RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease.
• Mutations in the superoxide dismutase 1 (SOD1) gene cause familial and some sporadic ALS cases.
• Mutant SOD1 is toxic to motor neurons, making SOD1 gene silencing a therapeutic target.

Purpose of the Study:

• To develop an improved therapeutic strategy for SOD1-mediated ALS.
• To create a chemically stabilized divalent siRNA (di-siRNA) for enhanced SOD1 suppression.
• To evaluate the efficacy of di-siRNA in preclinical ALS models.

Main Methods:

• Development of a chemically stabilized divalent siRNA (di-siRNA) targeting SOD1.
• In vitro and in vivo assessment of SOD1 gene silencing.
• Evaluation of di-siRNA efficacy in SOD1-G93A ALS mouse model via intraventricular administration.
• Assessment of survival, disease progression, and neuropathology.

Main Results:

• The di-siRNA effectively suppressed SOD1 expression both in vitro and in vivo.
• Optimized di-siRNA demonstrated significant CNS tissue permeation and SOD1 silencing in vivo.
• Intraventricular administration of di-siRNA extended survival in SOD1-G93A ALS mice, outperforming ASO modalities.
• The di-siRNA slowed disease progression and prevented ALS neuropathology in the mouse model.

Conclusions:

• Chemically stabilized di-siRNA represents an improved therapeutic strategy for SOD1-mediated ALS.
• The di-siRNA exhibits enhanced CNS penetration and SOD1 silencing compared to previous approaches.
• This approach holds potential for treating other dominantly inherited neurological disorders.