SAN DIEGO — Preclinical studies in animal models of multiple sclerosis (MS) have found that faceted crystalline gold nanoparticles can induce remyelination of axons and even improve motor function. The research addresses an underlying cause of dysfunction associated with MS disease activity.
"We are proposing that this gold nanocrystal can actually promote remyelination and fix damaged nerves," said Glen Frick, PhD, MD, chief medical officer at Clene Nanomedicine Inc, Salt Lake City, Utah. "This is unique and groundbreaking. It's a new therapeutic paradigm."
In an interview with Medscape Medical News, Dr Frick said a phase 1 dose escalation study in humans has shown the product to be safe and well-tolerated in daily oral doses up to 90 mg taken for 21 days.
The company will initiate a phase 2 trial next summer, in conjunction with the Brain and Mind Centre at the University of Sydney in Australia, in 150 patients with MS with chronic optic neuropathy.
So far, however, the bulk of the research has been in vitro and in animal models. Here at the third annual forum of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), Michael Hotchkin, chief business officer for Clene Nanomedicine, described the effects of the product they have labeled CNM-Au8.
According to Hotchkin, CNM-Au8 is a form of "medicinal or bio catalysis" that is part of the cellular energy process. "Our technology allows us to create tiny gold nanocrystals. Au8 is essentially a diamond — a faceted crystal — made of gold. Its decahedron shape gives it a unique biological function," he said.
"Bioenergetic failure is a rate-limiting step in remyelination. Au8 can get into cells and affect their ability to use energy more efficiently. Our thesis is that we are enabling energetic efficiency through medicinal catalysis," he said.
The researchers have applied these nanocrystals to a series of animal models of toxic demyelination and repair in MS, one involving cuprizone, a toxin added to chow, and another involving lysolecithin, a toxic detergent that is intrathecally injected.
In a number of different experiments, the researchers compared control animals, toxin-injured animals also treated with vehicle, healthy animals who received CNM-Au8 (to evaluate safety), and toxin-injured animals also treated with CNM-Au8. Treatment was for about 5 weeks.
Using transmission electron microscopy and immunohistochemistry of myelin markers, the investigators observed in these models of demyelination robust remyelination in response to treatment with CNM-Au8. They also showed improvement in function in a mouse model.
Myelin Repair Demonstrated
In an analysis of thousands of transmission electron microscopy images of corpus callosum cross-sections, diffuse loss of myelin and patchy axons were visible after 2 weeks of cuprizone-induced demyelination, but for animals treated with CNM-Au8, there was "striking, visible evidence of ongoing myelin protection," Hotchkin said in an interview.
Compared with their unprotected counterparts, treated animals had approximately a 2-fold decrease in small patches of demyelinated areas (P < .05). Degeneration of myelin sheaths was reduced by four- to fivefold over untreated, damaged animals (P < .05).
CNM-Au8 also significantly increased the immunohistochemistry staining of proteolipid protein, a component of myelin, in the damaged brains of mice. Scanned pixel density of proteolipid protein was only 0.55 for untreated mice, increasing to 3.22 for the treated mice (P < .007) and approaching the control levels of 3.38. "We basically raised [proteolipid protein] back to normal levels. This told us something really unique was happening," Hotchkin said.
CNM-Au8 also demonstrated in vitro differentiation of enriched primary oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, he added.
"Efficacy was demonstrated by CNM-Au8 in both prophylactic as well as postinjury contexts in the cuprizone model, suggesting that CNM-Au8 may be useful in clinical settings after disease progression has occurred," Dr Hotchkin said.
They repeated the experiments in the lysolecithin model and found the same protective and regenerative effects of CNM-Au8. Animals treated with CNM-Au8 had a 43% increase in myelin-wrapped axons per unit area (P < .05), as well as an increase in mature oligodendrocytes.
Improvement in Function
The next obvious question was whether the improvement in myelination and maturation of oligodendrocytes leads to functional benefit. For this, the researchers studied open-field behavior and fine motor kinematics of cuprizone-damaged mice, treated and not treated with CNM-Au8. In an "open field test," the treated mice demonstrated statistically significant improvements on multiple functional motor parameters.
"For example, mice in a box go to the perimeter of the space. They don't stay in the center," Hotchkin explained. "With cuprizone damage, they tended to stay in the center. With treatment, they spent significantly less time in the center and more in the perimeter."
CNM-Au8 also restored fine motor function, reducing abnormalities by 78%. "Over time, you get some remyelination [naturally]," he said, "but Au8 doubled that recovery, and by the end of week 6, these mice were not significantly different from controls."
Mark Freeman, MD, professor of neurology at the University of Ottawa and director of the MS Research Unit at Ottawa Hospital in Canada, told Medscape Medical News that the research is exploring a "contemporary" issue in the pathogenesis of MS.
"It looks like these researchers are identifying an underlying mechanism for demyelination," Dr Freeman said, "and linking it to this [compound]."
He has seen earlier versions of the research by these same investigators, but the missing link has been the lack of an explanation for the effect of gold nanocrystals on myelination. According to Dr Freeman, the team has now determined that gold nanocrystals must somehow affect the "lack of energy" that seems to underlie this destructive process, although the work is still early.
"They have uncovered this whole issue that is actually very contemporary in terms of our thoughts about why dysfunction occurs in axons. Why are axons not remyelinating?" he said. "They have identified this lack of energy. It's like a system running out of steam, or an orchestra that is no longer in tune. Maybe axons are not remyelinating because there's not enough energy there."
"This works is acting right at the basics of how energy is generated in the bioenvironment. It speaks to a very novel approach to a problem for which we have not yet had an answer," Dr Freeman commented.
Dr Frick and Mr Hotchkin are employees and shareholders of Clene Nanomedicine, Inc. Dr Freeman has disclosed no relevant financial relationships.
Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS): Abstract LB292. Presented February 2, 2018.
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Cite this: Gold Nanocrystals May Remyelinate Lesions in Multiple Sclerosis - Medscape - Feb 04, 2018.