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RNA-targeting strategy successfully blocks a vexing driver of Parkinson’s disease

JUPITER, FLA — Scientists at Scripps Research have developed a drug-like compound that selectively prevents production of the protein underlying most causes of Parkinson’s disease, alpha-synuclein.

The study underscores the untapped potential of addressing diseases mediated by “undruggable” proteins via the messenger RNAs that encode them.

Published on Jan. 3 in Proceedings of the National Academies of Sciences, the study is authored by Scripps Research chemistry professor Matthew D. Disney, PhD, graduate student Peiyuan Zhang, and their colleagues.

If DNA serves as the code of life, genes within DNA provide the code for specific proteins. For a gene to actually encode a protein, however, it must first be transcribed with the help of messenger RNA. The messenger RNA serves as a template for protein production, a process called translation, which is orchestrated by molecular machines called ribosomes.

Disney’s alpha-synuclein compound, which he named synucleozid, stops the ribosome from detecting the messenger RNA template, thus preventing the translation or “printing” of the alpha-synuclein protein. The Scripps Research team collaborated on the study with a team from Rutgers University led by M. Maral Mouradian, MD, director of the Institute for Neurological Therapeutics.

“We showed not only that we can inhibit the translation of alpha-synuclein, which is an important protein in Parkinson’s disease and dementia, but also that this compound can stop its messenger RNA from being recognized by a ribosome,” Disney says. “In other words, the compound doesn’t allow the messenger RNA to be made into the alpha-synuclein protein. We believe this unique mechanism is broadly applicable.”

Disney has spent more than a decade building technologies capable of identifying drug-like compounds to do this. A system he invented called “Inforna” computationally uses genetic sequence to predict complementary small molecule-RNA interactions.

Most drugs on the market work by binding to problematic proteins to limit their ability to cause harm. However, for a drug to bind, those proteins must have stable structures with favorable binding pockets.

The alpha-synuclein protein is one example of many  in the genome that have confounded scientists’ efforts to bind with medications, due to their undefined structure.

In fact, the so-called “druggable genome” is currently comprised of only about 3,000 genes out of an estimated 20,000 protein-coding genes. Disney says his research suggests that many undruggable proteins are transcribed by RNA that do have stable structures, meaning the RNA should be druggable, offering an effective workaround.

“We are applying this across a number of disease indications, with our priority being applying these approaches to the diseases that have the most urgent medical need,” Disney says.

Parkinson’s disease is clearly among them. With an estimated 1 million people in the United States alone living with the condition, at an estimated cost of over $50 billion annually, Parkinson’s causes chronic, progressive disability due to the death of dopamine-producing cells in the brain. The symptoms may include slowness of movements, impaired coordination, limb and trunk stiffness, tremor, and eventually dementia and psychiatric manifestations.

Symptoms emerge as the alpha-synuclein protein accumulates in brain cells, misfolding and aggregating to form clumps called Lewy bodies and Lewy neurites. Certain forms of these aggregates are toxic and eventually lead to the cell’s death.

Mouradian says down-regulating production of alpha-synuclein may have therapeutic promise.

“The precise molecular mechanisms driving Parkinson’s disease remain to be fully elucidated. However, the amount of alpha-synuclein protein levels is an important factor in its pathologic misfolding and aggregation, initiating a cascade of events that lead to neuronal damage and Parkinson’s symptoms,” Mouradian says. “Therefore, it stands to reason that reducing the amount of alpha-synuclein protein can mitigate this disease-causing cascade, and slow down or stop disease progression. Identification of this alpha-synuclein messenger RNA-targeting probe will enable us to evaluate the therapeutic value of reducing alpha-synuclein production in patients.”

Many people with Parkinson’s respond for a time to therapeutics that include dopamine replacement. But adding back dopamine doesn’t protect the nervous system from the progressively worsening disease process, and introduces its own set of sometimes serious side-effects.

“We wanted to see if we could inhibit this protein from even being made by targeting the messenger RNA that encodes it,” Disney says.

The benefit of choosing a small molecule to do this rather than an RNA-binding oligonucleotide is that a therapeutic agent must be very, very small to cross the blood-brain barrier. It must also be selective, and apparently these starting compounds are selective.

“We found the molecule was very selective at the RNA level. We also studied the effects at the protein level, and the molecule was also selective on that level,” Disney says.

But Disney notes that this is a proof-of-concept study, and that a long road lies ahead before Synucleozid might become a Parkinson’s drug candidate that can move into clinical trials in humans.

“We are just at the beginning here, and there is much work to do” Disney says. “We are showing that if you can inhibit a protein from being made, that may be advantageous over waiting to address its role in disease until after it is already made.”

The study, “Translation of the intrinsically disordered protein alpha-synuclein is inhibited by a small molecule targeting its structured mRNA,” is published in the Proceedings of the National Academies of Sciences the week of Dec. 30. Besides Disney and Zhang, authors include Hye-Jin Park, Jie Zhang, Eunsung Junn and M. Maral Mouradian of Rutgers Robert Wood Johnson Medical School, and Ryan Andrews, Sai Pradeep Velagapudi, Daniel Abegg, Kamalakannan Vishnu, Matthew Costales, Jessica Childs-Disney, and Alexander Adibekian of Scripps Research, along with Walter Moss of Iowa State University.

This work was funded by NIH Grants NS096032 (to M.M.M. and M.D.D.), GM97455 (to M.D.D.), and NS096898 (to M.D.D.). Additionally, M.M.M. is the William Dow Lovett Professor of Neurology and is supported by the Michael J. Fox Foundation for Parkinson’s Research, American Parkinson Disease Association, New Jersey Health Foundation, and NIH Grants AT006868, NS073994, and NS101134. E.J. is supported by NIH Grants NS070898 and NS095003 and by the State of New Jersey. Support to the Disney lab from the Nelson Family Fund also aided the research.