Glial cell derived neurotrophic factor structure (credit: Wikimedia Commons)

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A noninvasive avenue for Parkinson’s disease gene therapy

April 26, 2013

Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms.

The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain.

Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time.

Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.

The focus of Dr. Barbara Waszczak‘s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells.

Bypassing the blood-brain barrier

Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain.

To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.

Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF).

When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing.

Now, in new research presented at Experimental Biology 2013 in Boston, Harmon reported that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.

Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain.

This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.

Researchers at the Harvard Stem Cell Institute (HSCI) have discovered a hormone that holds promise for a dramatically more effective treatment of type 2 diabetes, a metabolic illness afflicting an estimated 26 million Americans.

The researchers believe that the hormone might also have a role in treating type 1, or juvenile, diabetes.

The work was published by the journal Cell.

The hormone, called betatrophin, causes mice to produce insulin-secreting pancreatic beta cells at up to 30 times the normal rate. The new beta cells only produce insulin when called for by the body, offering the potential for the natural regulation of insulin and a great reduction in the complications associated with diabetes, the leading medical cause of amputations and non-genetic loss of vision.

The researchers who discovered betatrophin, HSCI co-director Doug Melton and postdoctoral fellow Peng Yi, caution that much work remains to be done before it could be used as a treatment in humans. But the results of their work, which was supported in large part by a federal research grant, already have attracted the attention of drug manufacturers.

“If this could be used in people,” said Melton, Harvard’s Xander University Professor and co-chair of the University’s Department of Stem Cell and Regenerative Biology, “it could eventually mean that instead of taking insulin injections three times a day, you might take an injection of this hormone once a week or once a month, or in the best case maybe even once a year.”

Type 2 diabetes, a disease associated with the national obesity epidemic, is usually caused by a combination of excess weight and lack of exercise. It causes patients to slowly lose beta cells and the ability to produce adequate insulin. One recent study has estimated that diabetes treatment and complications cost the United States $218 billion annually, or about 10 percent of the nation’s entire health bill.

“Our idea here is relatively simple,” Melton said. “We would provide this hormone, the type 2 diabetic will make more of their own insulin-producing cells, and this will slow down, if not stop, the progression of their diabetes. I’ve never seen any treatment that causes such an enormous leap in beta cell replication.”

References:

• Peng Yi, Ji-Sun Park, Douglas A. Melton, Betatrophin: A Hormone that Controls Pancreatic β Cell Proliferation, Cell, 2013, DOI: 10.1016/j.cell.2013.04.008