Testing RNA Aptamers in SOD1 G93A ALS Mouse Model
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in the death of motor neurons in the brain and spinal cord. Excitotoxicity is a leading pathogenic mechanism for the selective death of motor neurons. Because excitotoxicity is mainly mediated by Ca2+ influx to motor neurons via abnormally expressed, Ca2+-permeable AMPA receptors, developing inhibitors to block excessive AMPA receptor activity is a promising ALS drug discovery strategy. In fact, riluzole and edaravone, the two ALS drugs, both act to reduce glutamate-induced excitotoxicity, among their other activities. Here we combine two approaches for developing a new class of AMPA receptor inhibitors or RNA aptamers that are different from traditional, small-molecule compounds. First, using an in vitro evolution approach called SELEX, we have previously identified a group of potent RNA aptamers selectively targeting AMPA receptors. These RNA aptamers are more potent and selective towards AMPA receptors, as compared with existing AMPA receptor inhibitors, and they are water soluble by nature. These superior properties would enable us to use aptamers at the lowest dose possible to achieve therapeutic efficacy by more tightly and selectively blocking AMPA receptor activities in vivo, but with minimal or no side effects. Next, we propose to test these aptamers in SOD1 G93A mice. Transgenic mice overexpressing human Cu/Zn superoxide dismutase type-1 with a glycine to alanine mutation in position 93 (SOD1 G93A) is a well-established rodent ALS model since these mice develop a phenotype similar to ALS in humans. The SOD1 G93A mouse model is the most widely used one for ALS research and drug development. Earlier studies have demonstrated that glutamate-induced toxicity has a contributing role in the neurodegeneration in the SOD1 G93A model, and glutamate receptor blockade leads to neuroprotection. This proposal has two major objectives: (a) making a group of highly potent, selective, water-soluble RNA-based aptamers that inhibit AMPA receptors, and (b) testing these aptamers for their safety and efficacy in rescuing the ALS phenotype in SOD1 G93A mouse model. The series of tests we propose to conduct include (i) behavioral assays, such as grip strength and rotarod assay to measure motor activity, body weight, (ii) tissue assays, such as the count of the number of motor neurons and the size of these motor neurons, and (iii) survival study. We hope to identify a set of aptamers that are efficacious and without any significant side effects. If successful, this research will lay critical groundwork for clinical testing of several most efficacious, safe and long-lasting RNA aptamers as a new ALS therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310374
Entities
People
- Li Niu
Organizations
- State University of New York at Albany
- United States Army