CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats) genome editing technologies have transformed the therapeutic landscape for [neurodegenerative /diseases[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/diseases by enabling precise correction or inactivation of disease-causing genes. Unlike [antisense oligonucleotides[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy[/treatments/[antisense-oligonucleotide-therapy--TEMP--/treatments)--FIX-- (ASOs), which require repeated dosing and produce temporary knockdown, CRISPR can achieve permanent genetic modification in a single treatment—a transformative prospect for monogenic neurodegenerative disorders such as [Huntington's disease[/mechanisms/[huntington-pathway[/mechanisms/[huntington-pathway[/mechanisms/[huntington-pathway--TEMP--/mechanisms)--FIX-- (HD), familial [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX-- (fAD), familial [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX-- (fPD), and [amyotrophic lateral sclerosis[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX-- (ALS).
The CRISPR toolkit has expanded beyond the original Cas9 nuclease to include base editors, prime editors, CRISPRi/CRISPRa for gene regulation, and RNA-targeting Cas13 systems—each offering distinct advantages for neurological applications where off-target DNA cuts in post-mitotic [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- pose irreversible risks (Akyuz et al., 2024; Bhatt et al., 2025).
The canonical system uses the Cas9 nuclease guided by a single-guide RNA (sgRNA) to create a double-strand break (DSB) at a specific genomic locus. In [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, DSBs are repaired primarily by non-homologous end joining (NHEJ), which can inactivate a gene by introducing insertions/deletions (indels).
Applications: Disruption of mutant alleles (e.g., mutant [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX--, [SOD1[/proteins/[sod1-protein[/proteins/[sod1-protein[/proteins/[sod1-protein--TEMP--/proteins)--FIX--, [APP[/genes/[app[/genes/[app[/genes/[app--TEMP--/genes)--FIX--
Limitations: Off-target DSBs in post-mitotic [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- are permanent and uncorrectable; risk of large deletions, translocations, or chromothripsis.
Base editors (cytosine base editors, CBE; adenine base editors, ABE) convert one base pair to another (C→T or A→G) without creating DSBs. This is safer for [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- and ideal for correcting point mutations.
Applications: Correcting [PSEN1[/genes/[psen1[/genes/[psen1[/genes/[psen1--TEMP--/genes)--FIX-- and [PSEN2[/genes/[psen2[/genes/[psen2[/genes/[psen2--TEMP--/genes)--FIX-- missense mutations in familial AD; [LRRK2[/genes/[lrrk2[/genes/[lrrk2[/genes/[lrrk2--TEMP--/genes)--FIX-- G2019S mutation in PD; specific [SOD1[/proteins/[sod1-protein[/proteins/[sod1-protein[/proteins/[sod1-protein--TEMP--/proteins)--FIX-- mutations in ALS.
Prime editors use a Cas9 nickase fused to a reverse transcriptase, guided by a prime editing guide RNA (pegRNA) that encodes the desired edit. Prime editing can make all 12 types of point mutations, small insertions, and small deletions without DSBs.
Applications: Precise correction of expanded [CAG repeats] in HD; correction of specific mutations in fAD and fPD.
Catalytically dead Cas9 (dCas9) fused to transcriptional repressors (CRISPRi) or activators (CRISPRa) modulates gene expression without altering DNA sequence.
Advantages: No permanent DNA alteration; reversible; lower risk of off-target damage.
Cas13 systems target and degrade specific RNA transcripts, functioning as programmable RNA knockdown tools. Unlike DNA-targeting systems, Cas13 leaves the genome intact.
Applications: Degradation of mutant [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- mRNA, [C9orf72[/genes/[c9orf72[/genes/[c9orf72[/genes/[c9orf72--TEMP--/genes)--FIX-- repeat RNA, or toxic [TDP-43[/entities/[tdp-43[/entities/[tdp-43[/entities/[tdp-43--TEMP--/entities)--FIX-- transcripts.
HD is the most advanced neurodegenerative target for CRISPR, given its monogenic etiology (expanded [CAG repeat] in [HTT):
Allele-specific silencing: CRISPR-Cas9 can selectively inactivate the mutant [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- allele while preserving normal [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- by targeting SNPs linked to the disease haplotype. This avoids the problem of total [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- loss-of-function, which is developmentally lethal (Monteys et al., 2017).
