Featured Research

from universities, journals, and other organizations

Scientists Construct 'Off Switch' For Parkinson Therapy

Date:
August 29, 2009
Source:
University of Florida
Summary:
Addressing safety concerns related to potential gene therapies for Parkinson's disease, researchers at the have constructed a gene transfer therapy that can be inhibited with a common antibiotic. Experiments in rats show that the gene therapy product can be completely shut off, indicating for the first time that genes that have been irrevocably delivered to the brain to treat Parkinson's can be regulated.

A common antibiotic can function as an "off switch" for a gene therapy being developed for Parkinson's disease, according to University of Florida researchers writing online in advance of September's Molecular Therapy.

The discovery in rats answers an important question — how can new, therapeutic genes that have been irrevocably delivered to the human brain to treat Parkinson's be controlled if the genes unexpectedly start causing problems?

Meanwhile, in a review of Parkinson treatments, the researchers say that prior experimental attempts using growth factors — naturally occurring substances that cause cells to grow and divide — to rescue dying brain cells may have failed because they occurred too late in the course of the disease.

Together, the findings suggest that gene therapy to enable the brain to retain its ability to produce dopamine, a neurotransmitter that falls in critically short supply in Parkinson's patients, could be safely attempted during earlier stages of the disease with an added likelihood of success.

Parkinson's disease affects more than 1 million Americans, causing patients to gradually develop movement problems, including tremors, stiffness and slowness. It is caused by degeneration and death of nerve connections that produce dopamine, a substance necessary for communication between cells that coordinate movement.

"We have worked every day for 10 years to design a construct to the gene delivery vector that enhances the safety profile of gene transfer for Parkinson's disease," said Ronald Mandel, a professor of neuroscience at UF's McKnight Brain Institute and the Powell Gene Therapy Center. "With that added measure of safety, we believe we can intervene with gene transfer in patients at earlier stages of the disease. We strongly believe that trials to save dopamine-producing connections in patients with Parkinson's disease have failed because the therapy went into patients who were in the late stages of the disease and who had too few remaining dopamine-producing connections."

Often patients are given prescriptions for levodopa, or L-dopa, which is converted into dopamine by enzymes in the brain. But the treatment loses its effectiveness over time and does nothing to slow the disease's progression.

Meanwhile, trials in the United States to treat Parkinson's involving direct infusion of growth factors or the transplantation of genes that produce growth factors have had limited success, with some side effects.

Mandel's research group has concentrated on using an adeno-associated virus to engineer brain cells in animal models with genes that can protect dopamine-producing cells, which then do the vital work of producing GDNF, short for glial cell line-derived neurotrophic factor. The naturally occurring protein is important for the survival of dopamine-producing neurons during brain development, and a survival factor when given to adults.

In this case, scientists engineered the virus with two genes that must act in concert to produce the protein. But this precise interaction can be inhibited with dietary doxycycline, an antibiotic that is often prescribed in low doses to treat bacterial growth related to acne.

Depending on the amount of the antibiotic, protein production can be reduced or stopped, which would for the first time give medical investigators the ability to regulate gene therapy after the treatment was delivered.

"With this technique, you could adjust the therapy in the patient," said Fredric P. Manfredsson, a postdoctoral associate in UF's department of neuroscience. "That would be extremely helpful because no one is really certain yet what dosage is required for a protective effect in humans. The process is also much more sensitive than we had imagined it would be. GDNF production can be shut down completely with a dose of doxycycline that is much smaller than what is commonly prescribed."

Mandel said that adding the safety construct to the gene vector and proving its effectiveness were arduous tasks in which Manfredsson played an essential role.

A variety of methods were used to gauge GDNF production, but one was uncommon and involved the novel observation of the rats' weight. In prior research, the scientists had found delivering the protein to certain regions of the brain would hinder weight gain in younger rats and can cause weight loss in older rats. In the recent experiments, scientists found they could control the rate of weight gain in the rats with dietary doxycycline, which essentially verified they were controlling the GDNF therapy.

"The ability to control gene regulation is important for the future development of gene therapy, and optimizing its safe application to humans," said Dr. Mark Tuszynski, a professor of neurosciences and director of the Center for Neural Repair at the University of California, San Diego, who did not participate in the research. "The work of Dr. Mandel and colleagues brings us an important step closer to this goal."

The work was supported by the National Institute of Neurological Disorders and Stroke.


Story Source:

The above story is based on materials provided by University of Florida. Note: Materials may be edited for content and length.


Cite This Page:

University of Florida. "Scientists Construct 'Off Switch' For Parkinson Therapy." ScienceDaily. ScienceDaily, 29 August 2009. <www.sciencedaily.com/releases/2009/08/090828145707.htm>.
University of Florida. (2009, August 29). Scientists Construct 'Off Switch' For Parkinson Therapy. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2009/08/090828145707.htm
University of Florida. "Scientists Construct 'Off Switch' For Parkinson Therapy." ScienceDaily. www.sciencedaily.com/releases/2009/08/090828145707.htm (accessed July 31, 2014).

Share This




More Mind & Brain News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Dieting At A Young Age Might Lead To Harmful Health Habits

Dieting At A Young Age Might Lead To Harmful Health Habits

Newsy (July 30, 2014) Researchers say women who diet at a young age are at greater risk of developing harmful health habits, including eating disorders and alcohol abuse. Video provided by Newsy
Powered by NewsLook.com
It's Not Just Facebook: OKCupid Experiments With Users Too

It's Not Just Facebook: OKCupid Experiments With Users Too

Newsy (July 29, 2014) If you've been looking for love online, there's a chance somebody has been looking at how you're looking. Video provided by Newsy
Powered by NewsLook.com
How Your Face Can Leave A Good Or Bad First Impression

How Your Face Can Leave A Good Or Bad First Impression

Newsy (July 29, 2014) Researchers have found certain facial features can make us seem more attractive or trustworthy. Video provided by Newsy
Powered by NewsLook.com
Losing Sleep Leaves You Vulnerable To 'False Memories'

Losing Sleep Leaves You Vulnerable To 'False Memories'

Newsy (July 27, 2014) A new study shows sleep deprivation can make it harder for people to remember specific details of an event. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins