HML-2 env knockdown by AAV9-mediated miRNAs attenuates amyotrophic lateral sclerosis-like manifestations in mice

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with unknown causes.
• Human endogenous retrovirus-K (HERV-K), specifically its HML-2 envelope (env) protein, is implicated in ALS pathogenesis.
• HERV-K env expression in neurons causes toxicity and ALS-like symptoms in mice.

Purpose of the Study:

• To investigate the therapeutic potential of Adeno-Associated Virus-9 (AAV9)-mediated artificial microRNAs (amiRNAs) targeting the HERV-K HML-2 env gene in an ALS mouse model.
• To assess the efficacy of AAV9-delivered tandem amiRNAs in reducing HERV-K env expression and mitigating ALS-like pathology.

Main Methods:

• Screened amiRNAs targeting HML-2 env in vitro and selected three for tandem insertion into an AAV9 vector.
• Administered a single intracerebroventricular injection of the AAV9 vector into an HML-2 Env transgenic ALS mouse model at postnatal day 1.
• Evaluated HML-2 env expression, motor neuron survival, muscle pathology, and motor function at 84 days post-injection.

Main Results:

• Tandem amiRNAs delivered via AAV9 achieved robust silencing of HML-2 env gene and protein expression in the brain and spinal cord.
• Reduced HML-2 env expression significantly decreased cortical and spinal motor neuron loss.
• Alleviated muscle fiber degeneration and improved motor function in the treated ALS mice.

Conclusions:

• AAV9-mediated delivery of multiple amiRNAs targeting HERV-K HML-2 env is a promising therapeutic strategy for ALS.
• This approach effectively reduces HERV-K env expression and ameliorates key pathological features and functional deficits in an ALS mouse model.
• Further research into HERV-K as a therapeutic target for ALS is warranted.