Repeat excision: Cas9 with two flanking sgRNAs can excise the expanded CAG repeat, replacing it with a normal-length repeat. This has been demonstrated in HD patient-derived iPSC [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- (Dabrowska et al., 2018).
CRISPRi approach: dCas9-KRAB targeted to the [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- promoter region suppresses mutant [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- expression by 60-80% in mouse striatal [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- without DNA cleavage.
In vivo delivery: AAV-packaged CRISPR targeting mutant [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- reduced [huntingtin[/proteins/[huntingtin[/proteins/[huntingtin[/proteins/[huntingtin--TEMP--/proteins)--FIX-- aggregates and improved motor function in HD mouse models (Ekman et al., 2019).
CRISPR approaches in AD target multiple pathogenic genes:
[APP[/genes/[app[/genes/[app[/genes/[app--TEMP--/genes)--FIX-- editing: CRISPR-mediated introduction of the protective A673T (Icelandic) mutation in [APP[/genes/[app[/genes/[app[/genes/[app--TEMP--/genes)--FIX-- reduces [Aβ[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- production by ~40%. This mutation decreases [BACE1[/entities/[bace1[/entities/[bace1[/entities/[bace1--TEMP--/entities)--FIX--.
[PSEN1[/genes/[psen1[/genes/[psen1[/genes/[psen1--TEMP--/genes)--FIX-- correction: Base editing can correct specific presenilin mutations that cause [familial Alzheimer's Disease]. Over 300 [PSEN1[/genes/[psen1[/genes/[psen1[/genes/[psen1--TEMP--/genes)--FIX-- mutations are known, many of which are single nucleotide changes amenable to base editing.
**[APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX-- using base editors has been demonstrated in human iPSC-derived [astrocytes[/cell-types/[astrocytes[/cell-types/[astrocytes[/cell-types/[astrocytes--TEMP--/cell-types)--FIX-- and [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, reducing [Aβ[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- production and tau] hyperphosphorylation (Lin et al., 2018).
[TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX-- activation: CRISPRa to upregulate [TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX-- expression in [microglia[/cell-types/[microglia[/cell-types/[microglia[/cell-types/[microglia--TEMP--/cell-types)--FIX--/entities/microglia. Adenine base editors can revert the pathogenic G→A mutation with high efficiency in patient iPSC-derived dopaminergic [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--.
[α-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein--TEMP--/proteins)--FIX-- (SNCA) reduction: CRISPRi-mediated downregulation of SNCA expression reduces [α-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein--TEMP--/proteins)--FIX-- aggregation. SNCA gene duplication/triplication causes familial PD, and even partial reduction of wild-type SNCA may be therapeutic.
[GBA1[/genes/[gba[/genes/[gba[/genes/[gba--TEMP--/genes)--FIX-- correction: GBA1 mutations (the most common genetic risk factor for PD) can be corrected by base or prime editing, restoring glucocerebrosidase activity and improving [lysosomal function].
[PINK1[/genes/[pink1[/genes/[pink1[/genes/[pink1--TEMP--/genes)--FIX--/[Parkin[/genes/[prkn[/genes/[prkn[/genes/[prkn--TEMP--/genes)--FIX-- enhancement: CRISPRa to upregulate mitophagy genes, enhancing clearance of damaged [mitochondria[/entities/[mitochondrial-dynamics[/entities/[mitochondrial-dynamics[/entities/[mitochondrial-dynamics--TEMP--/entities)--FIX--.
[SOD1[/proteins/[sod1-protein[/proteins/[sod1-protein[/proteins/[sod1-protein--TEMP--/proteins)--FIX-- silencing: CRISPR-Cas9 disruption of mutant SOD1 in the SOD1-G93A mouse model reduced mutant SOD1 protein levels by ~50% and extended survival. This approach complements the [ASO tofersen[/treatments/[tofersen[/treatments/[tofersen[/treatments/[tofersen--TEMP--/treatments)--FIX-- strategy.
