Self-delivering RNAi compounds as therapeutic agents in the central nervous system to enhance axonal regeneration after injury

Sarah A Woller; Joerg Ruschel; Barbara Morquette; James Cardia; Dinxue Yan; Katherine Holton; Taisia Shmushkovich; Emily Niederst; Karen Bulock; Alexey Wolfson; Matthew Abbinanti; Alyson E Fournier; Lisa McKerracher; Kenneth M Rosen

doi:10.1016/j.isci.2022.104379

Self-delivering RNAi compounds as therapeutic agents in the central nervous system to enhance axonal regeneration after injury

iScience. 2022 May 10;25(6):104379. doi: 10.1016/j.isci.2022.104379. eCollection 2022 Jun 17.

Affiliations

¹ BioAxone BioSciences Inc., Boston, MA, USA.
² Montréal Neurological Institute, McGill University, Montréal, QC, Canada.
³ Phio Pharmaceuticals, Marlborough, MA, USA.
⁴ Advirna, LLC, Worcester, MA, USA.

Abstract

The therapeutic use of RNAi has grown but often faces several hurdles related to delivery systems, compound stability, immune activation, and on-target/off-tissue effects. Self-delivering RNAi (sdRNA) molecules do not require delivery agents or excipients. Here we demonstrate the ability of sdRNA to reduce the expression of PTEN (phosphatase and tensin homolog) to stimulate regenerative axon regrowth in the injured adult CNS. PTEN-targeting sdRNA compounds were tested for efficacy in vivo by intravitreal injection after adult rat optic nerve injury. We describe critical steps in lead compound generation through the optimization of nucleotide modifications, enhancements for stability in biological matrices, and screening for off-target immunostimulatory activity. The data show that PTEN expression in vivo can be reduced using sdRNA and this enhances regeneration in adult CNS neurons after injury, raising the possibility that this method could be utilized for other clinically relevant nervous system indications.

Keywords: Biotechnology; Health sciences; Techniques in neuroscience.