Silencing of proviral transgene expression by CpG methylation in a gene therapy trial for chronic granulomatous disease

Schultze-Strasser, Stephan; Kramer, Rolf; Preiss, Carolin; Mg, Ott; Stein, Stefan; Grez, Manuel

doi:10.1016/j.bcmd.2007.10.075

Cited by 1 publication

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“…However, subsequent unexpected adverse events—namely leukemia (Hacein-Bey-Abina et al 2003) and loss of gene function due to gene silencing (Schultze-Strasser et al 2008)—provided the impetus to develop better models for the treatment of hematopoietic diseases by gene therapy (Williams 2006). …”

Section: Introductionmentioning

confidence: 99%

Potential Large Animal Models for Gene Therapy of Human Genetic Diseases of Immune and Blood Cell Systems

Bauer¹,

Adler²,

Hickstein³

2009

ILAR Journal

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Genetic mutations involving the cellular components of the hematopoietic system—red blood cells, white blood cells, and platelets—manifest clinically as anemia, infection, and bleeding. Although gene targeting has recapitulated many of these diseases in mice, these murine homologues are limited as translational models by their small size and brief life span as well as the fact that mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of such mutations in humans. Many of these limitations can be overcome by identifying large animals with genetic diseases of the hematopoietic system corresponding to their human disease counterparts. In this article, we describe human diseases of the cellular components of the hematopoietic system that have counterparts in large animal species, in most cases carrying mutations in the same gene (CD18 in leukocyte adhesion deficiency) or genes in interacting proteins (DNA cross-link repair 1C protein and protein kinase, DNA-activated, catalytic polypeptide in radiation-sensitive severe combined immunodeficiency). Furthermore, we describe the potential of these animal models to serve as disease-specific, preclinical models for testing the efficacy and safety of clinical interventions such as hematopoietic stem cell transplantation or gene therapy approaches before their use in humans with the corresponding disease.

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Section: Introductionmentioning

confidence: 99%