Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, characterized by the progressive loss of both upper and lower motor neurons. Most patients survive for only 2-5 years after disease onset, often due to respiratory muscle paralysis. To date, no therapy is available that effectively alters the disease course. Developing inhibitors to control the excessive activity of AMPA receptors is a promising strategy for ALS drug design. This is because Ca2+ influx through abnormally expressed, Ca2+-permeable AMPA receptors in motor neurons leads to selective cell death in ALS. This proposal combines two approaches for finding AMPA receptor inhibitors as a potential ALS drug. Using an in vitro evolution approach, we have identified a group of eight potent RNA inhibitors or aptamers targeting AMPA receptors. These aptamers are more potent, more selective and water soluble as compared with conventional small-molecule inhibitors. These properties would allow us to use aptamers at the lowest dose possible to achieve therapeutic efficacy by more tightly and selectively blocking AMPA receptor activities in vivo with minimal or no side effects. Here we propose to test these aptamers first in AR2 mice. In the motor neurons of this transgenic mouse model, Ca2+-permeable AMPA receptors are abnormally expressed. Therefore, the AR2 mouse model has been created to recapitulate molecular abnormalities found in the motor neurons of sporadic ALS patients, which counts for 90% of the ALS patient population. We will next test our aptamers in SOD1 mice that carry a G93A human mutation. Therefore, AR2 mice and SOD1 mice represent a sporadic and familial ALS mouse models respectively. Therefore, a better agent (AMPA receptor aptamers) and a well-suited mouse model (AMPA receptor dysregulation and expression) will offer an opportunity of developing an effective ALS drug targeting this important excitotoxic pathway mediated by excessive AMPA receptor activity.
In Aim 1, we will synthesize, purify and characterize a class of eight chemically modified RNA aptamers.
In Aim 2, we will test the safety and the therapeutic efficacy of these chemically modified aptamers, both alone and in various combinations, first in the AR2 ALS mice and then in SOD1 mice. RNA aptamers will be delivered using intrathecal injection to the spinal column to bypass the blood brain barrier. Aptamer- treated and untreated mice will be compared for immunohistochemical and behavioral changes, loss of motor neurons and survival rate. Whether there is an improvement of muscle functions and/or a delay of bodyweight loss will be also measured. Testing highly potent, selective and water-soluble aptamers in the two ALS mouse models will allow us to explore developing a new, effective ALS therapy.

Public Health Relevance

We propose to develop a class of potent, selective and chemically modified RNA aptamers that inhibit AMPA receptors, and test their efficacy and safety first in the AR2 mouse that models sporadic ALS, where motor neurons undergo selective neurodegeneration triggered by excessive activity of AMPA receptors. We will also test our aptamers in G93A SOD1 mice, which models familial ALS. If successful, our research will produce a novel RNA-based drug candidate for a potential ALS therapy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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State University of New York at Albany
Schools of Arts and Sciences
United States
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