Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS...

Area of Science:

• Neuroscience
• Pharmacology
• Translational Medicine

Background:

• Intrathecal (IT) drug delivery targets the central nervous system (CNS) directly via cerebrospinal fluid (CSF).
• Traditional IT catheterization in mice is challenging due to anatomical constraints and risks like spinal injury.
• Developing less invasive, reproducible IT methods is crucial for preclinical CNS therapeutic evaluation.

Purpose of the Study:

• To establish a less invasive, reproducible acute needle puncture technique for IT drug delivery in adult mice.
• To evaluate the efficacy of IT delivery of antisense oligonucleotides (ASOs) targeting SOD1 in a mouse model of amyotrophic lateral sclerosis (ALS).

Main Methods:

• An acute needle puncture technique was developed for IT drug delivery in adult mice.
• Antisense oligonucleotides (ASOs) targeting the SOD1 gene were administered IT to SOD1-G93A transgenic mice.
• Disease phenotype was assessed using electrophysiological and biomarker analyses.

Main Results:

• The acute IT needle puncture technique provided efficient and reproducible drug delivery in mice.
• IT administration of SOD1-targeting ASOs effectively downregulated mutant SOD1 expression.
• Significant amelioration of the ALS disease phenotype was observed in treated mice.

Conclusions:

• The acute IT needle puncture technique is a robust, reproducible, and clinically relevant method for CNS drug delivery in mice.
• This IT delivery strategy validates the therapeutic potential of SOD1-targeting ASOs for ALS treatment.
• The method offers strong translational relevance for preclinical CNS intervention studies.