Stem cell-derived vesicles show promise for SMA in mouse model
Tiny carriers of cellular cargo called extracellular vesicles (EVs) — isolated from stem cells found in fat tissue — improved motor performance and slowed motor nerve cell degeneration in a mouse model of spinal muscular atrophy (SMA), according to recent research.
Researchers believe these so-called ASC-EVs may offer the same therapeutic benefits as their parent cells, especially when used in combination with existing SMA therapies, while avoiding some of the safety concerns that surround stem cell therapy.
“Our results could encourage the use of ASC-EVs as a therapeutic combinatorial treatment for SMA, bypassing the controversial use of stem cells,” researchers wrote.
The study, “Administration of adipose-derived stem cells extracellular vesicles in a murine model of spinal muscular atrophy: effects of a new potential therapeutic strategy,” was published in the journal Stem Cell Research & Therapy.
In SMA, the lack of the SMN protein causes the progressive and irreversible loss of specialized nerve cells that communicate with muscles to coordinate voluntary movements. The loss of these cells, called lower motor neurons, drives SMA’s hallmark symptoms of muscle weakness and wasting.
Approved SMA therapies show ‘impressive … yet limited effect’
Approved SMA therapies are designed in different ways to increase SMN production to slow disease progression. Such treatments show “an impressive … yet limited effect,” the researchers wrote.
“Complementary SMN-independent strategies could be needed to address irreversible degenerative processes,” they noted.
Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for various neurodegenerative diseases. These unique, self-renewing cells have the ability to migrate to damaged tissues and stimulate regenerative processes.
MSCs can be isolated from a variety of different body tissues. Large amounts can be easily obtained from adipose, or fat, tissue, and thus could show promise for treating human disease. Indeed, adipose-derived MSCs, or ASCs, have shown the ability to improve motor neuron health in young SMA patients.
However, there are challenges to MSC-based treatments, including the risk for immune rejection after they’re transplanted, or the possibility that cancer could develop from their uncontrolled growth.
Mesenchymal stem cells exert reparative functions via extracellular vesicles
Research generally indicates MSCs exert their reparative functions via EVs. These tiny carriers are released from MSCs and act on nearby cells by releasing their neuroprotective and anti-inflammatory cargo.
Using the EVs, rather than the MSCs themselves, could offer a way of achieving the therapeutic benefits that MSCs provide, while avoiding some of the risks associated with a cell-based therapy. This approach has shown promise in models of other neurodegenerative diseases, according to the team.
In the study, researchers investigated whether the same approach might be of benefit in SMA. They isolated ASC-EVs from healthy mice and administered them to a mouse model of severe SMA via two injections given directly into the fluid-filled cavities of the brain during their first week of life.
EVs were well tolerated and had beneficial effects on SMA progression in these young animals, with treated animals showing improved motor performance relative to mice that were not treated. Yet, improvements in motor performance failed to put treated animals at the level of healthy mice.
Notably, EV treatment also delayed the degeneration of motor neurons in the spinal cord, which was accompanied by lower levels of proteins associated with cell death pathways. Markers of neuroinflammation in the spinal cord were also reduced with treatment.
Treatment led to partially protective effects against muscle atrophy
EV treatment in the SMA mouse model led to some partially protective effects against muscle atrophy and on the health of the neuromuscular junction, which is the region where nerve cells and muscles communicate to coordinate movements. However, these effects were overall not as robust as the influence of the treatment on nerve cells.
Taken together, “ASC-EVs seem to be promising candidates for SMA therapy, possibly in combination with SMN-dependent drugs to boost their effects,” the researchers wrote.
They noted that the exact protective mechanisms of the EVs in SMA “remain to be better clarified,” which could be the focus of future research.
When thinking about applying the same approach to humans, scientists also acknowledged that direct brain administration is invasive and may not be ideal.
Administration of therapeutics directly into the nose via drops or a spray, which is known as intranasal administration, has shown promise in various neurodegenerative diseases and could be an option for delivering EVs to the nervous system “in a tolerable and easy way,” the researchers wrote.
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