In a new study, researchers administered a single injection to tissues surrounding the spinal cords of paralyzed mice. Just four weeks later, the animals regained the ability to walk.
The research will be published in the Nov. 12 issue of
the journal Science.
By sending bioactive signals to trigger cells to
repair and regenerate, the breakthrough therapy dramatically improved severely
injured spinal cords in five key ways: (1) The severed extensions of neurons,
called axons, regenerated; (2) scar tissue, which can create a physical barrier
to regeneration and repair, significantly diminished; (3) myelin, the
insulating layer of axons that is important in transmitting electrical signals
efficiently, reformed around cells; (4) functional blood vessels formed to deliver
nutrients to cells at the injury site; and (5) more motor neurons survived.
After the therapy performs its function, the materials
biodegrade into nutrients for the cells within 12 weeks and then completely
disappear from the body without noticeable side effects. This is the first
study in which researchers controlled the collective motion of molecules
through changes in chemical structure to increase a therapeutic’s efficacy.
“Our research aims to find a therapy that can prevent
individuals from becoming paralyzed after major trauma or disease,” said
Northwestern’s Samuel I. Stupp, who led the study. “For decades, this has
remained a major challenge for scientists because our body’s central nervous
system, which includes the brain and spinal cord, does not have any significant
capacity to repair itself after injury or after the onset of a degenerative
disease. We are going straight to the FDA to start the process of getting this
new therapy approved for use in human patients, who currently have very few
treatment options.”
Stupp is Board of Trustees Professor of Materials
Science and Engineering, Chemistry, Medicine and Biomedical Engineering at
Northwestern, where he is founding director of the Simpson Querrey Institute
for BioNanotechnology (SQI) and its affiliated research center, the Center for
Regenerative Nanomedicine. He has appointments in the McCormick School of
Engineering, Weinberg College of Arts and Sciences and Feinberg School of
Medicine.
Life expectancy has
not improved since the 1980s
According to the National Spinal Cord Injury
Statistical Center, nearly 300,000 people are currently living with a spinal
cord injury in the United States. Life for these patients can be
extraordinarily difficult. Less than 3% of people with complete injury ever
recover basic physical functions. And approximately 30% are re-hospitalized at
least once during any given year after the initial injury, costing millions of
dollars in average lifetime health care costs per patient. Life expectancy for
people with spinal cord injuries is significantly lower than people without
spinal cord injuries and has not improved since the 1980s.
“Currently, there are no therapeutics that trigger
spinal cord regeneration,” said Stupp, an expert in regenerative medicine. “I
wanted to make a difference on the outcomes of spinal cord injury and to tackle
this problem, given the tremendous impact it could have on the lives of
patients. Also, new science to address spinal cord injury could have impact on
strategies for neurodegenerative diseases and stroke.”
‘Dancing molecules’
hit moving targets
The secret behind Stupp’s new breakthrough therapeutic
is tuning the motion of molecules, so they can find and properly engage
constantly moving cellular receptors. Injected as a liquid, the therapy
immediately gels into a complex network of nanofibers that mimic the
extracellular matrix of the spinal cord. By matching the matrix’s structure,
mimicking the motion of biological molecules and incorporating signals for
receptors, the synthetic materials are able to communicate with cells.
“Receptors in neurons and other cells constantly move
around,” Stupp said. “The key innovation in our research, which has never been
done before, is to control the collective motion of more than 100,000 molecules
within our nanofibers. By making the molecules move, ‘dance’ or even leap
temporarily out of these structures, known as supramolecular polymers, they are
able to connect more effectively with receptors.”
Stupp and his team found that fine-tuning the molecules’
motion within the nanofiber network to make them more agile resulted in greater
therapeutic efficacy in paralyzed mice. They also confirmed that formulations
of their therapy with enhanced molecular motion performed better during in
vitro tests with human cells, indicating increased bioactivity and cellular
signaling.
“Given that cells themselves and their receptors are
in constant motion, you can imagine that molecules moving more rapidly would
encounter these receptors more often,” Stupp said. “If the molecules are
sluggish and not as ‘social,’ they may never come into contact with the cells.”
One injection, two
signals
Once connected to the receptors, the moving molecules
trigger two cascading signals, both of which are critical to spinal cord repair.
One signal prompts the long tails of neurons in the spinal cord, called axons,
to regenerate. Similar to electrical cables, axons send signals between the
brain and the rest of the body. Severing or damaging axons can result in the
loss of feeling in the body or even paralysis. Repairing axons, on the other
hand, increases communication between the body and brain.
The second signal helps neurons survive after injury
because it causes other cell types to proliferate, promoting the regrowth of
lost blood vessels that feed neurons and critical cells for tissue repair. The
therapy also induces myelin to rebuild around axons and reduces glial scarring,
which acts as a physical barrier that prevents the spinal cord from healing.
“The signals used in the study mimic the natural
proteins that are needed to induce the desired biological responses. However,
proteins have extremely short half-lives and are expensive to produce,” said
Zaida Álvarez, the study’s first author and former research assistant professor
in Stupp’s laboratory. “Our synthetic signals are short, modified peptides that
— when bonded together by the thousands — will survive for weeks to deliver
bioactivity. The end result is a therapy that is less expensive to produce and
lasts much longer.”
Universal application
While the new therapy could be used to prevent
paralysis after major trauma (automobile accidents, falls, sports accidents and
gunshot wounds) as well as from diseases, Stupp believes the underlying
discovery — that “supramolecular motion” is a key factor in bioactivity — can
be applied to other therapies and targets.
“The central nervous system tissues we have
successfully regenerated in the injured spinal cord are similar to those in the
brain affected by stroke and neurodegenerative diseases, such as ALS,
Parkinson’s disease and Alzheimer’s disease,” Stupp said. “Beyond that, our
fundamental discovery about controlling the motion of molecular assemblies to
enhance cell signaling could be applied universally across biomedical targets.”
Journal article: https://www.science.org/doi/10.1126/science.abh3602
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