NEW YORK (GenomeWeb) – The National Institutes of Health this month awarded more than $1.1 million to fund three research projects related to a gene silencing-based treatment for amyotrophic lateral sclerosis (ALS), the role of RNAi in mammalian antiviral responses, and the effects of a specific microRNA in diabetes-associated cancer, respectively.
The first grant was awarded to University of Massachusetts researcher and RXi Pharmaceuticals collaborator Robert Brown to support his efforts to develop and test an miRNA-based expression system to treat a heritable form of ALS.
ALS involves the degeneration and death of motor neurons and is broadly categorized as sporadic, which accounts for around 90 percent of all cases and has no known risk factors, and familial, which is caused by mutations in either the C9orf72 or SOD1 genes.
Though Brown, both independently and in partnership with RXi, has largely focused on RNAi interventions for the SOD1 form of familial ALS, with the latest NIH funding he and his lab are focusing on the version linked to a G4C2 hexanucleotide repeat expansion in C9orf72.
Specifically, Brown plans to use an adeno-associated viral vector to deliver into patients an miRNA that silences the expression of C9orf72 transcripts that harbor the disease-causing G4C2 expansion.
The effort will begin with the identification and optimization of potential therapeutic miRNAs in vitro, followed by testing of the AAV-delivered miRNA in a C9orf72 mutant transgenic mouse that was developed in his lab.
With an eye toward clinical development of the therapy, Brown and his team aim to also test their approach in non-human primates using an intrathecal route of administration, which he stated in his grant's abstract enables widespread delivery within the central nervous system with doses that are an order-of-magnitude lower than are required via intravenous delivery.
The grant began on July 1 and runs until April 30, 2018. It is worth $377,369 in its first year.
The second grant went to Massachusetts General Hospital's Kate Jeffrey to fund her research into the role of cellular RNAi machinery in how mammals respond to viral infection.
RNAi is a well-established antiviral mechanism for plants, arthropods, and nematodes, and while the gene-silencing system functions in mammals via the miRNA pathway, it is believed that mammalian antiviral responses are limited to interferon induction. However, there have been recent reports suggesting that RNAi does, indeed, play an antiviral role in mammals.
To better understand this issue, Jeffrey plans to use her NIH funding to study the RNAi machinery in mice that have been engineered to lack Argonaute proteins, which are the key effector proteins of RNAi gene silencing.
In previous work, Jeffrey and her colleagues have shown that two such proteins, Ago2 and Ago4, have "profound but differential" effects on mammalian antiviral responses, she wrote in her grant's abstract. Notably, such responses are "markedly diminished" in the absence of Ago2 catalytic activity, suggesting that it negatively regulates other antiviral pathways.
With the NIH support, she and her team will characterize the role of Ago2 in silencing viruses and further explore Ago4's contribution to mammalian antiviral responses. Collectively, these studies are expected to help determine whether Ago proteins offer antiviral protection alone or if they aid/compete with other viral defense mechanisms including pattern recognition receptors and interferon responses.
Lastly, Jeffrey plans to examine which host and virus-derived RNA populations bind to Ago2 and Ago4 in influenza-infected macrophages, then further test them for antiviral capacity.
The five-year grant began on July 1 and is worth $435,000 in its first year.
Lastly, the NIH awarded a grant to Cleveland Clinic scientist Olga Stenina to explore how miR-467 influences diabetes-associated cancer growth.
Diabetes is associated with an increased incidence of several cancers including breast, bladder, and liver, and work conducted by Stenina and others suggests that the aberrant angiogenesis associated with diabetes may be the cause. Still, the molecular mechanisms driving the growth of new blood vessels are not clear.
In previous studies, Stenina and collaborators found that miR-467 is upregulated in response to hyperglycemia and that the miRNA inhibits production of the antiangiogenic protein thrombospondin-1 (TSP-1), promoting angiogenesis in a tissue-specific manner, according to the grant's abstract. In in vivo testing, they demonstrated the association between miR-467 antagonism and hyperglycemia-induced tumor growth.
With the NIH funding, Stenina and her team now plan to characterize the novel tissue-specific pathway activated by hyperglycemia that controls angiogenesis and cancer growth both in diabetic mouse models and human diabetic cancer tissue.
The investigators also hope to show that the stimulation of cancer growth by hyperglycemia is mediated by tissue-specific upregulation of miR-467 and its silencing of TSP-1 production. Further, they aim to establish in vivo that hyperglycemia-induced tumor growth can be prevented by blocking miR-467 in specific tissues.
The grant started on July 1 and runs until May 31, 2019. It is worth $328,888 in the first year.