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Immunomodulatory gene therapy in lysosomal storage disorders.

ABSTRACT: Significant advances in therapy for lysosomal storage disorders have occurred with an accelerating pace over the past decade. Although enzyme replacement therapy has improved the outcome of lysosomal storage disorders, antibody responses have occurred and sometimes prevented efficacy, especially in cross-reacting immune material negative patients with Pompe disease. Preclinical gene therapy experiments have revealed the relevance of immune responses to long-term efficacy. The choice of regulatory cassette played a critical role in evading humoral and cellular immune responses to gene therapy in knockout mouse models, at least in adult animals. Liver-specific regulatory cassettes prevented antibody formation and enhanced the efficacy of gene therapy. Regulatory T cells prevented transgene directed immune responses, as shown by adoptive transfer of antigen-specific immune tolerance to enzyme therapy. Immunomodulatory gene therapy with a very low vector dose could enhance the efficacy of enzyme therapy in Pompe disease and other lysosomal storage disorders.

SUBMITTER: Koeberl DD

PROVIDER: S-EPMC2893380 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Immunomodulatory gene therapy in lysosomal storage disorders.

Koeberl Dwight D DD Kishnani Priya S PS

Current gene therapy 20091201 6

Significant advances in therapy for lysosomal storage disorders have occurred with an accelerating pace over the past decade. Although enzyme replacement therapy has improved the outcome of lysosomal storage disorders, antibody responses have occurred and sometimes prevented efficacy, especially in cross-reacting immune material negative patients with Pompe disease. Preclinical gene therapy experiments have revealed the relevance of immune responses to long-term efficacy. The choice of regulator ...[more]

PMID: 19807648

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Project description:IntroductionSeveral new treatment modalities are being developed for lysosomal storage disorders (LSDs), including gene therapy. As the currently available treatment options and their influence on disease progression differ greatly within the spectrum of LSDs, willingness to undergo gene therapy might vary among patients with LSDs and/or their representatives. The width of the LSD spectrum is illustrated by the differences between type 1 Gaucher disease, Fabry disease and Mucopolysaccharidosis type III (MPS III). For type 1 Gaucher and Fabry disease several therapies are available, resulting in a near normal or improved, but individually varying, prognosis. No treatment options are available for MPS III.AimTo identify factors influencing patients' and/or their representatives' decisions regarding undergoing gene therapy.MethodsFocus group discussions and semi-structured interviews were conducted with patients with type 1 Gaucher disease, Fabry disease and MPS III. Parents of MPS III patients were included as patients' representatives.ResultsNine Gaucher patients, 23 Fabry patients, two adult MPS III patients and five parents of MPS III patients participated in the study. The five main themes that arose were: outcome of gene therapy, risks and side effects, burden of gene therapy treatment, current situation and ethical aspects. Participants' views ranged from hesitance to eagerness to undergo gene therapy, which seemed to be mostly related to disease severity and currently available treatment options. Severe disease, limited treatment options and limited effectiveness of current treatment augmented the willingness to choose gene therapy. Gaucher and Fabry patients deemed the burden of treatment important. Fabry and MPS III patients and parents considered outcome important, suggesting hope for improvement. When asked to rank the factors discussed in the focus group discussions, Gaucher patients ranked outcome low, which could indicate a more cautious attitude towards gene therapy.ConclusionThis study underlines the importance of exploring patients' needs and expectations before using limited resources in the development of therapies for patient groups of which a significant subset may not be willing to undergo that specific therapy.

Dataset Information

Immunomodulatory gene therapy in lysosomal storage disorders.

Publications

Immunomodulatory gene therapy in lysosomal storage disorders.

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