Determining the Efficacy of NLX-112 in a Mouse Experimental Model of Cerebellar Ataxia
Abstract
The Fiscal Year 2018 Peer Reviewed Medical Research Program includes a Topic Area Cerebellar Ataxia, and specifically requests “Research to identify therapeutic targets and novel therapeutic modalities.” Cerebellar ataxia is a serious condition that can profoundly affect the lives of patients by impairing muscle control or coordination of voluntary movements, such as walking or picking up objects. Ataxia can also affect other movements, creating difficulties with speech, eye movement, and swallowing. Other serious symptoms are also observed, including difficulties in thinking and problem-solving, as well depressed mood and sleeping problems. Cerebellar ataxia presents in several different forms, some of whom are genetic. Of these, spinocerebellar ataxia Type 3 (SCA3; also known as Machado–Joseph disease, MJD) is the most common and is a progressive neurodegenerative disorder with no cure. Life expectancy is often reduced, and with the most severe forms of SCA3, patients die in their mid-30s. There is no approved pharmaceutical treatment for SCA3 patients, and no medication has proven effective in relieving symptoms or slowing down (or stopping) the progression of the disease. Neurolixis is a biotech company developing small molecules targeting the serotonergic system that may have utility in improving symptoms and attenuating disease progression in SCA3 patients. Importantly, these small molecules are anticipated to also be beneficial for treatment of other ataxias such as those caused by head trauma or substance abuse. Indeed, similar neurological deficits (muscle weakness and paralysis, disturbed balance, slowed thinking and problem solving) are common symptoms in patients (such as military personnel) that have experienced traumatic brain injury (TBI), or that display ataxia caused by chronic alcohol or drug abuse. A brain region that is found to be particularly affected in military personnel with blast-related TBI is also known to be highly affected in SCA3 patients, with damage correlated to SCA3 disease severity, including movement disorder and cognitive difficulties. Thus, the mechanism of damage in TBI and SCA3 likely involves overlapping pathological mechanisms. The present project proposes to test a first-in-class serotonergic activator, NLX-112, which specifically targets neuronal proteins known as 5-HT1A receptors. Older molecules of this class are known to display neuroprotective properties and improve motor control, but they are poorly selective and insufficiently active. In contrast, NLX-112 is exceptionally selective and robustly improves performance in models of movement disorders in rodent and monkey. Here, we plan to test whether NLX-112 can slow down or reverse ataxia symptoms in transgenic mice expressing the SCA3 mutation. Mice will be treated with NLX-112 for up to 35 weeks, and their behavior and biomarkers will be tracked and compared with those of control mice. If these tests show that NLX-112 can indeed prevent and/or reverse the development of ataxia in these transgenic mice, Neurolixis plans to carry out a proof-of concept clinical trial of NLX-112 in ataxia patients. This could be done rapidly because NLX-112 has already been shown to be safe and well-tolerated in humans, and Neurolixis has prepared the regulatory filings necessary for authorization of clinical testing in the USA. Overall, Neurolixis believes that NLX-112 constitutes a promising drug candidate for treatment of ataxia-related symptoms in SCA3 patients as well as in patients with other neurodegenerative disorders, including blast-related TBI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910638
Entities
People
- Adrian Newman-Tancredi
Organizations
- Neurolixis
- United States Army