Use of Nanoparticles to Combat Neurodegenerative Disease

Jennifer S. Sun, PhD

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 mediators^3,8 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 relief^2,3,5,9,10; 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 cells^6,9; metal NPs catalyze reduction-oxidation (redox) reactions to combat cellular oxidative stress^11,12; NPs shield drugs to overcome the lipophilic requirement to pass the BBB^2,9; NPs improve drug stability and change the drug-releasing pattern, thereby increasing bioavailability and decreasing the required therapeutic dose^2,3,9; 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

Click the image to enlarge.

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

REFERENCES

1. Ouellette J, Lacoste B. From neurodevelopmental to neurodegenerative disorders: the vascular continuum. Front Aging Neurosci. 2021;13:749026. doi:10.3389/fnagi.2021.749026

2. Silveira G de B, Muller AP, Machado-de-Ávila RA, Silveira PCL. Advance in the use of gold nanoparticles in the treatment of neurodegenerative diseases: new perspectives. Neural Regen Res. 2021;16(12):2425-2426. doi:10.4103/1673-5374.313040

3. Zhu FD, Hu YJ, Yu L, et al. Nanoparticles: a hope for the treatment of inflammation in CNS. Front Pharmacol. 2021;12:683935. doi:10.3389/fphar.2021.683935

4. Feigin VL, Vos T, Nichols E, et al. The global burden of neurological disorders: translating evidence into policy. Lancet Neurol. 2020;19(3):255-265. doi:10.1016/S1474-4422(19)30411-9

5. Kumar A, Chaudhary RK, Singh R, et al. Nanotheranostic applications for detection and targeting neurodegenerative diseases. Front Neurosci. 2020;14:305. doi:10.3389/fnins.2020.00305

6. Chiang MC, Nicol CJB, Lin CH, Chen SJ, Yen C, Huang RN. Nanogold induces anti-inflammation against oxidative stress induced in human neural stem cells exposed to amyloid-beta peptide. Neurochem Int. 2021;145:104992. doi:10.1016/j.neuint.2021.104992

7. Robinson AP, Zhang JZ, Titus HE, et al. Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis. Sci Rep. 2020;10(1):1936. doi:10.1038/s41598-020-58709-w

8. Zhao N, Francis NL, Calvelli HR, Moghe PV. Microglia-targeting nanotherapeutics for neurodegenerative diseases. APL Bioeng. 2020;4(3):030902. doi:10.1063/5.0013178

9. Asefy Z, Hoseinnejhad S, Ceferov Z. Nanoparticles approaches in neurodegenerative diseases diagnosis and treatment. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2021;42(7):2653-2660. doi:10.1007/s10072-021-05234-x

10. Vucic S, Kiernan MC, Menon P, et al. Study protocol of RESCUE-ALS: a phase 2, randomised, double-blind, placebo-controlled study in early symptomatic amyotrophic lateral sclerosis patients to assess bioenergetic catalysis with CNM-Au8 as a mechanism to slow disease progression. BMJ Open. 2021;11(1):e041479. doi:10.1136/bmjopen-2020-041479

11. Li J, Zhang J, Chen Y, Kawazoe N, Chen G. TEMPO-conjugated gold nanoparticles for reactive oxygen species scavenging and regulation of stem cell differentiation. ACS Appl Mater Interfaces. 2017;9(41):35683-35692. doi:10.1021/acsami.7b12486

12. Huang X, El-Sayed IH, Yi X, El-Sayed MA. Gold nanoparticles: catalyst for the oxidation of NADH to NAD(+). J Photochem Photobiol B. 2005;81(2):76-83. doi:10.1016/j.jphotobiol.2005.05.010

13. Du L, Suo S, Wang G, et al. Mechanism and cellular kinetic studies of the enhancement of antioxidant activity by using surface-functionalized gold nanoparticles. Chem Weinh Bergstr Ger. 2013;19(4):1281-1287. doi:10.1002/chem.201203506

14. Bryson S. RESCUE-ALS data: CNM-Au8 fails at key goals, trends ‘encouraging.’ ALS News Today. November 5, 2021. Accessed August 1, 2022. https://alsnewstoday.com/news/cnm-au8-failed-primary-rescue-als-goals-top-line-trial-data/

15. Wexler M. #MDA2022 – CNM-Au8 may slow ALS progression, reduce mortality risk. ALS News Today. March 17, 2022. Accessed July 26, 2022. https://alsnewstoday.com/news/mda-2022-cnm-au8-may-slow-als-progression-reduce-mortality-risk/

16. A multi-center, open-label long-term extension study assessing the safety, efficacy, tolerability, and pharmacokinetics of CNM-Au8 in patients with stable relapsing multiple sclerosis (VISIONARY-MS LTE). ClinicalTrials.gov. November 13, 2020. Accessed July 26, 2022. https://clinicaltrials.gov/ct2/show/NCT0462692

17. Nanocrystalline gold to treat remyelination failure in chronic optic neuropathy in multiple sclerosis (VISIONARY-MS). ClinicalTrials.gov. Posted May 24, 2018. Accessed July 28, 2022. https://clinicaltrials.gov/ct2/show/NCT03536559

18. Therapeutic nanocatalysis to slow disease progression of amyotrophic lateral sclerosis (ALS) (RESCUE-ALS). ClinicalTrials.gov. September 19, 2019. Accessed July 28, 2022. https://clinicaltrials.gov/ct2/show/NCT04098406

19. Clene receives positive ema opinion on orphan drug designation for CNM-Au8 for the treatment of ALS. News release. Global Newswire. July 19, 2022. Accessed July 26, 2022. https://www.morningstar.com/news/globe-newswire/8601363/clene-receives-positive-ema-opinion-on-orphan-drug-designation-for-cnm-au8-for-the-treatment-of-als

20. HEALEY ALS Platform Trial - Master Protocol. ClinicalTrials.gov. March 5, 2020. Accessed July 28, 2022. https://clinicaltrials.gov/ct2/show/NCT04297683