Approaches to Gene Therapy in the Leukodystrophies

Background: Leukodystrophies are among the most devastating disorders of childhood. They are characterized by degeneration of brain white matter and are usually caused by single gene mutations. Gene therapy has emerged with potential benefit to these diseases long thought to be incurable.

Methods: Many innovative strategies are in development, including gene replacement or correction, inhibition/corrective splicing of disease-causing mRNAs, and ex vivo gene correction. Viral vectors [adeno-associated virus (AAV) and lentivirus] and genetically modified cells (hematopoietic and neural stem cells) are currently used for gene correction in multiple leukodystrophies.

Results: Preclinical data in several disease models demonstrates promising biochemical and behavioral correction. X-linked adrenoleukodystrophy, caused by ABCD1 gene mutations leading to loss of function of a peroxisomal membrane half-transporter, will be used as a case study to discuss different approaches necessary to target various aspects of the pathobiology and disease phenotype. While ex vivo gene therapy may benefit the inflammatory brain disease of childhood, a direct transduction approach using AAV9 is needed to target the non-inflammatory axonopathy of the adult onset spinal cord disease (adrenomyeloneuropathy). I report first trial results of the STARBEAM trial examining the safety and efficacy of ex vivo lentiviral hematopoietic stem cell gene transfer for cerebral adrenoleukodystrophy.

Conclusion: The optimal approach depends not only on the nature of the disease-causing gene, but also on target cell/tissue and understanding of disease phenotype. Early results from the STARBEAM study suggest that Lenti-D gene therapy may offer an alternative to allogeneic bone marrow transplantation, particularly for patients with no matched sibling donor.

No conflict of interest has been declared by the author(s).