by Arlene Weintraub |
Jul 26, 2018 12:24pm
Cells that promote muscle
repair have a dark side—a tendency to change so radically that they actually
cause wasting and scarring rather than healing. A team led by Sanford Burnham
Prebys Medical Discovery Institute discovered this transformation in mouse models
of amyotrophic lateral sclerosis (ALS), spinal atrophy and spinal cord injury.
The discovery could inspire new ways of treating those and other neurological
conditions.
The muscle-repair cells
that the researchers zeroed in on are called fibro-adipogenic progenitors
(FAPs). By studying the mice, along with muscles from ALS patients, they found that FAPs activate a signaling
pathway called IL-6-STAT3, which in turn alerts the immune system to go
into overdrive, causing muscle wasting. When they blocked the pathway, the
muscle wasting stopped. They published the discovery in the journal Nature Cell
Biology.
Senior author Pier
Lorenzo Puri, M.D., called the characterization of FAPs a “critical step
forward” in the understanding of motor neuron diseases. "Now we can start
working on designing medicines that target these cells or possibly use them as
markers of disease progression, which can't come soon enough for patients and
their caregivers," said Puri, professor in the development, aging and
regeneration program at Sanford Burnham, in a statement.
Puri’s team made their
discovery by tracking many of the key players in muscle repair, including stem
cells and macrophages, which are immune cells that clean up debris. They found
that when muscles sustain acute injuries, FAPs show up after macrophages but
before stem cells, and they leave within about a week, when the muscle is well
on its way to recovery.
But when there is muscle
“denervation,” meaning a loss of neurons, FAPs gather in high numbers inside
muscles and never leave. The scientists could not find signs of macrophages or
muscle stem cells in denervation models. It was when they studied the odd FAPs
more closely that they found elevated levels of IL-6, an inflammatory protein
that promotes muscle atrophy.
Despite a history of
failed drug development in neurological disorders, the biopharma industry
continues to pursue new ideas, particularly in ALS. Just this week, Biogen
struck a $535 million dealwith AliveGen, for example, to develop
drugs for muscle-wasting disorders that block myostatin, which regulates muscle
function. And startup Aquinnah Pharmaceuticals is pursuing therapies for
neurodegenerative diseases that target stress granules that form in response to
injury.
Academic researchers are
progressing in their efforts to better understand the underpinnings of ALS and
other brain disorders. Scientists at Stanford announced earlier this year that
they used the gene-editing system CRISPR-Cas9 to discover a gene that can be
blocked in order to shield neurons from cell death.
The next step for Puri’s
team is to better characterize the IL-6-STAT3 pathway, to help promote the
development of medicines to target it. "Now that we have found a key
difference in these FAP cells, we have an opportunity to selectively remove the
bad, disease-causing cells, or convert the cells so they can repair nerves,” he
said.
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