Collagen proteins play a vital role in numerous processes throughout the body, contributing to the function of various tissues. Consequently, pathogenic variants in genes encoding collagens are linked to a similarly diverse range of disorders, often with significant and severe effects.Developments in gene editing now show promising avenues to tackle the root cause of these diseases in previously inconceivable ways. Kocsy et al., in their review [1], describe the diverse methods being investigated to target collagen disorders at a genetic level, their challenges, and new investigations that may resolve these issues. Exciting developments bringing the first gene editing therapies to patients may illuminate paths to take the discussed approaches to clinic [2,3,4].The genetic causes of collagen disease can be tackled via several approaches (Fig. 1). Perhaps the most intuitive is to correct disease-causing variants at a genomic level, with many corrective methodologies for pathogenic collagen variants highlighted in this review. The emergence of CRISPR/Cas9 marked a turning point in genetic medicine, offering a versatile tool with the promise of editing disease-causing pathogenic variants. Traditional CRISPR/Cas9 uses RNA to guide Cas9 nuclease to cut a double stranded break (DSB) in target DNA, which can be combined with a donor template encoding the desired sequence. Homology directed repair (HDR), active in dividing cells, can then recombine the DSB, integrating the desired sequence. However, DSBs can risk random insertions/deletions (INDELS) of nucleotides at the cut site and induce apoptosis via p53 activation. By modifying Cas9 to nick a single strand of DNA, alternative gene editing tools have been created, further developed by fusing this nCas9 to other proteins. One such method is base editing, allowing biochemical conversion of individual nucleotides to correct variants [5, 6]. Prime editing provides a more versatile tool to correct disease variants, combining nCas9 and a reverse transcriptase, able to precisely integrate edits tens of bases long [7].Fig. 1: Gene editing approaches for personal medicine.A Showing delivery routes taken in gene editing treatments, indicating cell therapy, topical application, and systematic delivery. B A schematic of approaches taken in the treatment of genetic variants showing gene replacement, correction of pathogenic variants, knockout of pathogenic gene, disease without genetic intervention, and gene suppression at an RNA level, each annotated with relevant techniques. Created in BioRender.Full size imageAlongside the development of new technologies, reapplying existing ones also show promise. In this way, Cas9’s DSBs have been used to induce INDELs, selectively knocking out pathogenic variants [8, 9]. The desire to silence pathogenic variants has also inspired investigation into non-CRISPR approaches, including siRNA [10] and GAPMER [11], antisense oligonucleotides which prevent transcription of pathogenic transcripts by complementarily binding mRNA.Though many of the approaches covered by Kocsy et al. are effective in vitro, the expression patterns of each collagen come with unique requirements in therapeutic delivery. Gene editing treatments can be administered in vivo (applied topically or systematically), or ex vivo, with cells treated outside the body and then re-grafted into patients (Fig. 1A). The choice of gene delivery system depends on factors like cargo size (DNA, RNA, or protein), the desired duration of cargo expression (transient or genomic integration), and whether the target cells are dividing or non-dividing. Various viral vectors have seen application based on these factors [3, 12, 13], but concerns of immunogenicity and tumourgenicity of integrating viruses have led to recent clinical use of non-viral gene editor delivery, such as electroporation [4] and lipid nanoparticles (LNPs) [2].While these approaches remain subjects of much research, gene replacement – introducing a healthy copy of diseased genes to recover protein expression – has successfully reached patients with positive results [3]. For clinical gene therapy, Vyjuvek’s approval for dystrophic epidermolysis bullosa (DEB) treatment marked a pioneering moment. It is the first topical gene therapy approved by the Food and Drug administration (FDA) (2023) and the European Medicines Agency (EMA) (2025), utilising a modified herpes simplex virus (HSV-1) to deliver functional COL7A1 genes in vivo. Other therapies in clinical trial use lentiviral vectors: one approach uses edited keratinocytes to create epidermal grafts with functional COL7A1 for transplantation (NCT01263379) [12], while another administered intradermal injections with lentiviral vectors containing the full-length COL7A1 cDNA (NCT02493816) [13]. Both demonstrated robust safety profiles and promising improvements to wound healing, paving the way for more benchside-to-bedside transition to transform current treatments.Despite these early successes, challenges linger and most novel technologies described in Kocsy et al. struggle to translate from preclinical promise to therapeutic reality. Gene replacement dominates the clinical pipeline, and while exciting in potential, precise editing therapy for collagen disorders have yet to leave the bench. In other fields, CRISPR programming is quickly proving to drive future advancements, with recent breakthroughs cementing its role in treating rare genetic diseases. The first approved CRISPR-based therapy, Casgevy, has established durable clinical benefits in sickle cell disease patients through targeted DNA modification [4]. Notably, a personalised base editor therapy was developed for an infant with neonatal-onset carbamoyl-phosphate synthetase 1 (CPS1) deficiency, successfully correcting a point variation and improving patient prognosis [2]. The process from diagnosis to delivery was realised within 8 months, highlighting how precise editing treatments can be developed with remarkable speed, provided the right resources are available. Why, then, is it so difficult to replicate these clinical achievements in collagen disorders?Some critical hurdles include low efficiency, delivery system limitations and off-target effects. COL6A1 silencing in Ullrich congenital muscular dystrophy (UCMD) showed low editing efficiencies (