New MJFF grant to fund lab studies of one-time Parkinson’s gene therapy
US developer hopes research results will lead to trials in humans
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- The Michael J. Fox Foundation for Parkinson's Research is funding preclinical studies of a one-time gene therapy candidate .
- The experimental therapy from Shape Therapeutics aims to target toxic alpha-synuclein protein clumps in the brain.
- These lab studies could support regulatory submissions that would allow human testing of the gene therapy.
New funding from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) will support lab studies of a one-time gene therapy candidate for Parkinson’s disease.
Shape Therapeutics, a U.S. company that investigates RNA-based therapies, will use the newly awarded research grant to conduct preclinical studies of its experimental gene therapy SHP-201. These animal studies could support an investigational new drug (IND) submission to U.S. regulators. If accepted, an IND would allow Shape to begin clinical trials testing the treatment in humans.
“We are delighted to receive this support from MJFF, which will significantly help us advance SHP-201 and contribute to the development of new therapeutic strategies for Parkinson’s disease,” Adrian Briggs, PhD, chief technology officer of Shape Therapeutics, said in a company press release announcing the award. The amount of the grant was not disclosed.
Now, “with MJFF’s support,” the company is planning pharmacology and toxicology studies of SHP-201, and will test the treatment across a range of doses to determine which one to use in potential future clinical trials, per the release.
A progressive neurological condition, Parkinson’s is marked by both motor and nonmotor symptoms. These occur due to the death of nerve cells that produce the chemical messenger dopamine, which plays vital roles in a variety of brain functions. Still, researchers do not understand precisely why dopamine-producing cells begin to die.
Gene therapy targets protein clumps underlying Parkinson’s
One hypothesis about these underlying causes focuses on toxic protein clumps in the brain. These aggregates, a hallmark feature of Parkinson’s, contain a protein called alpha-synuclein, which is thought to contribute to ongoing disease processes.
According to Shalini Padmanabhan, PhD, senior vice president and head of translational research at MJFF, “alpha-synuclein remains one of the most important therapeutic targets in Parkinson’s disease, but significant challenges remain in delivering potential therapies broadly and effectively throughout the brain.”
There are three notable challenges that make targeting alpha-synuclein especially difficult. First, medications would need to cross the blood-brain barrier, a semipermeable protective membrane that separates the circulatory system from the nervous system. Next, any therapies making it that far would then need to reach areas deep in the brain — where many of the neurological changes in Parkinson’s get their start.
Once a treatment reaches these targets, it would need to durably reduce alpha-synuclein aggregates or disrupt the protein’s production.
Alpha-synuclein remains one of the most important therapeutic targets in Parkinson’s disease, but significant challenges remain in delivering potential therapies broadly and effectively throughout the brain.
SHP-201’s design aims to overcome these challenges with a one-time dose. It is a gene editing therapy that targets SNCA RNA, a piece of genetic code that cells use to build alpha-synuclein. By altering the RNA sequence, SHP-201 can lower alpha-synuclein production, which could then reduce protein buildup.
Using a specially engineered adeno-associated virus, or AAV, SHP-201 can cross the blood-brain barrier and reach the target brain areas. The AAV is designed so as not to cause disease in humans.
To complete the gene editing in the target areas, the AAV carries medication that uses Shape’s proprietary RNAfix technology. This alters SNCA RNA while leaving the DNA, which contains the genetic blueprint for the alpha-synuclein protein, unchanged. Researchers believe that when cells attempt to use the edited RNA to build alpha-synuclein, the process will be less effective, reducing protein production.
In early animal studies, a single intravenous, or into-the-vein, infusion of SHP-201 led to durable decreases in alpha-synuclein production. It was most active in the deep brain regions that it was designed to target.
The MJFF grant will support additional preclinical studies of the candidate therapy, designed to enable an IND. These will include studies of SHP-201’s effects on the body, or its pharmacology, as well as its movement into and through the body, called pharmacokinetics. Shape researchers will test SHP-201 at various doses to select an appropriate dose for potential clinical trials.
Shape received the grant as part of MJFF’s Therapeutics Pipeline Program. By supporting late preclinical and early clinical studies of investigational medications and nondrug therapies, this program aims to de-risk the development of therapies for Parkinson’s. In addition to funding, it connects developers to MJFF’s network of resources.
“The studies supported through this award will generate important translational data that may help evaluate this approach and inform the broader field of alpha-synuclein-targeted therapeutic development,” Padmanabhan said.
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