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UT Southwestern Team Uncovers Role of miRNA in Slowing ALS Progression

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By Doug Macron

A team of investigators led by University of Texas Southwestern Medical Center researcher Eric Olson published a paper this week showing that a specific microRNA plays a role in the regeneration of damaged neuromuscular synapses and can slow the progression of amyotrophic lateral sclerosis in a mouse model.

Based on these and other findings, miRNA drug developer Miragen Therapeutics, which Olson co-founded, is advancing a program in ALS, having already licensed the relevant intellectual property from UTSWMC, according to Miragen President and CEO Bill Marshall.

Still, the work is early-stage, Marshall told RNAi News, and the company is unlikely to move it forward in any significant way unless it can find a partner "with an intense focus in the therapeutic area."

"We have a strong interest [in Olson's ALS work] because it's muscle-specific, but realistically, we need to keep our focus on the clinical indications we can move forward," namely post-myocardial infarction remodeling and chronic heart failure, he noted.

Nonetheless, Miragen views Olson's findings as "a breakthrough with significant implications for human health," Marshall said in a statement.

According to Olson's paper, which appeared in the online edition of Science, the decision to investigate whether ALS progression was accompanied by changes in miRNA expression stemmed from recent studies implicating the small, non-coding RNAs in muscle stress responses.

Of 320 miRNAs they tested, the team found that one, miR-206, was "the most dramatically up-regulated" in the muscles of ALS mice, coinciding with the onset of neurological symptoms. And "because ALS leads to denervation of skeletal muscle, we determined whether miR-206 up-regulation was a consequence of denervation," they wrote.

"Indeed, 10 days after severing the sciatic nerve of wild-type mice to denervate lower leg muscles, levels of mature and primary miR-206 transcripts were robustly increased," the researchers noted. Meanwhile, miR-206 inactivation in ALS mice accelerated disease progression and reduced survival, although it did not affect disease onset, suggesting that the miRNA "counteracts, albeit ultimately unsuccessfully, the pathogenesis of ALS."

Further analysis revealed that inactivation of miR-206 in normal adult mice "profoundly influenced" the formation of new neuromuscular junctions following nerve injury that denervates muscle, according to the Science paper.

"Three weeks after surgical denervation, both wild-type and [miR-206-deficient] mice exhibited similar degrees of muscle atrophy, but reinnervation of denervated muscles by motor axons was delayed in the absence" of the miRNA, Olson's team wrote.

For the wild-type mice, reinnveration began between two and three weeks following the nerve cut and was nearly complete at week five. By comparison, reinnervation of muscle in the miR-206-deficient mice did not start until week three and remained slow for at least two more weeks.

At the same time, reinnervation that did occur in the mice lacking miR-206 was often defective, "suggesting a possible lack of 'stop and differentiate' signals emanating from the muscles," according to the paper.

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"The role of miR-206 in reinnervation after nerve damage may explain its salutary function in ALS," the team noted. "As motor neurons die in ALS, denervated muscle fibers are reinnervated by the axon branches of the surviving motor neurons. Compensatory reinnervation may account for the clinical observations that ALS is nearly asymptomatic in humans until a large fraction of motor neurons have died, at which point the few remaining ones cannot sufficiently compensate."

Looking to discover just how miR-206 promotes this "partially successful compensatory response to denervation," the investigators turned their attention to histone deacetylase 4, which is a predicted target of the miRNA and has been implicated in the control of neuromuscular gene expression.

"Using reporter constructs, we showed that miR-206 represses HDAC4 translation," they wrote. "Moreover, HDAC4 protein expression was increased in skeletal muscle of [miR-206 deficient] animals as compared with that of wild-type controls after denervation."

Aiming to see if HDAC4 acts antagonistically to miR-206, as predicted for a miRNA target, Olson and his colleagues generated mice in which the gene's messenger was selectively deleted in skeletal muscle.

"Neuromuscular junctions formed and matured normally in the absence of HDAC4, but mutant muscles were reinnervated more rapidly than those of controls after nerve crush or cut, a phenotype opposite" of miR-206-deficient mice.

"These findings suggest that miR-206 functions to counteract the negative influence of HDAC4 on reinnervation after injury," they wrote. Further experimentation indicated that this occurs via opposing effects on fibroblast growth factor binding protein 1, which is a regulator of synapse formation that is down-regulated in muscles of miR-206-deficient mice and up-regulated in the muscles of mice lacking HDAC4 following denervation.

"Our results reveal miR-206 as a modifier of ALS pathogenesis and suggest that the salutary actions of miR-206 are mediated by muscle-derived factors that promote nerve-muscle interactions in response to motor neuron injury," the investigators concluded. The data further suggest "opportunities for intervention through the modulation of miR-206 or the downstream pathways it regulates."

Olson is a co-founder of Miragen Therapeutics, which is developing miRNA drugs for a variety of cardiovascular and muscle diseases, including ALS.

In an accompanying article in Science, University of Massachusetts Medical School professor and noted ALS researcher Robert Brown noted that the findings "support a growing body of literature documenting that variants in [miRNAs] and their binding sites modify neurological function and influence disease susceptibility."

The report in Science also "encourages the screening of both [miRNAs] and their target binding sites for DNA variants that influence the pathogenesis of a wide array of disorders," Brown wrote.

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