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

Authors

Anitha Krishnan, Aviceda Therapeutics, Cambridge, MA 02142, USA.
David G. Callanan, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Victor G. Sendra, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Amit Lad, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Sunny Christian, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Ravinder Earla, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Ali Khanehzar, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Andrew J. Tolentino, Department of Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Valory Anne Vailoces, School of Medicine and Health Sciences, George Washington University, Washington, DC 20052, USA.
Michelle K. Greene, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Christopher J. Scott, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Derek Y. Kunimoto, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Tarek S. Hassan, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Mohamed A. Genead, Aviceda Therapeutics, Cambridge, MA 02142, USA.
Michael J. Tolentino, Aviceda Therapeutics, Cambridge, MA 02142, USA.

Document Type

Journal Article

Publication Date

4-9-2024

Journal

Pharmaceuticals (Basel, Switzerland)

Volume

17

Issue

4

DOI

10.3390/ph17040481

Keywords

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

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 strains and , 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.

APA Citation

Krishnan, Anitha; Callanan, David G.; Sendra, Victor G.; Lad, Amit; Christian, Sunny; Earla, Ravinder; Khanehzar, Ali; Tolentino, Andrew J.; Vailoces, Valory Anne; Greene, Michelle K.; Scott, Christopher J.; Kunimoto, Derek Y.; Hassan, Tarek S.; Genead, Mohamed A.; and Tolentino, Michael J., "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" (2024). GW Authored Works. Paper 4745.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4745

Department

School of Medicine and Health Sciences Student Works