Gene and Cellular Therapies for Leukodystrophies

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Aerts Kaya F. S. F., Van Til N. P.

PHARMACEUTICS, vol.15, no.11, pp.1-25, 2023 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Review
  • Volume: 15 Issue: 11
  • Publication Date: 2023
  • Doi Number: 10.3390/pharmaceutics15112522
  • Journal Name: PHARMACEUTICS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Directory of Open Access Journals
  • Page Numbers: pp.1-25
  • Hacettepe University Affiliated: Yes


Leukodystrophies are a heterogenous group of inherited, degenerative encephalopathies, that if left untreated, are often lethal at an early age. Although some of the leukodystrophies can be treated with allogeneic hematopoietic stem cell transplantation, not all patients have suitable donors, and new treatment strategies, such as gene therapy, are rapidly being developed. Recent developments in the field of gene therapy for severe combined immune deficiencies, Leber’s amaurosis, epidermolysis bullosa, Duchenne’s muscular dystrophy and spinal muscular atrophy, have paved the way for the treatment of leukodystrophies, revealing some of the pitfalls, but overall showing promising results. Gene therapy offers the possibility for overexpression of secretable enzymes that can be released and through uptake, allow cross-correction of affected cells. Here, we discuss some of the leukodystrophies that have demonstrated strong potential for gene therapy interventions, such as X-linked adrenoleukodystrophy (X-ALD), and metachromatic leukodystrophy (MLD), which have reached clinical application. We further discuss the advantages and disadvantages of ex vivo lentiviral hematopoietic stem cell gene therapy, an approach for targeting microglia-like cells or rendering cross-correction. In addition, we summarize ongoing developments in the field of in vivo administration of recombinant adeno-associated viral (rAAV) vectors, which can be used for direct targeting of affected cells, and other recently developed molecular technologies that may be applicable to treating leukodystrophies in the future.