Gene editing technologies represent a transformative approach for treating neurodegenerative diseases by directly modifying disease-causing genetic mutations. Using tools like CRISPR-Cas9, base editing, and prime editing, researchers can correct pathogenic variants, reduce toxic protein expression, or modulate gene expression to halt or reverse disease progression.
The CRISPR-Cas9 system uses a guide RNA (gRNA) to direct the Cas9 nuclease to specific genomic loci for double-strand break formation:
- Standard CRISPR-Cas9 — Creates double-strand breaks that are repaired by non-homologous end joining (NHEJ) or homology-directed repair (HDR)
- Cas9 nickases — Create single-strand breaks for reduced off-target effects
- Dead Cas9 (dCas9) — Catalytically inactive Cas9 fused to effector domains for gene regulation
Base editors enable precise single-nucleotide changes without double-strand breaks:
- Cytosine base editors (CBE) — Convert C→T or G→A
- Adenine base editors (ABE) — Convert A→G or T→C
- Prime editors — Enable all types of conversions and small insertions/deletions
- AAV vectors — Adeno-associated viruses for CNS delivery
- LNP (Lipid Nanoparticles) — Alternative delivery vehicles
- Viral vectors — Lentivirus, adenovirus for different applications
Gene editing targets:
| Gene |
Approach |
Status |
| APP |
Reduce Aβ production |
Preclinical |
| PSEN1 |
Correct familial AD mutations |
Preclinical |
| PSEN2 |
Correct mutations |
Preclinical |
| APOE |
Convert APOE4 to APOE3 |
Preclinical |
Gene editing targets:
Gene editing targets:
- SOD1 — Silence toxic mutant SOD1
- C9orf72 — Reduce toxic repeat expansions
- FUS — Correct mutations
- TARDBP — Address TDP-43 pathology
Gene editing approaches:
- HTT — Reduce mutant huntingtin protein
- Allele-specific editing targeting mutant allele
- Non-allele-specific approaches
¶ Current Trials and Programs
- Ionis-HTTRx — Antisense oligonucleotide (not gene editing, but related)
- CRISPR trials for other diseases — Foundation Medicine, Editas trials
- Preclinical programs — Multiple programs advancing toward clinical testing
- Delivery to the brain — AAV capsid engineering for enhanced CNS targeting
- Off-target effects — Minimizing unintended genome modifications
- Immune responses — Against Cas9 proteins
- Large genes — Some disease genes exceed AAV capacity
- Regulatory considerations — Germline vs. somatic editing ethics
- CRISPRi/dCas9-KRAB for transcriptional repression
- Guide RNA approaches for allele-specific silencing
- Combined with RNA interference
- HDR-based correction of pathogenic mutations
- Base editing for precise nucleotide changes
- Prime editing for complex corrections
- Epigenetic editing to increase beneficial gene expression
- Protective allele introduction
- Regulatory element modification
- In vivo delivery — Direct administration to CNS
- Multiplexed editing — Targeting multiple genes simultaneously
- Cell-type specificity — Promoter-based targeting
- Prime editing — More precise genome modifications
- Base editing — Reduced off-target effects
- Somatic vs. germline editing boundaries
- Equitable access to expensive therapies
- Informed consent for experimental treatments
- Long-term monitoring requirements