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

iScience

Kenneth M. Rosen¹  Taisia Shmushkovich²  Alexey Wolfson²  Sarah A. Woller³  Emily Niederst³  Matthew Abbinanti³  Joerg Ruschel³  Lisa McKerracher³  Barbara Morquette⁴  Alyson E. Fournier⁴  Dinxue Yan⁵  Karen Bulock⁵  James Cardia⁵  Katherine Holton⁵ 

[1] Corresponding author;Advirna, LLC, Worcester, MA, USA;BioAxone BioSciences Inc., Boston, MA, USA;Montréal Neurological Institute, McGill University, Montréal, QC, Canada;Phio Pharmaceuticals, Marlborough, MA, USA;

关键词: Biotechnology;    Health sciences;    Techniques in neuroscience;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown