Phase 2 clinical trials using orally administered gold nanocrystals to treat multiple sclerosis and Parkinson’s disease have produced promising results, restoring metabolites linked to crucial energy activity in the brain that are depleted in these neurodegenerative conditions.
The brain depends on a continuous supply of energy in the form of adenosine triphosphate (ATP) to fuel its resting and active-state functions. Essential to ATP production is the molecule nicotinamide adenine dinucleotide (NAD+).
As glucose is broken down into smaller molecules by the cells, the chemical bonds holding it together break. The energy held in the broken bonds is harnessed when an electron freed during the process is captured by NAD+, converting it to its reduced form, nicotinamide adenine dinucleotide + hydrogen (NADH). NADH donates the electron to the mitochondria, which use the electron’s energy to produce ATP, a process that oxidizes NADH back to NAD+.
Energy metabolism is compromised as we age, evidenced by a reduced NAD+/NADH ratio, which is considered a measure of global brain energy capacity. In neurodegenerative diseases like multiple sclerosis (MS), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), this reduction is much faster and more severe.
Now, researchers from the University of Texas Southwestern (UT Southwestern) Medical Center have conducted two phase 2 clinical trials on patients with MS and PD to see whether treating these neurodegenerative diseases with orally administered gold nanocrystals could restore the NAD+/NADH ratio.
“We are cautiously optimistic that we will be able to prevent or even reverse some neurological disabilities with this strategy,” said Peter Sguigna, one of the study’s co-authors and lead on the MS trial.
CNM-Au8 is a concentrated suspension of gold nanocrystals whose surfaces catalyze the rapid oxidation of NADH to NAD+, shown to increase the availability of both NAD+ and ATP in in vitro studies. It’s also known to cross the blood-brain barrier and penetrate cell membranes.
The objective of the clinical trials was to demonstrate the effects of CNM-Au8 on key brain energy metabolites, including ATP, total NAD+ and the NAD+/NADH ratio, in the setting of neurodegenerative disease. The REPAIR-PD trial recruited 13 participants aged 30 to 80 with a diagnosis of PD. Participants had a disease duration equal to or less than three years and were receiving dopaminergic medications for the disease for at least 12 weeks, with no change in dose for at least six weeks before starting the trial. The REPAIR-MS trial recruited 11 participants aged 18 to 55 with a diagnosis of stable relapsing MS within 15 years of screening, a form of the condition that’s marked by worsening symptoms (relapse) followed by a period of remission. Participants were receiving treatment with the immunotherapy drug natalizumab.
All participants received 120 ml of CNM-Au8, which they drank each morning for 12 weeks. Beginning with the baseline visit, participants had ECG, blood tests, physical exams, and scoring of either motor and non-motor Parkinson’s symptoms or the degree of disability caused by MS. Phosphorous magnetic resonance spectroscopy (P-MRS) was used to noninvasively assess energy metabolites of the whole brain.
After 12 weeks of treatment with CNM-Au8, the mean change in NAD+/NADH ratio from baseline across both cohorts demonstrated a statistically significant increase by an average of 10.4%, demonstrating that the gold nanocrystals were targeting the brain as intended. The effect on the NAD+/NADH ratio ceased after the 12-week CNM-Au9 treatment was concluded. The researchers also observed an inverse correlation between the baseline and post-treatment levels of ATP and other brain energy metabolites; participants with relatively lower baseline levels demonstrated increases, and participants with relatively higher baseline levels demonstrated a re-balancing that brought levels down.
In participants with PD, the treatment produced a statistically significant improvement in scores measuring “motor experiences of daily living,” driven mainly by a significant improvement at week four. This score reflects the impact rather than the presence of symptoms and includes an assessment of chewing and swallowing, cutting food and handling utensils, dressing, hygiene, speech, writing, walking, and the interference caused by tremor.
Adverse events were reported as mild or moderate, none of which were considered by the researchers to be related to the study drug. Common side effects included sinusitis, the common cold, and ‘pins and needles’.
“To our knowledge, CNM-Au8 is the only drug in development with catalytic activity targeted at intracellular NADH conversion to NAD+ with a demonstrated, potentially beneficial, effect on these metabolites in participants with neurodegenerative disease,” said the researchers.
The REPAIR-MS trial is ongoing, enrolling participants to see whether similar findings can be reproduced in those with progressive MS, characterized by worsening symptoms without relapses or remissions.
The researchers say that the results of these clinical trials support advancing to larger phase 3 trials to test whether CNM-Au8 offers a treatment benefit to those with neurodegenerative diseases.
Clene Nanomedicine Inc., which produced the CNM-Au8 oral suspension, funded the study published in the Journal of Nanobiotechnology. The below video, produced by Clene Nanomedicine, explains how CNM-Au8 works.
Source: UT Southwestern Medical Center