SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.
This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Operations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.
In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.
Treatment Improved Two Models of Demyelination
Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.
The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.
CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.
In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.
Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.
The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.
Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.
Therapy Promotes Bioenergetics Catalysis
CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.
In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.
Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.
Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.