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Gene Therapy Approach Targets Both Parkinson’s and Pediatric Neurotransmitter Disease

Gene Therapy Approach Targets Both Parkinson’s and Pediatric Neurotransmitter Disease

Last month, we reported on a novel partnership between biotech Genzyme and the University of California San Francisco (UCSF) on a gene therapy approach to treat Parkinson’s disease (PD).

In this project, UCSF Professor Krys Bankiewicz, MD, PhD, seeks to address the dopamine depletion common to PD by targeting an enzyme in the brain called aromatic L-amino acid decarboxylase, or AADC.

AADC is necessary to convert levodopa into dopamine. As dopamine neurons die off, the enzyme AADC also lessens. By getting more AADC into the right areas of the brain, it’s hoped, Parkinson’s patients taking levodopa might be able to lessen doses of the drug necessary for effect. Limiting doses of levodopa could, in turn, help to prevent the dyskinesias that are often a side effect of the drug. 

But while the Bankiewicz project has great potential for PD, it’s perhaps even more intriguing for a Pediatric Neurotransmitter Disease (PND) called AADC deficiency. In this disease, children as young as two years old experience parkinsonian-like symptoms such as rigidity, stiffness, and limb tremor. 

Currently, many children with PNDs (a class of various diseases) respond to levodopa treatment, explains Toni Pearson, MD, an advisor to the PND Association. However, those children with AADC deficiency do not respond to levodopa at all.

Here’s why: the AADC enzyme is what converts levodopa to dopamine in the brain, which in turn, can improve parkinsonian symptoms (this is the same process that happens for those with Parkinson’s who benefit from levodopa treatment). But without sufficient levels of AADC, dopamine levels are not improved. For this reason, the vast majority of children with AADC deficiency get no relief. 

Bankiewicz, however, is hopeful that this gene therapy approach could provide a viable option moving forward. “Basically, the wiring in the brain needed to make dopamine is intact in these children,” says Bankiewicz. “The cells that die in Parkinson’s that cause the motor symptoms of the disease still exist for these children, but these cells just don’t know how to produce dopamine, because they’re lacking AADC. But we think that delivering AADC into certain parts of the brain could inspire these cells to begin to make dopamine again.”

The therapeutic approach of the Bankiewicz gene therapy for AADC deficiency is much more straightforward than it is for Parkinson’s, which has many more aspects to the disease, he says. Still, there is enough overlap to inform how the treatment might be successful in PD as well. “It’s scary how similar these diseases are,” he says. 

AADC deficiency is an orphan disease; estimates place the number of children worldwide with the condition somewhere around 120. “The small numbers mean that these children have a limited voice when it comes to drug development,” says PND Association founder Nancy Speller, whose son J.J. died in 2005 at the age of 15 from complications of his underlying neurotransmitter disease. For this reason, Speller aims to advocate for her late son, and those living with these diseases today.

In one respect, the fact that AADC deficiency is classified as an orphan disease could help to speed the work being done by Bankiewicz’s team: With such a small population of people worldwide with the disease, later and larger clinical studies are impossible, and unethical. If a planned upcoming clinical study of 12 children proves safe and shows positive results, the therapy could be fast-tracked to go to market. Bankiewicz hopes the trial could launch sometime in early 2014, and in a best case scenario, it should open in several clinical centers in the U.S. and European Union, allowing for parallel patient recruitment.    

“This clinical trial could have major implications for developing new treatments for all PNDs moving forward,” says Pearson. “We are hopeful that it will be successful, and await these clinical results with much anticipation.” 

Stay tuned to this space for further updates into gene therapy approaches to treat PD, and AADC deficiency. To learn more about Pediatric Neurotransmitter Disease, visit the PND Association Web site.   


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