Gene and nucleic acid therapies for MMUT-deficient methylmalonic acidemia: from AAV-mediated gene addition to LNP-mediated mRNA delivery and precision genome editing
Aug 2026· Orphanet Journal of Rare Diseases· 0 citations
TL;DR
Current therapeutic evidence is concentrated primarily in MMUT- deficient isolated MMA, and further progress will require safer and more durable delivery platforms, improved tissue targeting, robust long-term safety assessment, clinically meaningful endpoints, and careful evaluation of accessibility and cost.
Abstract
Methylmalonic acidemia (MMA) comprises a heterogeneous group of inherited metabolic disorders characterized by the accumulation of methylmalonic acid and related toxic metabolites. Among these conditions, isolated MMA caused by pathogenic variants in
MMUT
is the disease subtype in which gene and nucleic acid therapies have been investigated most extensively. Current management, including dietary protein restriction, L-carnitine supplementation, acute decompensation management, assessment of cobalamin responsiveness, and liver or combined liver-kidney transplantation, can improve metabolic stability but often remains insufficient to prevent recurrent metabolic crises, neurological injury, renal impairment, and reduced quality of life.
This review summarizes the development of gene and nucleic acid therapies for
MMUT-
deficient MMA over the past three decades. The field has evolved from cellular correction and early nonviral, adenoviral, retroviral, and lentiviral approaches to adeno-associated virus (AAV)-mediated
MMUT
gene addition,
albumin
(
ALB
)-locus genome editing, lipid nanoparticle (LNP)-mediated
MMUT
mRNA delivery, central nervous system and extrahepatic targeting, antisense-based splicing correction, mitochondrial protein delivery, and emerging precision-editing strategies. AAV8, AAV9, AAV44.9, and nuclease-free
ALB
-locus editing studies have provided a substantial preclinical foundation, while mRNA-based therapy and liver-directed genome editing have begun to enter clinical translation. However, AAV immunotoxicity, pre-existing neutralizing antibodies, redosing barriers, dilution of episomal transgene expression in the growing pediatric liver, incomplete correction of extrahepatic tissues, delivery safety, treatment burden, and cost remain major obstacles.
Current therapeutic evidence is concentrated primarily in
MMUT-
deficient isolated MMA. Further progress will require safer and more durable delivery platforms, improved tissue targeting, robust long-term safety assessment, clinically meaningful endpoints, and careful evaluation of accessibility and cost.
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.
Anh Tuan Quan· Clinics And Research in Hepa...· 0 citations
ABSTRACT Introduction Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling caused by dysregulation of the kallikrein–kinin pathway. Although current therapies effectively reduce attack frequency, treatment remains lifelong. Lonvoguran ziclumeran (Lonvo-z; NTLA-2002) is the first systemically administered in vivo CRISPR/Cas9 gene-editing therapy designed to provide durable suppression of plasma kallikrein through permanent disruption of the KLKB1 gene. Areas covered This review summarizes the pathophysiology and current management of HAE, the development of Lonvo-z, its lipid nanoparticle delivery platform, and the technical advances enabling in vivo genome editing. Preclinical studies and clinical evidence, including early-phase trials and the Phase 3 HAELO study, are reviewed with emphasis on efficacy, safety and clinical implications. Expert opinion Lonvo-z represents a major milestone in precision medicine and the clinical application of systemic genome editing. A single administration has produced sustained reductions in plasma kallikrein levels and HAE attack frequency. Although long-term follow-up is ongoing, current evidence supports its potential as the first one-time disease-modifying treatment for HAE and a landmark advance in CRISPR-based therapeutics. PLAIN LANGUAGE SUMMARY Lonvo-z uses CRISPR/Cas9 technology to permanently reduce production of prekallikrein that triggers swelling attacks in HAE, potentially providing long-lasting disease control after a single treatment.
L. H. Luong, Shane Stone, Van Bui et al.· Expert Opinion on Investigat...· 0 citations
INTRODUCTION
Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic hematopoietic stem cell transplantation for IEIs.
AREAS COVERED
Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition - which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis - to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene editing technologies, including CRISPR/Cas9, and base/prime editing, which offer targeted correction with minimized genotoxicity.
EXPERT OPINION
Recent milestones in diseases like Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.
Jasmeen Dara, Claire Booth· Expert Opinion on Biological...· 0 citations
Hematopoietic stem and progenitor cells (HSPCs) gene therapy may transform the therapeutic landscape for inherited hematological disorders and already offers potentially curative options for some diseases, including inborn errors of immunity and β-hemoglobinopathies. Its continued success relies on further refinement of gene transfer technologies, gene editing tools such as CRISPR-Cas, and optimized ex vivo HSPC manipulation protocols that ensure robust, long-term engraftment and clonal diversity with reduced-toxicity, non-genotoxic conditioning strategies. Here, we review recent developments and refinements in gene transfer and editing technologies for HSPCs, while also discussing the critical limitations and hurdles to clinical translation, as recently presented at the New Investigator Committee Gene Therapy webinar. Future directions must prioritize integrating technological innovation with the development of equitable and simplified models to reduce costs and ensure that these life-saving cellular therapies reach patients worldwide. Teaser abstract Hematopoietic stem and progenitor cells (HSPCs) gene therapy is advancing rapidly, with lentiviral gene transfer, genome editing, and emerging in vivo delivery approaches expanding the therapeutic landscape for inherited hematologic disorders. Recent clinical successes have demonstrated the potential for durable correction, while ongoing refinements continue to improve safety, efficacy, and feasibility. Key challenges remain in genotoxicity, conditioning toxicity, manufacturing scalability, and equitable global access.
Kohei Shiroshita, A. Stolz, C. Malouf et al.· Experimental Hematology· 0 citations
Several therapies using adeno-associated virus (AAVs) as gene delivery tool have received marketing approval in the past. However, potential applications of AAVs are limited by their restricted gene packaging capacities (<4,7kb). Many monogenic diseases are caused by large complex genes with hundreds of pathogenic variants that exceed AAV capacity. Merosin-deficient Congenital Muscular dystrophy type 1A is a severe monogenic recessive disease caused by the absence of functional copies of the LAMA2 gene. To date, no treatment options are available, with the most promising approach being gene replacement therapy to provide a functional copy. The LAMA2 coding sequence, spanning 9,3 kb, encodes for the laminin-α2, a subunit of the trimeric protein Laminin-211 found in the basement membrane of skeletal muscle cells and Schwan cells. Efforts have been focused on gene or protein replacement along with basement membrane engineering. Here, we exploit the ability of inteins to reconstitute full-length protein in a scarless manner. Using a combination of three AAVs, each encoding for one fragment of the laminin-α2 protein flanked by short split intein, resulted in the complete reconstitution of the Laminin-α2 and an improvement of the histopathological features of the dy2j dystrophic mouse model.
Núria Rafel-Millan, Carles Bayod-Girón, Maria Pallarès-Masmitjà et al.· Molecular Therapy· 0 citations
Clinically applicable gene therapy for RTT will likely need to move beyond simple MECP2 replacement and instead rely on precise cell- and dose-dependent regulation of its expression, with an emphasis on non-coding RNA-based and epigenetic mechanisms.
I. Kabdesh, A. Rizvanov, Y. Mukhamedshina· Non-Coding RNA· 0 citations
