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science on tHe cutting edge
ferocious heads, a potential them to develop rigid, tense muscles and tremors, and causes
Parkinson’s medicine created difficulties with sleep, mood, speech, eating and movement.
in the lab of chemist Matthew Commonly used treatments include drugs that replace the
Inspired By Greek Mythology, Disney, Ph.D., is also a type dopamine. Other treatments, such as deep-brain stimulation,
This Potential Drug Shows Promise of chimera bearing two heads. help with movement problems that develop as the disease
One seeks out a key piece of
worsens. But while these types of treatments alleviate
For Vanquishing Parkinson’s RNA Parkinson’s-causing RNA, symptoms, they are not a cure, come with side effects and do
not change the trajectory of the disease. An estimated 500,000
while the other goads the cell to
In Early Studies chop it to pieces for recycling. people in the United States live with Parkinson’s.
The research is described “To change the course of this disease, we need to address
A new discovery from in the Jan. 9 issue of the Matthew D. Disney, Ph.D., its cause. For many Parkinson’s patients, that apparent cause is
the lab of chemist Matthew Proceedings of the National is professor and chair of the the accumulation of a toxic protein called alpha-synuclein, in
Disney, Ph.D., at The Herbert Academy of Sciences, or Department of Chemistry and around their neurons,” said Disney, the endowed Institute
Wertheim UF Scripps Institute PNAS. at UF Scripps Biomedical Professor and chair of the chemistry department at The Herbert
for Biomedical Innovation & Parkinson’s is a frustrating Research. Photo by Scott Wertheim UF Scripps Institute for Biomedical Innovation &
Technology, takes its inspiration and all too common disease. Wiseman Technology in Jupiter, Fla.
from Greek mythology. The compound is a chimera, and it battles Sl o wl y, p e o p l e wi t h Unfortunately, alpha-synuclein has proven an especially
a toxic cause of Parkinson’s in two ways. Parkinson’s lose brain cells and other neurons needed to make challenging protein to medicate due to its unruly, disorganized
Like the Greek mythological beast with a snake’s tail and two the neurotransmitter dopamine. This progressive loss leads form and lack of clear druggable structures, Disney added.
“In situations like this, we have found that targeting the RNA
needed to build the toxic protein may be an optimal strategy to
slowing or even stopping disease progression,” he added.
Disney’s lab focuses on interfering with or degrading RNA
needed to assemble the proteins implicated in disease. This is
a relatively new concept. Most drugs on the market work by
binding to proteins to change their function. But not all disease-
causing proteins can be successfully targeted with drugs. Some
are too changeable, some lack druggable structures, some fold
in a way that conceals their active sites.
Disney’s approach is to prevent the problematic proteins
from being made in the first place. To do that requires targeting
their RNA. Here’s why: Proteins are assembled in cells through
a process that involves the reading and translation of a gene,
the transport of that information from the cell nucleus to its
cytoplasm via messenger RNA, and the assembly of protein-
building factories called ribosomes, also built of RNA, in the
cytoplasm. The ribosomes stitch the proteins together one
amino acid at a time. Disney’s potential Parkinson’s drug,
which he calls Syn-RiboTAC, binds to a section of messenger
RNA that tells a ribosome to start protein assembly. Without
the “start” signal, the toxic protein isn’t built.
Disney’s first authors on the PNAS study were graduate
students in his lab. Yuquan Tong is a current student of the
Skaggs Graduate School of Chemical and Biological Sciences
on the Jupiter campus, and Peiyuan Zhang, Ph.D., is a recent
graduate, now a postdoctoral researcher at the Massachusetts
Institute of Technology.
“In Parkinson’s mouse models, we see that reducing alpha-
synuclein by even 25 percent is therapeutically beneficial,”
Tong said. “In studies from induced neurons of Parkinson’s
patients, we see the Syn-RiboTAC strategy reduces alpha-
synuclein production by about 50 percent. We saw that adding
the RiboTAC produces a significant gain in potency.”
Disney added that the compound also showed good
selectivity, important for avoiding unwanted side effects, and
improved brain-barrier penetration relative to other compounds
they studied.
Other collaborators on the study included physician-
scientist M. Maral Mouradian, M.D., of Rutgers University,
whose patients donated tissue to create induced neurons.
Much work lies ahead, as the team works to refine the
two-headed drug and improve its drug-like properties,
the scientists said. Preparing an experimental compound
for clinical trials in humans can sometimes take years, as
refinements are made and data are gathered.
“The medical need for a truly disease-modifying treatment
is significant, and we know that patients are awaiting better
options,” Disney said. “We’re hopeful that we’re on the road
to better days for people living with Parkinson’s.”
The study, “Decreasing the intrinsically disordered protein
α-synuclein by targeting its structured mRNA with a ribonuclease
targeting chimera,”appears in the Jan. 9, 2024 issue of the Journal
Proceedings of the National Academy of Sciences. In addition to
Mouradian, Disney, Tong and Zhang, co-authors include Xueyi
Yang, Xiaohui Liu, Jie Zhang, Magda Grudniewska, Ikrak Jung,
Daniel Abegg, Jun Liu, Jessica L. Childs-Disney, Quentin M. R.
Gibaut, Hafeez S. Haniff and Alexander Adibekian.
The research was funded by grants from the National
Institutes of Health as well as foundations and private
donors. NIH grants include R21/R33NS096032 to M.M.M.
and M.D.D., plus R01GM097455, DP1NS096898 and
R35NS116846 to M.D.D. Other support was provided by the
Nelson Family Fund and Ed and Jane Greenberg. 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, and NIH
Grants R01NS101134, RF1NS130702, UG3/UH3NS116921,
R21NS123770 and R21AG075656.
Disney is a founder of Expansion Therapeutics and other
biotechnology companies.
Science On The Cutting Edge on page 22