[C9orf72[/genes/[c9orf72[/genes/[c9orf72[/genes/[c9orf72--TEMP--/genes)--FIX-- repeat excision: Cas9 with flanking guides can excise the hexanucleotide repeat expansion, eliminating both RNA foci and dipeptide repeat protein production (Selvaraj et al., 2018).
[FUS[/entities/[fus[/entities/[fus[/entities/[fus--TEMP--/entities)--FIX-- correction: Base editing of FUS mutations that disrupt nuclear localization (affecting the PY-NLS recognized by transportin-1), restoring proper [nucleocytoplasmic transport].
| Disease | CRISPR Target | Approach |
|---|---|---|
| [Friedreich's Ataxia[/diseases/[friedreichs-ataxia[/diseases/[friedreichs-ataxia[/diseases/[friedreichs-ataxia--TEMP--/diseases)--FIX-- | GAA repeat in FXN | Repeat excision, CRISPRa for FXN upregulation |
| [SCA] (various) | Expanded CAG in ATXN genes | Allele-specific knockout or repeat excision |
| [SMA[/diseases/[spinal-muscular-atrophy[/diseases/[spinal-muscular-atrophy[/diseases/[spinal-muscular-atrophy--TEMP--/diseases)--FIX-- | SMN2 exon 7 inclusion | Base editing to convert SMN2 → SMN1-like |
| [Batten Disease[/diseases/[batten-disease[/diseases/[batten-disease[/diseases/[batten-disease--TEMP--/diseases)--FIX-- | CLN gene mutations | Gene correction via HDR or base editing |
| [Wilson's Disease[/diseases/[wilson-disease[/diseases/[wilson-disease[/diseases/[wilson-disease--TEMP--/diseases)--FIX-- | ATP7B mutations | Gene correction |
| [Rett Syndrome[/diseases/[rett-syndrome[/diseases/[rett-syndrome[/diseases/[rett-syndrome--TEMP--/diseases)--FIX-- | MECP2 mutations | Gene correction, CRISPRa |
The greatest challenge for CRISPR-based neurotherapeutics is delivering editing machinery across the [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- to target cells in the CNS.
Adeno-associated virus (AAV):
Lentiviral vectors:
Lipid nanoparticles (LNPs):
Extracellular vesicles/exosomes:
Polymer nanoparticles:
CRISPR-Cas9 can cut at genomic sites with partial sgRNA complementarity. In post-mitotic [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, off-target DSBs are irreversible and could activate oncogenes, inactivate tumor suppressors, or disrupt essential genes.
Mitigation strategies:
| Disease | Target | Stage | Notes |
|---|---|---|---|
| [HD] | [HTT[/genes/[htt[/genes/[htt[/genes/[htt--TEMP--/genes)--FIX-- | Preclinical (advanced) | Multiple AAV-CRISPR approaches in NHP studies |
| [ALS[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX-- (SOD1) | SOD1 | Preclinical | Complementing approved ASO ([tofersen[/treatments/[tofersen[/treatments/[tofersen[/treatments/[tofersen--TEMP--/treatments)--FIX-- |
| [AD] (fAD) | [APP[/genes/[app[/genes/[app[/genes/[app--TEMP--/genes)--FIX--, [PSEN1[/genes/[psen1[/genes/[psen1[/genes/[psen1--TEMP--/genes)--FIX-- | Preclinical | APOE4→APOE3 conversion in development |
| [PD] (LRRK2) | LRRK2 | Preclinical | Base editing approach |
| [SCA] | ATXN genes | Preclinical | AAV-delivered Cas9 |
| Transthyretin amyloidosis | TTR | Phase I (Intellia NTLA-2001) | First in vivo CRISPR therapy for a systemic disease; proof of concept for neurodegeneration |
The Intellia Therapeutics NTLA-2001 trial for transthyretin amyloidosis—using LNP-delivered Cas9 to inactivate TTR in the liver—demonstrated >90% reduction in serum transthyretin after a single dose, providing the first clinical proof that in vivo CRISPR editing is feasible and effective (Gillmore et al., 2021).
The study of Crispr Gene Editing For Neurodegenerative Diseases has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.