CRISPR/Cas9 Gene Editing Therapy for Genetic Disease Correction — Regenerative Therapies
Revolutionary gene editing technology enabling precise DNA modifications. First FDA-approved CRISPR therapy (Casgevy) in December 2023.
Overview
CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) is a revolutionary gene editing technology derived from bacterial adaptive immune systems. Discovered by Jennifer Doudna and Emmanuelle Charpentier (Nobel Prize 2020), CRISPR-Cas9 enables precise, programmable cutting of DNA at specific genomic locations. In December 2023, FDA approved Casgevy (exagamglogene autotemcel, Vertex/CRISPR Therapeutics) - the first-ever CRISPR-based therapy - for sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). Casgevy works by editing the BCL11A gene in patient's own HSCs to reactivate fetal hemoglobin. Cost: approximately $2.2 million per patient. Beyond Casgevy, CRISPR trials investigate transthyretin amyloidosis (NTLA-2001, Intellia - in vivo liver editing), hereditary angioedema, cancer immunotherapy (CRISPR-enhanced CAR-T), HIV cure strategies, and inherited blindness. Next-generation tools include base editing and prime editing.
Indications
- Sickle cell disease (FDA-APPROVED: Casgevy)
- Transfusion-dependent beta-thalassemia (FDA-APPROVED: Casgevy)
- Transthyretin amyloidosis (NTLA-2001 - Phase 1/2, in vivo liver editing)
- Hereditary angioedema (NTLA-2002 - Phase 1/2)
- Leber congenital amaurosis type 10 (EDIT-101 - in vivo retinal editing)
- Cancer immunotherapy (CRISPR-enhanced CAR-T cells)
- HIV-1 cure strategies (CCR5 knockout in CD4+ T cells)
- Duchenne muscular dystrophy (exon skipping approaches)
- Hemophilia A and B (factor VIII/IX gene correction)
Mechanism of Action
Synthetic guide RNA designed to target specific genomic sequence. Delivered as mRNA + gRNA in lipid nanoparticles (in vivo) or via electroporation (ex vivo)
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Exagamglogene autotemcel (Casgevy) | Patient-specific (edited HSCs) | Single infusion (curative intent) | Autologous CRISPR-edited CD34+ HSCs for SCD/TDT (Casgevy) |
| NTLA-2001 (Cas9 mRNA + gRNA in LNP) | 0.1-0.7 mg/kg | Single infusion | In vivo liver-directed editing for TTR amyloidosis (NTLA-2001 Phase 1) |
| EDIT-101 (AAV5-delivered CRISPR) | Subretinal injection | Single injection per eye | In vivo retinal editing for LCA10 (EDIT-101) |
Evidence Grade
GRADE C
Safety & Contraindications
- Off-target editing: Cas9 may cut at unintended genomic sites
- Large chromosomal rearrangements (chromothripsis) reported in preclinical studies
- p53 pathway inactivation may be selected for during editing (cancer risk)
- Immune response to Cas9 protein (bacterial origin) - anti-Cas9 antibodies in ~70% of humans
- Mosaicism: not all target cells may be edited
- Casgevy requires myeloablative conditioning (busulfan) - significant toxicity including infertility
- Cost: ~$2.2 million per patient for Casgevy
- Long-term oncogenicity surveillance required
- Ethical considerations for germline editing (prohibited in clinical settings)
- In vivo editing carries risk of editing non-target tissues