CRISPR-Based Gene Editing in Rare Genetic Disorders

Abstract

CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9) gene editing -- the programmable RNA-guided endonuclease system that generates sequence-specific DNA double-strand breaks followed by cellular repair through homology-directed repair (HDR) or non-homologous end joining (NHEJ) -- has moved from bacterial immune system curiosity to clinical therapeutic reality within a decade. The first CRISPR-based medicine, exagamglogene autotemcel (exa-cel; Casgevy; Vertex/CRISPR Therapeutics), received FDA approval in December 2023 for sickle cell disease and transfusion-dependent beta-thalassaemia -- a landmark that validates CRISPR gene editing as a clinically actionable therapeutic modality for rare haematological disorders. This review evaluates the clinical and late-stage preclinical evidence for CRISPR therapy across twelve rare genetic disorder indications, categorised by delivery strategy (ex vivo haematopoietic stem cell editing; in vivo LNP-delivered liver targeting; in vivo AAV-delivered tissue-specific editing) and editing mechanism (gene disruption; gene correction; base editing; prime editing). Ex vivo HSC editing for sickle cell disease and beta-thalassaemia achieves the most robust clinical outcomes -- fetal haemoglobin induction >= 30% HbF (median 43.2% in CTX001 trial) correlating with freedom from vaso-occlusive crises in 29 of 29 patients with >= 12 months follow-up. In vivo CRISPR therapy (NTLA-2001 for transthyretin amyloidosis) achieved 87% serum TTR reduction with a single dose -- performance superior to existing RNAi therapy. Off-target editing remains the primary safety concern, with next-generation high-fidelity Cas9 variants (HiFi Cas9; eSpCas9) reducing off-target rates by 10-100-fold vs. wild-type.