Gene and Cellular Therapies for Leukodystrophies

**Background:** Leukodystrophies are a heterogeneous group of inherited degenerative encephalopathies primarily affecting CNS white matter, with an incidence as high as 1:7500 persons. Over 30 distinct types exist, including X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (Krabbe disease). Historically, treatment options were limited to supportive care, with allogeneic hematopoietic stem cell transplantation (HSCT) offering benefit only when performed pre-symptomatically and associated with high morbidity and mortality. Gene therapy has emerged as a promising alternative, providing supraphysiological levels of the missing enzyme and avoiding graft-versus-host disease.

**Methods:** This is a narrative review summarizing the literature on gene and cellular therapies for leukodystrophies. The authors describe the classification, pathophysiology, and clinical features of major leukodystrophies, then detail the development of ex vivo lentiviral HSPC gene therapy and in vivo adeno-associated virus (AAV) vector approaches. They review completed and ongoing clinical trials registered on ClinicalTrials.gov, including phase I/II and III studies for X-ALD, MLD, Krabbe, and Canavan disease. The review also covers emerging technologies such as CRISPR/Cas9 gene editing and base editing.

**Key Results:** For X-ALD, a phase II/III trial of Lenti-D (elivaldogene autotemcel, Skysona) in 17 boys showed measurable ALD protein levels, absence of integrations near known oncogenes, and an 88% success rate in survival and absence of functional disability. For MLD, a phase I/II trial using a lentiviral vector with a PGK promoter demonstrated high ARSA activity in peripheral blood, improved survival, locomotor function, and normal cognitive development in patients treated before symptom onset. This product (Libmeldy, OTL-200) received EMA approval in 2020. For Krabbe disease, preclinical studies using AAVrh10-GALC vectors are ongoing, with clinical trials (RESKUE, GALax-C) recruiting. For Canavan disease, a phase I/II trial of rAAV-Olig001-ASPA (CAN-GT) and a separate study of rAAV9-ASPA (CANaspire) are underway; one patient receiving dual i.v. and i.c.v. injections showed enhanced myelination, improved motor function, and decreased NAA levels for up to four years. The review notes that 14 clinical trials have been registered for primary leukodystrophies, with 5 actively recruiting. However, three approved gene therapies (Skysona, Glybera, Zynteglo) have been withdrawn from the European market due to reimbursement challenges.

**Clinical Implications:** Gene therapy for leukodystrophies has transitioned from preclinical to clinical application, with two products (Libmeldy and Skysona) receiving regulatory approval. Early treatment, ideally before symptom onset, is critical for optimal outcomes. Ex vivo lentiviral HSPC gene therapy offers advantages over allogeneic HSCT, including avoidance of graft-versus-host disease and the ability to achieve supraphysiological enzyme levels. In vivo AAV vectors provide direct CNS targeting but face challenges in biodistribution, immunogenicity, and dose limitations. Emerging gene editing technologies (CRISPR/Cas9, base editors) may offer precise correction but require further development for safe and efficient delivery. The review emphasizes that leukodystrophies are diverse and require tailor-made therapies, and that future success depends on addressing issues of toxicity, cell targeting, and market access through collaboration between developers, patient representatives, insurers, and governments.