Intra-Cerebroventricular (ICV) Route In Mice For Administrating Gene Therapy Products

By Julie Forget, Serah Tanno, Adeline Varnet, George De Los Santos, Matthew Schneider, John MacMaster, and Norbert Makori

Gene therapy (GT) offers a groundbreaking approach to treating a variety of genetic disorders and diseases, with intracerebroventricular (ICV) administration emerging as a novel method for delivering therapeutic agents directly into the cerebrospinal fluid (CSF) within the brain’s ventricles. This approach efficiently targets the central nervous system (CNS), bypassing the blood-brain barrier (BBB), a significant obstacle for systemic delivery methods, making it particularly effective for conditions affecting the brain and spinal cord. Since intrathecal injection is impractical in mice, ICV is the preferred method for preclinical studies.

To evaluate the effects of pain management and ICV injections on animal behavior, functional observational battery (FOB) assessments were conducted 4 and 24 hours post-dose, examining behavioral, sensorimotor, and physiological responses. The positive control group received Buprenorphine ER and Meloxicam without undergoing surgical procedures, while the second group underwent ICV injection with 0.9% saline and received the same pain management. Both groups exhibited increased activity levels compared to pre-dose assessments, indicating the analgesics' effectiveness in enhancing general behavior. However, animals in the ICV group showed a higher incidence and severity of unusual postures and abnormal gait compared to the positive control group, suggesting potential exacerbation of conditions related to the ICV procedure.

Further optimization of analgesic protocols may be required to mitigate increased activity observed at 4 hours post-dose, improving the ability to differentiate potential test article-related behavioral effects. By overcoming the BBB and enabling widespread CNS distribution, ICV administration holds immense promise for treating neurodegenerative diseases and genetic disorders, paving the way for better patient outcomes and enhanced quality of life.