The National Institutes of Health last month awarded nearly $850,000 in grants to fund research into microRNA-based treatments for neurological, catabolic, and viral disorders.
The first grant was awarded to Washington University's Timothy Miller to support his work on an miRNA-therapy for amyotrophic lateral sclerosis.
Miller, who is collaborating with Isis Pharmaceuticals on the phase I antisense drug ISIS-SOD1Rx for ALS, and his colleagues have identified changes in miRNA expression in both animal models and patients with the disease. With the NIH funding, they aim to validate one specific miRNA as a therapeutic target.
“We hypothesize that inhibition of this miRNA will substantially slow ALS in animal models,” he wrote in the grant's abstract. “Given our current experience in [a] phase I trial using antisense oligonucleotides in ALS patients, we intend to translate our findings from this grant to a novel therapeutic for ALS.
“In addition, we are pioneering the use of antisense oligonucleotide inhibitors of miRNA in the brain and spinal cord, a technology that may have therapeutic implications for many neurological disorders,” he added.
Miller's research project began on April 15 and runs until the end of February 2017. It is worth $332,500 in its first year.
The second grant went to Emory University's Xiaonan Wang, who is investigating the role of miR-29 in muscle-wasting conditions.
According to the grant's abstract, she and her colleagues have found that accelerated muscle protein degradation in patients with chronic kidney disease “is due to an increase in muscle protein degradation and a decrease in muscle regeneration.” Further, chronic kidney disease has been associated with a “sharp increase” in collagen deposition and fibrosis in regenerating muscles of mice.
These three hallmarks of kidney disease — protein degradation, regeneration and fibrosis — have been tied to down-regulation of miR-29, and Wang aims to determine if the miRNA plays a major role in the loss of muscle in mouse models of chronic kidney disease, the abstract states.
Then, her team plans to see if an increase in miR-29 promotes muscle cell differentiation and prevents fibrosis by down-regulation of the protein YY1, which inhibits such differentiation, and collagens in the animals.
“We anticipate finding that in normal animals, miR-29 regulates PTEN, [which is associated with cell growth inhibition], YY1, and multiple collagens by directly interacting with the 3'-UTR of their mRNAs and affecting them on a post-transcription level,” she wrote in her grant's abstract. She and her colleagues also hypothesize that increasing miR-29 will prevent accelerated muscle protein degradation, promote muscle regeneration, and attenuate injured-induced muscle fibrosis in chronic kidney disease.
“These results should provide new approaches for developing therapeutic strategies to correct muscle wasting in catabolic disease,” she noted.
The grant began on April 11 and runs until March 31, 2017. It is worth $329,693 in its first year.
The last grant was received by Marc Thibonnier, chief medical officer at cancer therapeutics firm American Gene Technologies, to fund his efforts to therapeutically target miRNAs for hepatitis C infection in HCV/HIV co-infected drug users.
“We plan to simultaneously inhibit several steps of the HCV life cycle by purposely targeting various segments of the HCV gene and its host cell companion proteins,” he wrote in the grant's abstract.
Thibonnier and colleagues plan to develop liver-targeting lentiviral vectors carrying three microRNA clusters. One is designed to prevent HCV docking and entry into hepatocytes by targeting the HCV envelope and four host proteins — scavenger receptor B1, CD81, claudin-1, and occludin.
Another targets various sections of the HCV genome, and the last targets “various sections of the HCV genome known to be the targets on interferon-induced microRNAs,” Thibonnier wrote.
“This cluster attack on the HCV genome may particularly benefit injecting drug users infected with HCV or HIV/HCV because of the more severe course of their diseases, their more limited and often delayed treatment, their poor adherence to current treatments, and higher risk of emergence of resistant HCV strains,” he noted.
“Barriers to HCV diagnosis, assessment, treatment, and monitoring, as well as considerable treatment-related toxicities, result in extremely low treatment uptake and success among [intravenous drug users] with the currently available therapies,” he added. “However, improved clinical outcomes occur after successful treatment in patients who achieve a sustained virologic response.
“For difficult-to-treat IDUs, we propose to achieve SVR and possible virus eradication by one time systemic delivery to the liver of several miRNAs,” the abstract states. “This offers the advantage of a simplified, yet effective regimen, very few medical interventions, and reduced toxicities and cost.”
Meantime, targeting different aspects of the virus is expected to prolong viral suppression and decrease the likelihood of escape.
The project began on April 1 and runs until the end of September. It is worth $181,796.