CRISPR/cas genome editing for neurodegenerative diseases: Mechanisms, therapeutic advances, and clinical prospects

Oct 18, 2025Ageing research reviews

Using CRISPR Gene Editing to Treat Brain Diseases: How It Works, Recent Progress, and Future Possibilities

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Abstract

CRISPR/Cas genome editing technologies may offer targeted repair of pathological mutations in neurodegenerative diseases.

CRISPR/Cas9 has shown potential in disrupting mutant genes associated with Alzheimer's disease, reducing toxic protein aggregation.
Correction of CAG nucleotide repeats has been observed in Huntington's disease models.
Reduction of alpha-synuclein expression has been achieved in Parkinson's disease models.
RNA targeting systems like Cas13 could selectively degrade disease-associated transcripts without altering genomic DNA.
Challenges such as off-target effects, mosaicism, and blood-brain barrier delivery remain significant.
Ethical considerations are focused on the implications of somatic versus germline editing and equitable access to therapies.

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Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebral Ataxia (SCA), and Huntington's disease (HD) are major global health challenges. Current treatments are only symptomatic and do not address the underlying pathogenic genetic mechanisms. The development of the CRISPR/Cas genome editing technologies, has increased possibilities for targeted repair of pathological mutations. CRISPR/Cas9, Cas12, and Cas13 systems enable targeted editing and transcriptome modulation in various preclinical models. CRISPR/Cas9 disruption of mutant APP, Tau, and LRRK2 genes, reducing toxic protein aggregration in AD models has restored normal genetic function. While correction of CAG nucleotide repeats in HD, and reduction of alpha-synuclein expression in PD. RNA targeting systems like Cas13 offers additional therapeutics potential by selectively degrading disease assciated transcript without altering genomic DNA. Advancements in engineered Cas variants with enhanced specificity, such as SpCas9-HF1, base editors and prime editors, with innovative delivery strategies including adeno-associated virus (AAVs) and nanoparticle-based systems, have improved genome editing. However, challenges remain, including off-target effects, mosaicism, and delivery across the BBB, and long-term safety. Ethical consideration focuses on somatic versus germline editing, equitable access, and regulatory oversight. While somatic editing shows acceptance in treating neurological disorders. Germline interventions face strict regulations due to potential multigeneration impacts. Collectively, these technologies are the vanguard of precision molecular medicine, advancing from symptom management towards potentially curative gene therapies for neurological disorders.

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CRISPR/cas genome editing for neurodegenerative diseases: Mechanisms, therapeutic advances, and clinical prospects

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