PNAS: RNA-targeted strategies repair genetic causes of amyotrophic lateral sclerosis and dementia

Scientists at the Scripps Biomedical Research Center at the University of Florida have developed a potential drug to treat the main causes of ALS and dementia, which works
by eliminating disease-causing RNA fragments.
In the lab, the compound restored the health of neurons and saved mice
with the disease.

This week's issue of Science magazine describes the potential drug, said lead inventor Dr.
Matthew Disney, chair of the Scripps chemistry department at the University of Florida, which was designed in pill or injectable form
.
Importantly, experiments have shown that the compound is small enough to cross the blood-brain barrier, a barrier that no other method can overcome, he said
.

Amyotrophic lateral sclerosis (ALS) progressively destroys the neurons that control muscles, leading to increased muscle wasting and eventually death
.
This mutation is the main cause of inherited ALS and is known as "C9 Open Reading Box 72," or C9orf72
.
The mutation can also lead to a form of frontotemporal dementia, a brain disorder that causes the frontal and temporal lobes of the brain to atrophy, leading to changes in personality, behavior and language, and ultimately death
.

The C9orf72 mutation is characterized by the enlargement of the 6 "letters" of the genetic code GGGGCC on chromosome 9, which can be repeated 65 to tens of thousands of times
.
When this mutated RNA appears, it leads to the production of toxic proteins that disease the affected neurons and eventually die
.
The compound, developed by Disney Labs, targets RNA that carries these genetic instructions, preventing toxic proteins from assembling
in cells.

"This compound eliminates disease-causing RNA by binding and utilizing natural cellular processes, reminding the cell's degradation machinery to dispose of it as waste," Disney said
.

He added that it is conceivable that this approach could be used for other untreatable neurological diseases where toxic RNA plays a role
.

The paper's first author is Jessica Bush, a graduate student at the University of Florida's Scripps Graduate School of Chemical and Biological Sciences who works
in Disney's lab.
Other co-authors include Leonard Petrucelli, Ph.
D.
, and Raphael Benhamou of the Jacksonville Mayo Clinic, a former postdoctoral fellow at Disney Labs who now teaches
at the Hebrew University of Jerusalem.

"This was identified on a large screen from the compound of the Calibr Library at the Scripps Research Center, which consists of
11,000 drug-like molecules," Bush said.

From the initial screening, they identified 69 compounds
that inhibit the translation of toxic C9 mutations.
They then further refined the compounds, removing those that could not cross the blood-brain barrier based on size, weight, structure and other factors
.
The result was 16 candidate compounds, one of which was selected for further refinement
based on its potency and structural simplicity.

"A series of tests on neurons and in vivo models of amyotrophic lateral sclerosis patients showed that compound 1 selectively binds tightly to toxic RNA, forcing it to be degraded
in the body's own natural processes," Bush said.

Patients treated for amyotrophic lateral sclerosis at the Neurodegenerative Research Laboratory at the Johns Hopkins University School of Medicine donated skin samples for the study
.
These skin cells are genetically reduced to stem cells, after which Disney's team processes the cells for several months to develop into neurons
.

"We evaluated using cells from four different patients, all of which showed a dose-dependent reduction in known amyotrophic lateral sclerosis markers without off-target effects
," Bush said.

They also tested the compound in mice with the C9orf72 mutation and exhibited typical amyotrophic lateral sclerosis (ALS) behavior and blood markers
.
The mice were treated daily for two weeks, after which their disease markers were significantly reduced and their health improved
.

Disney said the next step will be to further investigate the compound's effects
on cell health and rodent models of C9 ALS.
He said the evidence so far suggests that this approach represents a significant advance
in RNA drug discovery.

Disney said: "We have shown for the first time that you can make molecules that penetrate the brain and eliminate toxic genetic products
.
" "We highlighted this in amyotrophic lateral sclerosis (ALS), suggesting that this can be a universal treatment for other neurological disorders, including Huntington's disease, muscular dystrophy, etc
.
"