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Use of Nanoparticles to Combat Neurodegenerative Disease

NeurologyLive, October 2022, Volume 5, Issue 5

Available neurodegenerative disease treatments are generally unsafe and ineffective at penetrating the blood-brain barrier, though the use of nanoparticles can provide improved penetration and exert a neuroprotective effect.

NEUROLOGICAL DISORDERS, including neurodegenerative diseases1, present significant social and economic implications for the millions of people affected worldwide,2,3 with the expectation for increased incidences over the next 30 years.4 Neurodegenerative diseases are characterized by progressive neuronal death in the central (CNS) and peripheral (PNS) nervous systems, which leads to disabling impairments of motor and cognitive functions.2,3 Neurodegenerative diseases can be triggered by neurotoxic events that result in dysregulated energy metabolism, extensive neuronal loss, synaptic abnormalities, and aberrant protein accumulation.2,3,5,6

Neurodegenerative disease therapeutics necessitate optimal pharmacokinetic distribution of drugs through the CNS, with minimal systemic adverse effects (eg, motor complications).2,7 Because of the complex pathophysiology of neurodegenerative diseases, targeted pharmacological approaches are lacking.2 Many neurodegenerative diseases share hallmarks of energy depletion, mitochondrial dysfunction, and metabolic stress prior to clinical symptom onset.7 Neuroinflammation due to microglial and axoglial activation and the secretion of pro-inflammatory mediators3,8 is also a common feature of neurodegenerative diseases; thus, neuroinflammation could be a novel target for therapeutic intervention.6,8 Moreover, available neurodegenerative disease treatments are generally unsafe and ineffective at penetrating the blood-brain barrier (BBB), and provide only symptomatic relief2,3,5,9,10; here, the use of nanoparticles (NPs) can provide improved BBB penetration and exert a neuroprotective effect.3

NPs are very small (1-1000 nm) particles composed of organic (ie, lipids, nanoemulsions and polymers) or inorganic (ie, Au, gold; TiO2, titanium dioxide; IO, iron oxide; and other metals) materials, proteins, and polysaccharides.3,9 NP systems are beneficial for several reasons (FIGURE): NPs destroy inflammatory molecules without adverse effects to normal cells6,9; metal NPs catalyze reduction-oxidation (redox) reactions to combat cellular oxidative stress11,12; NPs shield drugs to overcome the lipophilic requirement to pass the BBB2,9; NPs improve drug stability and change the drug-releasing pattern, thereby increasing bioavailability and decreasing the required therapeutic dose2,3,9; NPs are modifiable for cell-specific and selective targeting (eg, brain-targeting) purposes2; and NPs can be tailored to the disease and patients’ needs.5,7 Yet, despite the potent neuroprotection and anti-inflammatory effects of NPs, some NPs have been associated with damaging neurotoxicity and pro-inflammatory responses.2,3

NP design affects compatibility with subsequent applications.2 NP shape contributes to biological functions such as drug delivery, half-life, endothelial intake, and targeting ability.2,3 Small NPs provide faster drug release because of their large surface-to-volume ratio,3 whereas large NPs provide slower drug release because of faster polymer degradation.3 NP surface charge and hydrophobicity influence NP biodistribution, circulation time, and toxicity.2,3 Positively charged NPs enhance imaging, gene transfer, and drug delivery, but exhibit higher cytotoxicity.3

Because of their biocompatibility and tunable size, gold NPs (AuNPs) are ideal candidates for delivering large amounts of antibiotics.2 The shape, size, and surface properties of AuNPs modulate their interactions with cells.11 When AuNPs self-assemble, functional groups are exposed on the surface, significantly enhancing the activity of the functional groups themselves.2,7,13 In particular, surface-bound oxygen catalyzes the oxidation reaction of nicotinamide adenine dinucleotide (NADH) to the critical energetic cofactor, NAD+.6,12 NADH oxidation drives cellular respiratory and metabolic processes that power the myelination process.6,7 Thus, AuNPs can support remyelinating therapy to restore functions that were affected by neurodegenerative disease activity, thereby improving patients’ quality of life and potentially reversing disease progression.7 AuNPs can also transform drug delivery to benefit neural cell amplification; for instance, AuNPs have improved cognitive and antioxidant function in models for Alzheimer disease.2 AuNPs paired with stem cell therapy further improve cell-specific targeting and the promotion of self-renewal, proliferation, and differentiation of endogenous and exogenous neural stem cells.9

CNM-Au8 (Clene Nanomedicine Inc) is an oral AuNP suspension which leverages NAD+ and NADH to drive redox reactions, protecting cells from reactive oxygen species while improving myelin production.7,14 CNM-Au8 is designed to help brain cells boost their energy reserves and increase stress resistance.7,15 As the mechanism of action of CNM-Au8 is not limited to a single protein target or cell type, CNM-Au8 is a potentially wide-ranging neurotherapeutic that can rescue neurodegenerative disease-impaired cellular bioenergetics.7 Au@PEG3SA, another AuNP, was recently synthesized using a novel layer-by-layer self-assembly approach that resulted in a highly efficient surface-functionalized AuNP with improved kinetics in vivo.13

CNM-Au8 has been in clinical trials for neurodegenerative diseases including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).10,16,17 Among these, VISIONMS-LTE (NCT0462692116) is an open-label, long-term extension study available to participants who completed VISIONARY-MS (NCT0353655917), a randomized, double-blind, parallel group, placebo-controlled study for the treatment of visual pathway defects in patients with stable relapsing multiple sclerosis (RMS), though this was terminated because of COVID-19 changes.16,17 VISIONMS-LTE participants received a daily dose of 30 mg CNM-Au8, with subsequent adjustments to individual dosage based upon outcomes from VISIONARY-MS.16 The primary end point is to assess the efficacy and safety of CNM-Au8 as a remyelinating therapy in RMS.16,17 Results are expected in late 2024.16

RESCUE-ALS (NCT0409840618), a multicenter, randomized, double-blind, parallel group, placebo-controlled study, assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients with amyotrophic lateral sclerosis (ALS).10 RESCUE-ALS used electromyography to monitor motor neuron loss (motor unit number index), lung health (forced vital capacity), and reinnervation (motor unit size index).10,18 Despite failing these primary and secondary goals, CNM-Au8 showed promise in slowing disease progression and benefiting long-term survival.14 In July 2022, CNM-Au8 received orphan drug designation for the treatment of ALS from the European Medicines Agency Committee for Orphan Medicinal Products.19 CNM-Au8 remains under investigation in the multiregimen HEALEY ALS Platform trial (NCT0429768320), a perpetual multicenter clinical trial evaluating the safety and efficacy of investigational products, administered simultaneously or sequentially, for ALS.14,20 Results are expected in late 2022.14,20

Effective therapies are critical for neurodegenerative disease treatment and prevention.9 NPs could transform the management of neurodegenerative diseases by stimulating physiological responses with minimal adverse effects.5 As neurodegenerative disease mechanisms are complex and multifaceted, combinatorial therapeutics could be more effective.3 In this regard, AuNPs are highly compatible with pharmacological drugs, such that AuNPs can decrease the drugs’ harmful effects, increase their beneficial effects, and prolong their efficacy.2

For correspondence: jennsun@rutgers.edu
Rutgers University, New Brunswick, NJ

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