Gene therapy for Wiskott-Aldrich Syndrome—Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis

Braun, Christian; Witzel, Maximilian; Paruzynski, Anna; Boztuğ, Kaan; Kalle, Christof von; Schmidt, Manfred; Klein, Christoph

doi:10.4161/21675511.2014.947749

Cited by 24 publications

(19 citation statements)

References 39 publications

(26 reference statements)

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“… 12 The inability to purify and specifically target multipotent HSCs limits the targeting efficiency, 7 , 13 – 15 increases the costs for modifying reagents, 16 – 18 and poses the risk of potential gene therapy off-target effects. 19 – 25 …”

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confidence: 99%

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA− Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model

Colonna

Perez

Hoffman

et al. 2020

Transplantation Direct

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Background. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a common treatment for patients suffering from different hematological disorders. Allo-HCT in combination with hematopoietic stem cell (HSC) gene therapy is considered a promising treatment option for millions of patients with HIV+ and acute myeloid leukemia. Most currently available HSC gene therapy approaches target CD34-enriched cell fractions, a heterogeneous mix of mostly progenitor cells and only very few HSCs with long-term multilineage engraftment potential. As a consequence, gene therapy approaches are currently limited in their HSC targeting efficiency, very expensive consuming huge quantities of modifying reagents, and can lead to unwanted side effects in nontarget cells. We have previously shown that purified CD34+CD90+CD45RA− cells are enriched for multipotent HSCs with long-term multilineage engraftment potential, which can reconstitute the entire hematopoietic system in an autologous nonhuman primate transplant model. Here, we tested the feasibility of transplantation with purified CD34+CD90+CD45RA− cells in the allogeneic setting in a nonhuman primate model. Methods. To evaluate the feasibility of this approach, CD34+CD90+CD45RA− cells from 2 fully major histocompatibility complex-matched, full sibling rhesus macaques were sort-purified, quality controlled, and transplanted. Engraftment and donor chimerism were evaluated in the peripheral blood and bone marrow of both animals. Results. Despite limited survival due to infectious complications, we show that the large-scale sort-purification and transplantation of CD34+CD90+CD45RA− cells is technically feasible and leads to rapid engraftment of cells in bone marrow in the allogeneic setting and absence of cotransferred T cells. Conclusions. We show that purification of an HSC-enriched CD34+ subset can serve as a potential stem cell source for allo-HCTs. Most importantly, the combination of allo-HCT and HSC gene therapy has the potential to treat a wide array of hematologic and nonhematologic disorders.

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confidence: 99%

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA− Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model

Colonna

Perez

Hoffman

et al. 2020

Transplantation Direct

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“…Currently, bone marrow transplantation offers the best chance of cure for patients with mutations in actin regulatory proteins. Gene therapy is also proving to be a promising avenue, especially for treatment of WAS . Through better understanding of the expression, function, and interactions of these proteins, we seek to develop better targeted and tolerated therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Gene therapy is also proving to be a promising avenue, especially for treatment of WAS. [210][211][212][213][214] Through better understanding of the expression, function, and interactions of these proteins, we seek to develop better targeted and tolerated therapies.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Janssen

2018

Immunological Reviews

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Summary The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.

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“…In the development of ex vivo gene therapy, a critical issue is the risk of oncogenic transformation of ex vivo gene-transduced cells by a genome-integrating viral vector, as reported in certain immune deficiencies. [11][12][13][14][15] Adipogenic potential has been demonstrated to suppress tumorigenic activity of ink4a knock-out mesenchymal stem cells. 73) Considering the risk of genotoxicity, cells with more adipogenic potential would be safer vehicles for ex vivo gene therapy applications.…”

Section: Adipocytes As Potential Target Cells For Developing Ex Vivo mentioning

confidence: 99%

A Novel Approach to the Treatment of Plasma Protein Deficiency: <i>Ex Vivo</i>-Manipulated Adipocytes for Sustained Secretion of Therapeutic Proteins

Kuroda

Saitō²,

Aso³

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Despite the critical need for lifelong treatment of inherited and genetic diseases, there are no developmental efforts for most such diseases due to their rarity. Recent progress in gene therapy, including the approvals of two products (Glybera and Strimvelis) that may provide patients with sustained effects, has shed light on the development of gene therapy products. Most gene therapy products are based on either adeno-associated virus-mediated in vivo gene transfer to target tissues or administration of ex vivo gene-transduced hematopoietic cells. In such circumstances, there is room for different approaches to provide clinicians with other therapeutic options through a variety of principles based on studies not only to gain an understanding of the pathological mechanisms of diseases, but also to understand the physiological functions of target tissues and cells. In this review, we summarize recent progress in gene therapy-mediated enzyme replacement and introduce a different approach using adipocytes to enable lifelong treatment for intractable plasma protein deficiencies.

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Gene therapy for Wiskott-Aldrich Syndrome—Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis

Abstract: Wiskott-Aldrich-Syndrome (WAS) is a rare X-linked recessive disease caused by mutations of the WAS gene. It is characterized by immunodeficiency, autoimmunity, low numbers of small platelets (microthrombocytopenia) and a high risk of cancer, especially B cell lymphoma and leukemia.

Cited by 24 publications

References 39 publications

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA− Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model

Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA− Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model

Primary immunodeficiencies caused by mutations in actin regulatory proteins

A Novel Approach to the Treatment of Plasma Protein Deficiency: <i>Ex Vivo</i>-Manipulated Adipocytes for Sustained Secretion of Therapeutic Proteins

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