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. 2024 Apr 9;17(4):481.
doi: 10.3390/ph17040481.

Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials

Anitha Krishnan  1 , David G Callanan  1 , Victor G Sendra  1 , Amit Lad  1 , Sunny Christian  1 , Ravinder Earla  1 , Ali Khanehzar  1 , Andrew J Tolentino  2 , Valory Anne Sarmiento Vailoces  3 , Michelle K Greene  1   4 , Christopher J Scott  1   4 , Derek Y Kunimoto  1 , Tarek S Hassan  1   5 , Mohamed A Genead  1 , Michael J Tolentino  1   6   7
Affiliations

Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials

Anitha Krishnan et al. Pharmaceuticals (Basel). .

Abstract

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.

Keywords: geographic atrophy; intravenous administration; intravitreal administration; macular degeneration; nanoparticle; polysialic acid; toxicity.

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Conflict of interest statement

The authors Anitha Krishnan, David G. Callanan, Victor G. Sendra, Amit Lad, Sunny Christian, Ravinder Earla, Tarek S. Hassan, Derek Y. Kunimoto, Mohamed A. Genead and Michael J. Tolentino are employed by Aviceda Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Relationship between PolySia-NPs vs. mean body weight (A) and mean food consumption (B) in mice.
Figure 2
Figure 2
Effects of IV injection of PolySia-NPs on tidal volume (A), minute volume (B), and respiration rate (C) in Sprague Dawley rats.
Figure 3
Figure 3
Effect of IVT administration of PolySia-NPs on body weight in Dutch Belted rabbits.
Figure 4
Figure 4
Ocular examination scores in OS and OD from rabbits treated with IVT injections of PolySia-NPs (A). OE score in rabbits treated with IVT injections of PolySia-NPs (B).
Figure 5
Figure 5
(A) ONL thickness and (B) total retinal thickness of the OS and OD groups.
Figure 6
Figure 6
Experimental design (A) and bodyweight changes in male non-human primates after IVT administrations of PolySia-NPs recorded for 28 days (B) and from day 35 to day 42 (C).
Figure 7
Figure 7
Effect of IVT administrations of PolySia-NPs on intraocular pressure (IOP) (A), electroretinography (ERG) (B), and optical coherence tomography (OCT) (C). Readings were performed at baseline (pre-test), on Day 14 (terminal), and on Day 28 (recovery). Green line represents the transversal axis of the eye for the OCT imaging.
See this image and copyright information in PMC

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