UC San Diego-led team receives $ 9 million to advance treatments for Parkinson’s disease

Researchers around the world have tried in many ways, and for many years, to generate neurons in the laboratory in order to better study them. Neurons on demand could also provide a therapeutic option to replace neurons lost in neurodegenerative conditions, such as Parkinson’s disease. In June 2020, researchers at the University of California San Diego School of Medicine announced a milestone Towards that goal: With a dose of a new proto-drug, they were able to turn other types of cells directly into neurons, a feat that alleviated all of the symptoms of Parkinson’s disease in a mouse model.

Now, the UC San Diego-led team will receive a $ 9 million Aligning Science Across Parkinson (ASAP) grant to help advance this research and position it for the next phases of drug development. ASAP is a coordinated research initiative aimed at advancing basic research focused on Parkinson’s disease. Its mission is to accelerate the pace of discovery and light the path to a cure through collaboration, resources for research and data sharing. The Michael J. Fox Foundation for Parkinson’s Research is ASAP’s implementing partner and grant issuer, which contributes to the UC San Diego Campaign.

Top: Mouse brain before treatment, with dopamine-producing neurons shown in green. Bottom: Mouse brain after treatment with PTB antisense oligonucleotides, which convert supporting brain cells into dopamine-producing neurons (green).

Xiang-Dong Fu, PhD, distinguished professor of cellular and molecular medicine is the project’s principal investigator, with William C. Mobley, MD, PhD, distinguished professor of neuroscience; and Bing Ren, PhD, and Steve Dowdy, PhD, both professors of cellular and molecular medicine at UC San Diego School of Medicine. The team also includes researchers from the Chinese Academy of Sciences.

“This grant supports some of the most incredible advances in Parkinson’s disease. It’s a revolutionary strategy that we hope will improve the way Parkinson’s disease is treated, ”said David Brenner, MD, vice chancellor of health sciences. “We are grateful to ASAP for making these advances possible. “

The team’s work focuses on a protein called PTB, known to bind RNA and influence which genes are turned on or off in a cell. Their previous studies have shown that inhibiting the gene that encodes PTB turns several types of mouse cells directly into new neurons in lab boxes.

To inhibit PTB in living organisms, researchers developed a virus that carries an antisense oligonucleotide sequence – a piece of artificial DNA designed to specifically bind the RNA encoding PTB, thus preventing it from being translated into a functional protein and instead stimulating the development of neurons. The virus infects brain cells, but cannot be passed from injected mice to others.

Researchers have shown that a single treatment to inhibit PTB in mice converts native astrocytes, star-shaped support cells in the brain, into neurons that produce the neurotransmitter dopamine. The treatment restores normal dopamine levels in mice designed to mimic Parkinson’s disease. Physically, mice recover their motor function within three months of a single treatment and remain free from Parkinson’s symptoms for the rest of their lives.

Of course, mice aren’t humans, and the animal model used by the team doesn’t perfectly summarize all the essential features of Parkinson’s disease. But the study provides exciting proof of concept, they said.

With the support of ASAP, researchers will now be able to optimize their methods and test the methodology in other preclinical models. They also patented the PTB antisense oligonucleotide treatment in order to move forward to testing in clinical trials.

Parkinson’s disease is a brain disorder that gradually gets worse, causing tremors, difficulty in coordinating, and difficulty walking and speaking. The condition occurs when neurons in an area of ​​the brain that controls movement slowly stop working properly and die. Normally, these neurons produce a chemical in the brain called dopamine. When neurons are weakened, they produce less dopamine, which causes movement problems indicative of the disease.

Although there is currently no cure for Parkinson’s disease, certain medications and surgical treatments can relieve certain symptoms, such as drugs that increase dopamine levels or that therapeutically affect other chemicals in the brain.

Private support, like the ASAP grant, contributes to the Campaign for UC San Diego – a university-wide global fundraising effort ending in 2022. Along with philanthropic partners of the ‘UC San Diego, the university continues its non-traditional path towards revolutionary ideas, unexpected answers, vital discoveries and impact on the planet. Learn more about Campaign for UC San Diego.