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 a significant portion of familial and sporadic ALS cases.
• Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a key therapeutic strategy.

Purpose of the Study:

• To develop an improved therapeutic strategy for SOD1-mediated ALS.
• To create a chemically stabilized divalent siRNA (di-siRNA) scaffold for effective SOD1 gene 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 expression suppression.
• Evaluation of CNS tissue permeation and SOD1 silencing in vivo.
• Intraventricular administration of di-siRNA in SOD1-G93A ALS mice.
• Assessment of survival, disease progression, and neuropathology in treated mice.

Main Results:

• The di-siRNA scaffold effectively suppressed SOD1 expression in vitro and in vivo.
• Optimized chemical modification led to remarkable CNS tissue permeation and SOD1 silencing.
• Intraventricular administration of di-siRNA extended survival in SOD1-G93A ALS mice beyond ASO modalities.
• The treatment slowed disease progression and attenuated neuropathology in the preclinical model.

Conclusions:

• Chemically stabilized di-siRNA is a promising therapeutic strategy for SOD1-mediated ALS.
• This approach offers improved pharmacodynamics and pharmacokinetics compared to existing ASO therapies.
• The di-siRNA platform may be applicable to other dominantly inherited neurological disorders.