Gene therapy for lysosomal storage diseases and peroxisomal diseases

Abstract

Gene therapies for lysosomal storage diseases (LSD) and peroxisomal diseases (PD) are rapidly advancing. Most LSDs and PDs are characterized by brain involvement, prompting the development of therapies targeting the brain. There are two types of gene therapy for brain involvement in LSD and PD, i.e., the direct transfer of a therapeutic gene into brain cells and hematopoietic stem cell-targeted gene therapy. The rationale for the latter approach is that brain microglia are derived from hematopoietic cells. Thus, gene-corrected hematopoietic cells migrate into the brain and differentiate into microglial cells. These gene-corrected microglial cells correct the metabolic defects associated with LSD and reduce inflammation in PD and LSD, leading to a clinical benefit. Gene editing technology has recently been applied in this area and a trial focused on LSD is currently ongoing. Although these approaches are still under investigation, very encouraging results have been obtained. This review provides an overview of recently developed gene therapies for various LSDs and PDs, including the results of clinical trials, with an emphasis on the benefits of this approach for these diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

    CAS  Article  Google Scholar 

  2. 2.

    Dunbar CE, Kohn DB, Schiffmann R, Barton NW, Nolta JA, Esplin JA, et al. Retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with Gaucher disease: in vivo detection of transduced cells without myeloablation. Hum Gene Ther. 1998;9:2629–40.

    CAS  Article  Google Scholar 

  3. 3.

    Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818–23.

    CAS  Article  Google Scholar 

  4. 4.

    Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2017;377:1630–8.

    CAS  Article  Google Scholar 

  5. 5.

    Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341:1233158.

    Article  Google Scholar 

  6. 6.

    Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388:476–87.

    CAS  Article  Google Scholar 

  7. 7.

    Tardieu M, Zerah M, Husson B, de Bournonville S, Deiva K, Adamsbaum C, et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther. 2014;25:506–16.

    CAS  Article  Google Scholar 

  8. 8.

    Tardieu M, Zerah M, Gougeon ML, Ausseil J, de Bournonville S, Husson B, et al. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol. 2017;16:712–20.

    CAS  Article  Google Scholar 

  9. 9.

    Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, et al. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013;24:630–40.

    CAS  Article  Google Scholar 

  10. 10.

    Sharma R, Anguela XM, Doyon Y, Wechsler T, DeKelver RC, Sproul S, et al. In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood. 2015;126:1777–84.

    CAS  Article  Google Scholar 

  11. 11.

    Laoharawee K, DeKelver RC, Podetz-Pedersen KM, Rohde M, Sproul S, Nguyen HO, et al. Dose-dependent prevention of metabolic and neurologic disease in murine MPS II by ZFN-mediated in vivo genome editing. Mol Ther. 2018;26:1127–36.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Toya Ohashi.

Ethics declarations

Conflict of interest

T. Ohashi have active research support from Sanofi Genzyme Corporation, Sumitomo Dainippon Pharma and Avrobio, Inc. . These activities have been fully disclosed and are managed under Memorandum of Understanding with the Conflict of Interest Resolution Board of the Jikei University School of Medicine.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ohashi, T. Gene therapy for lysosomal storage diseases and peroxisomal diseases. J Hum Genet 64, 139–143 (2019). https://doi.org/10.1038/s10038-018-0537-5

Download citation

Further reading