkinson's, which strikes as many as 100,000 Americans each year, is characterized by severe tremors and rigidity in the limbs, and loss of muscle control. It results from the death of brain cells that produce the neurotransmitter dopamine, which plays a key role in transmitting commands from the brain's muscle-control centers. The disorder's cause is unknown.

Both teams used the same gene therapy technology, inserting a desired gene into the common adeno-associated virus. AAV readily infects humans but has never been shown to cause disease.

One team, led by Dr. Matthew J. During of the Weill Cornell Medical Center in New York, used a gene that is the blueprint for an enzyme called glutamic acid decarboxylase. That enzyme converts chemicals in the cell into a neurotransmitter called GABA, which is essential for controlling muscle movements.

Earlier studies have shown that Parkinson's disease is marked by a deficiency of GABA in a part of the brain called the subthalamic nucleus. Injecting GABA into the brain can ease disease symptoms, but the neurotransmitter is quickly cleared, limiting its benefits.

During's team injected one side of the brains of 12 patients with one of three different concentrations of the gene therapy agent.

He told Tuesday's meeting of the Society for Neuroscience in Atlanta that all 12 patients had an improvement of at least 25% on a conventional scoring system used to assess the severity of Parkinson's symptoms, four of whom improved at least 37% and five others 40% to 65%.

The benefits have persisted for a year. Placebo benefits are usually transient, researchers noted.

Brain imaging showed an increase in metabolism on the side where patients received the gene therapy, and the amount of increase correlated with the degree of improvement in symptoms, During said.

The gene therapy agent was manufactured by Neurologix Inc. of Fort Lee, N.J., a company created by During and his colleagues to commercialize the technology. Neurologix paid for the study. During said the neurologists who assessed the patients' condition had no financial ties to the company.

The second study, led by Dr. William J. Marks Jr. of UC San Francisco, used the gene for a growth factor called neurturin, which is closely related to the better-known growth factor GDNF.

Studies have shown that injecting GDNF into the section of the brain known as the putamen can impede, and possibly reverse, the loss of dopaminesecreting cells.

Marks and his colleagues injected 12 Parkinson's patients with one of two doses of the gene therapy agent. Patients receiving the lower dose had a 40% decrease in Parkinson's symptoms, and those receiving the higher dose had a 50% reduction, he reported at last week's American Neurological Assn. meeting in Chicago. The researchers have monitored the patients for nine months.

"This is a clinically meaningful benefit that has been sustained over time," Marks said.

The gene therapy agent used by Marks was developed by Ceregene Inc. of San Diego. Marks said he had no financial ties to Ceregene.

The company paid for the trial with the Fox foundation. The foundation recently announced it would invest $1.9 million in a controlled trial of the approach.

I have been watching Neurologix especially for a long time, wish I had some spare cash to invest in them.

Really, (IMHO), gene therapy has to be our best bet, considering the "debate" over stem cells which will likely delay this treatment (forever !!). Gene therapy has had a 20 year maturation period and (hopefully) now is starting to live upto its promise.

I am hoping gene therapy / Spheramine is our ticket out of DBS, a one off injection, good to think if it works.

and Oxford Biomedica are hoping to kick off Prosavin imminently.

Some light on the horizon perhaps.

Take care,
Aftermathman.

have been following Neurologix www.neurologix.net with great interest for about a year or so. Ever since Neurologix first started their human trials on Parkinson patients with the development of their ten year Gene therapy research.

Dr Mat During commutes beween his home town of Auckland NZ and New York to carry out his valued research. Dr During's gene therapy research made headlines in these parts in 1995 when he cured two young children of a previous incurable devastating neurological disorder using a gene therapy technique he had perfected after years of research. (name escapes me what that neuro disorder was.)

It is no surprise that the results coming through now from Neurologix on the 12 Parki heros who have under gone treatment has been successful. Although there is plenty of caution attached to the latest findings, one cannot be excussed for being a little excited given Mat During's track record.

Science can now leap forward and carry on to the next development in gene therapy given the success of the human trials to date.

GO HARD SCIENCE aka Rationalist

Thanks for your replies. This IS exciting. Another good article about it:

http://www.cbsnews.com/stories/2006/...n2100621.shtml

the www.neurologix.net web site and intergrate the headlines on their home page. The latest news points to an interview by Wall Street dot net of Neurologix CEO John Mordock as he explains the exciting completion (and success) of Phase 2 Gene Therapy trials on 12 Parkinson's patients. And goes on to explain the start of Phase 3 trials beginning in the first quater of 07 which is expected to conclude in 18 months.

This is powerful stuff. A probable cure within two years via the technology of Gene Therapy, for 1.5 million Americans suffering the ills of Parkinson's, and a further 1 million in developed nations around the world.

Neurologix will have no competition once their G.T. trials are concluded. Any other human trials using stem cells (for instance) are seemingly years away.The Neurologix shares are a give away at .85 cents. A good time to triple double your money perhaps, by investing in a few Neurologix shares now. If this thing takes off, and indications appear more than favourable, Neurologix shares are going to make a lot of individuals plenty of spondulous (money) and satisfy 2 million plus individuals currently living the debilitating Parkinson's experience.

GO HARD SCIENCE



What is exciting about Neurologic's Gene Therapy research is the fact success in human trials are well advanced and commercialization for a cure for PARKINSON'S is but a nano second away.