Project Overview

Rationale: Mitochondrial dysfunction has been identified as a contributing factor for bioenergetic dysregulation and neurodegeneration in the motor cortex and spinal cord of patients with ALS. CNM-Au8 is an investigational compound designed to promote biocatalytic activity and is effective in improving mitochondrial function and survival in preclinical ALS models.  Oral CNM-Au8 is currently being tested in phase-2 and Healey platform clinical trials in ALS patients; however, the therapeutic effect of CNM-Au8 is expected to be suboptimal due to limited permeability across the blood-spinal cord and blood brain barrier (BBB). Considering the importance of the motor cortex in contributing to ALS pathogenesis, to achieve therapeutic success it is essential to optimize bioavailability of CNM-Au8 in degenerating cortical motor neurons. Using the non-invasive technique of MR-guided focused ultrasound (MRgFUS) which recently demonstrated safety in ALS (Abrahao et al), BBB permeability can be enhanced to increase drug delivery to the targeted motor cortex.

Objective & Specific Aims: We propose to couple oral administration of CNM-Au8 with BBB opening in the motor cortex to increase bioavailability and bioenergetic effects in an open-label, dose-ascending, safety trial. This study will evaluate the following specific aims: 1) the safety and feasibility of oral CNM-Au8 30 or 60 mg administration over 8 weeks in conjunction with a single primary motor cortex MRgFUS BBB opening procedure in 10 volunteers with ALS; 2) target engagement and bioenergetic pharmacodynamics of enhanced motor cortex delivery of CNM-Au8 with MRgFUS, measured by 31P magnetic resonance spectroscopy (MRS) in the treated hemisphere, normalized to the contralateral side; 3) pharmacokinetics and exploratory pharmacodynamic signals of enhanced CNM-Au8 CNS delivery as measured by changes in upper motor neuron neurophysiology using transcranial magnetic stimulation, serum and CSF metabolomics and light chain neurofilament levels, and advanced neuroimaging with MRS (in collaboration with the Canada-wide CAPTURE study).

Significance: CNM-Au8 improves mitochondrial function by modulating biocatalytic activity and thereby improves motor neuron health. Its low bioavailability secondary to limited BBB permeability is a critical limitation, which can be remedied by coupling oral CNM-Au8 administration with MRgFUS targeted BBB opening. This study will demonstrate the safety, enhanced delivery and target engagement of CNM-Au8 using MRgFUS. Importantly, this is the first study to use MRgFUS to enhance the delivery of a therapeutic across the BBB in the ALS population and is the essential next step for establishing a non-invasive delivery platform for a variety of ALS therapeutics.