Development of Ciliary Neurotrophic Factor (CNTF) Receptor Agonists for ALS Therapy

Background: Amyotrophic lateral sclerosis (ALS) is also known as 'Lou Gehrig's Disease' after the famous baseball player who was diagnosed with it in 1939 at the Mayo Clinic. More recently, noted physicist Stephen Hawking succumbed to ALS. It is a nervous system (neurological) disease that progresses to destroy nerve cells (motor neurons) and their long extensions (axons) that control voluntary muscle movement, taking away the ability to move, speak, eat, and breathe. There is no cure for ALS and no effective treatment to halt or reverse the progression of this devastating and fatal disease. In the past 22 years only two drugs, Riluzole and Radicava, have been approved and their benefits remain controversial, as they slow disease progression only minimally. The human body produces proteins that enhance the growth, survival, and final maturation of both developing and mature neurons, called neurotrophic factors. The most promising of these for ALS treatment is ciliary neurotrophic factor (CNTF), which prevents not only the loss of motor neurons, but also axonal degeneration in cellular and animal models of ALS and axon injury. These findings provide 'proof of concept' that nerve damage can be prevented and raise hopes for effective treatments. CNTF acts by binding specifically to a CNTF-receptor (CNTFR), which is in complex with two other large proteins. However, despite these promising preclinical data in animal models, subsequent large clinical trials with recombinant CNTF protein in human ALS patients have been unsuccessful due to three challenges: (1) CNTF is a very large molecule and does not readily cross membranes that sheath neuron and axons, even when injected directly into the bloodstream or muscle. CNTF is also rapidly degraded, so effective CNTF levels in neurons and axons are difficult to attain or maintain. This poor 'pharmacokinetic' profile is a known challenge for most large biomolecule drugs. (2) Patients can develop an immune response to recombinant CNTF. (3) CNTF can bind to an alternative IL-6 receptor (IL-6R) that activates a severe inflammatory response and adverse side effects. While CNTF variants with a preference for CNTFR over IL-6R have been generated, these still are still plagued with the problems of a short half-life and immunogenicity. Therefore, there remains an urgent need for the development of novel small molecules 'agonists' that specifically bind to CNTFR and stimulate neurotrophic effects in ALS patients that preserve both cell bodies and axons of motor neurons, and overcome the challenges of large biomolecules. ALS is inherited in 5%-10% of cases, while the rest have no known cause. Recent studies indicate people who have served in the military are at higher risk of ALS, independent of the branch of service, the geographic region of deployment, and whether service was during a time of peace or a time of war. Therefore, this project to discover new compounds to seed development of novel drugs for all types and stages of ALS is aligned with the central priority of this Department of Defense grant opportunity and highly relevant to active duty Service members, Veterans, military beneficiaries, and the American public. Scientific Objective of the Project: Our primary objective is to identify selective small molecule agonists of CNTFR to overcome the problems that caused the failure of clinical trials with CNTF protein. We hope to address the need for systemic treatment of patients and military Veterans with ALS at all stages, with the hope of preserving, restoring, or even improving the remaining neuron and axon function through such CNTFR agonists. Since targeting the underlying biology of maintaining the connections between nerve cells and muscle is independent of specific disease mechanisms, this intervention is expected to help patients with all types of ALS. Project Design and Aims: We will collaborate to screen a large diverse chemical collection (about 100,000 compounds) th