Jul 2026· Clinics And Research in Hepatology and Gastroenterology· pp.
102892
· 0 citations· 70 references
Medicine
TL;DR
This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, and underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
Abstract
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
Gene therapy is undergoing continued clinical translation and technological development. This progress has been marked by regulatory approvals and broadened therapeutic indications across genetic, metabolic, and oncologic diseases and disorders. The field has evolved over decades from early viral-mediated gene addition to approaches capable of targeted editing, regulation, or replacement of genetic information. These systems include base and prime editors, epigenetic modulators, CRISPR-Cas, RNA therapeutics and programmable integration platforms. When paired with increasingly sophisticated viral and nonviral delivery strategies, these technologies enable greater control over tissue targeting, duration of activity, and therapeutic exposure. Recent clinical successes, including approved ex vivo CRISPR-based therapies for hemoglobinopathies, in vivo CRISPR editing for transthyretin amyloidosis, and emerging clinical applications of base and prime editing, provide growing clinical evidence for the feasibility of genetic medicines. However, technological advancement has also made platform selection increasingly complex. Therapeutic performance is determined not by editing efficiency alone, but by the interaction among genetic precision, temporal control, dosage tunability, delivery efficiency, durability, and disease-specific safety requirements. A molecularly efficient platform may still have limited therapeutic value if it cannot reach the disease-relevant cell population at sufficient and safe exposure. In this review, we examine recent technological and clinical advances in genetic medicine with particular emphasis on developments during the past approximately five years. We propose a multidimensional framework in which gene therapy platforms are evaluated according to three intrinsic properties—genetic precision, temporal control, and dosage tunability—while delivery, clinical maturity, and disease context act as major translational constraints. This framework highlights that no single platform is universally optimal; rather, successful therapeutic design depends on matching the biological characteristics of the intervention to the requirements of the disease and target tissue. Remaining challenges in extrahepatic delivery, genomic safety, immunogenicity, manufacturing, and long-term monitoring remain important determinants of broader clinical implementation.
Jared Wieland, Peyton Jackson, William Penrod et al.· Cells· 0 citations
Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints, delivery constraints, immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts.
Moksada Regmi, K. Ma, Changhao Bi et al.· Cell Genomics· 0 citations
The success of CRISPR-Cas9 in monogenic diseases represents the prelude to precision medicine, whereas conquering complex diseases will require systematic leaps in target discovery, delivery technology, and safety profiles.
CRISPR-Cas9, adapted from the bacterial Type II CRISPR adaptive immune system, functions as a programmable RNA-guided endonuclease that employs a single-guide RNA to direct Cas9 to specific genomic loci. CRISPR-Cas9 has transformed targeted genome editing by replacing complex protein engineering with programmable Watson–Crick base pairing between the guide RNA and target DNA. This review was developed following a structured literature search of major biomedical databases and clinical trial registries to synthesize current evidence on the therapeutic applications of CRISPR-Cas9 in oncology and inherited genetic disorders. Clinical studies of
ex vivo BCL11A
-enhancer editing have shown fetal hemoglobin reactivation, with most evaluable participants with sickle cell disease remaining free of severe vaso-occlusive crises for the prespecified period and most evaluable participants with transfusion-dependent β-thalassemia achieving sustained transfusion independence.
In vivo
reductions in circulating transthyretin protein levels have been achieved for transthyretin amyloidosis via lipid nanoparticle delivery, while clinically meaningful improvements in selected measures of visual function were observed in a subset of patients receiving subretinal AAV-delivered CRISPR editing for
CEP290
-associated Leber congenital amaurosis type 10. Preclinical and early clinical studies have further investigated CRISPR-engineered T cells designed to improve antitumor activity, persistence, or resistance to inhibitory signaling. Despite these advances, key translational hurdles include the risk of off-target mutations and large-scale chromosomal rearrangements. Furthermore, immune responses against bacterial Cas9 nucleases and viral delivery vectors may limit the long-term efficacy of CRISPR-based therapies, while technical barriers surrounding delivery to extrahepatic tissues, such as skeletal muscle and the central nervous system, continue to hinder broader clinical success. Ethical concerns regarding germline modifications and the high cost of individualized therapies present additional translational challenges. Consequently, emerging DSB-independent technologies, such as base editing and prime editing, may reduce selected DSB-associated liabilities, but each introduces distinct editing, delivery, and genotoxicity risks that require product-specific evaluation.
Khushi Bashir, Prathiksha Vasudev, Vikas Chhetri et al.· Frontiers in Genome Editing· 0 citations
Atherosclerosis continues to be a primary contributor to global cardiovascular mortality, influenced by intricate lipid and inflammatory mechanisms. Despite the efficacy of conventional pharmacotherapies, ongoing issues of patient non-adherence and residual risk have prompted the exploration of more enduring therapeutic alternatives. This review examines the significant transition in cardiovascular research from conventional, wide knockout models to the utilization of advanced precision genome editing methods, particularly emphasizing CRISPR-Cas9, base editing, and prime editing. These sophisticated molecular tools allow for the accurate insertion and rectification of single-nucleotide variants without causing double-strand breaks, marking a significant shift from rudimentary gene disruption to precise variant engineering. By specifically targeting essential lipid-regulating genes like proprotein convertase subtilisin/kexin type 9 (PCSK9) and angiopoietin-like 3 (ANGPTL3), precision editing presents an exceptional opportunity for lasting, one-shot lipid-lowering treatments. Additionally, we examine the advancement of preclinical modeling, emphasizing humanized models that precisely represent population genetics. This review highlights the essential obstacles to clinical translation, focusing on the optimization of delivery systems such as adeno-associated viruses (AAVs) and lipid nanoparticles (LNPs), as well as the thorough assessment of off-target effects and ethical implications.
Durlav Chowdhury, Nirdesh Singh, Swarnalata Garai et al.· European Journal of Pharmaco...· 0 citations
CRISPR gene-editing technology has revolutionized modern genetics, offering precise and efficient modifications across multiple domains, including human medicine, agriculture, and veterinary science. This study explores the diverse applications of CRISPR, highlighting its role in treating genetic disorders such as sickle cell anemia and Duchenne muscular dystrophy, advancing cancer immunotherapies, and developing CRISPR-based antiviral therapies for HIV and COVID-19. In agriculture, CRISPR has facilitated the development of disease-resistant livestock, enhanced crop yields, and improved food sustainability. Additionally, CRISPR is being integrated with artificial intelligence (AI) and bioinformatics to optimize gene-editing accuracy, predict off-target effects, and accelerate drug discovery. Despite these advancements, CRISPR faces significant challenges, including ethical dilemmas surrounding germline editing, regulatory inconsistencies across countries, high costs of gene therapies, and concerns about genetic inequality. The legal and social implications of CRISPR remain complex, requiring global cooperation to establish standardized regulations and ensure equitable access to genetic therapies. Emerging innovations such as base editing, prime editing, and epigenetic modifications offer promising solutions to improve CRISPR’s precision and safety. Looking ahead, CRISPR’s long-term success will depend on responsible scientific advancements, ethical oversight, and public acceptance. With the continued refinement of gene-editing techniques and AI-driven CRISPR optimizations, this technology holds the potential to revolutionize medicine, agriculture, and environmental conservation. However, careful implementation and transparent discussions are essential to navigate the ethical, legal, and societal challenges that accompany CRISPR’s rapid development.
B. Aloufi· Journal of Pure and Applied...· 0 citations
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