Gold Nanocrystals in Phase 2 Testing Show ‘Robust’ Remyelination Potential in Animal Models

Clene Nanomedicine‘s remyelination therapy candidate, CNM-Au8, showed a “robust” ability to stimulate the production of new myelin and increase the number of myelin-wrapped nerve fibers in the brain and spinal cord of animals in models of demyelinating disease, allowing mice to recover motor skills, a study reports.

Such preclinical data support the efficacy of this potential treatment, now being tested in clinical trials with multiple sclerosis (MS) patients.

These early findings were reported in the study “Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis,” published in the journal Nature Scientific Reports.

In MS, the immune system attacks myelin, the protective sheath around nerve fibers or axons. Myelin is essential for the fast transmission of electrical signals between neurons, and its loss (demyelination) damages the integrity of nerve cells and their ability to communicate with each other.

Finding therapies that promote remyelination — the recovery of myelin — is a “high priority” for MS, the researchers noted. Such treatments could potentially repair demyelinating lesions in the central nervous system (the brain and spinal cord), restoring function to nerve cells affected by the disease.

Most approved MS therapies dampen the immune system’s activity to prevent further myelin damage. However, they cannot undo existing damage or replace the myelin sheaths that have been lost.

Clene Nanomedicine’s lead compound, CNM-Au8, is a potential remyelination therapy for MS and other neurodegenerative disorders, including Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

CNM-Au8 is a solution of gold (Au) nanoparticles with a patented crystal structure, named a clean-surfaced nanocrystal (CSN). According to the company, these nanocrystals have properties that make them “highly biologically active,” allowing them to facilitate certain energy-related reactions within cells.

In the brain, both neurons and supporting cells, including oligodendrocytes that produce myelin, need substantial amounts of energy to work. In fact, the brain consumes more than 25% of the body’s metabolic resources in order to sustain the efficient flux of information through its vast network of nerve fibers.

CNM-Au8 is expected to enhance key metabolic reactions in neurons and oligodendrocytes so to increase energy reserves within these cells, while decreasing the harmful molecules naturally generated by the cells’ metabolism. This process, which Clene calls nanocatalysis, is thought to improve the survival and function of neurons, and to support the ability of oligodendrocytes to create new myelin.

CNM-Au8 has demonstrated a good safety profile in Phase 1 studies in healthy volunteers, and preclinical studies in animal models of MS and other diseases indicate the therapy has both remyelination and neuroprotection effects.

Several ongoing Phase 2 trials are evaluating CNM-Au8 in neurodegenerative diseases, including two studies in people with non-active, relapsing MS (which includes those with relapsing-remitting and secondary progressive disease).

REPAIR-MS (NCT03993171) is an open-label Phase 2 trial assessing the safety, pharmacokinetics (availability of the therapy in the body) and pharmacodynamics (its effects) of differing oral doses of CNM-Au8 in 24 adults. This study is currently enrolling eligible patients at the University of Texas Southwestern. More details can be found here. It is expected to conclude in the fall.

Another Phase 2 trial, called VISIONARY-MS (NCT03536559), is investigating the efficacy and safety of CNM-Au8 in up to 150 adult patients who have chronic vision problems due to lesions (chronic optic neuropathy). This study is also recruiting at nine sites across Australia, and is supported by the National Multiple Sclerosis Society. Contact and site information is available here. Results from VISIONARY-MS are expected in 2021.

Now, the preclinical work by researchers at Clene Nanomedicine, Northwestern University, and George Washington University provides additional evidence supporting the ability of these gold nanocrystals to promote remyelination in cell and animal models of MS.

“We are gratified at the publication of these data. These results establish the rationale for our ongoing Phase 2 clinical trial, VISIONARY-MS, which is designed to demonstrate the efficacy of CNM-Au8 for the treatment of chronic optic neuropathy in patients with non-active relapsing MS,” Robert Glanzman, MD, chief medical officer of Clene Nanomedicine, said in a press release.

Researchers found that oral delivery of CNM-Au8 to mice and rat models of demyelination led to “robust remyelination activity” in the brain and spinal cord, leading to higher numbers of myelin-wrapped axons. Study data also showed that CNM-Au8 resulted in a greater migration of oligodendrocytes to lesion sites, and increased myelin production.

The remyelination promoted by CNM-Au8 was also matched by a significant recovery of physical abilities in the mice, evaluated using different locomotor and fine motor tests.

Working on cells in lab dishes, known as in vitro assays, the scientists showed that treating oligodendrocyte precursor cells with CNM-Au8 stimulated their differentiation and maturation, and the expression of myelin-related markers.

The gold nanocrystals were seen to act via a novel energy metabolism pathway that speeds the conversion of NADH to NAD+, a critical factor for sensing and producing energy in cells. CNM-Au8 also increased the levels of adenosine triphosphate (ATP), a small molecule used as “fuel” by cells, and turned on genes related to myelin production, “collectively resulting in functional myelin generation,” the researchers reported.

“These results further validate our entirely new approach using therapeutic gold nanocatalysts as a mechanism to support the cellular viability and enhanced function of neurons and oligodendrocytes,” said Karen Ho, PhD, one of the study’s authors and director of Translational Medicine at Clene Nanomedicine.

“CNM-Au8 is one of a limited number of drugs being developed which have demonstrated remyelination capabilities. We believe these data exemplify a strong step forward in the development of a treatment to improve function in the lives of more than one million people living with MS in the U.S.,” Ho concluded.