Defining curative endpoints for transfusion‐dependent β‐thalassemia in the era of gene therapy and gene editing

Author:

Corbacioglu Selim1ORCID,Frangoul Haydar2,Locatelli Franco3ORCID,Hobbs William4,Walters Mark5ORCID

Affiliation:

1. University of Regensburg Regensburg Germany

2. Sarah Cannon Research Institute and the Children's Hospital at TriStar Centennial Nashville Tennessee USA

3. IRCCS, Ospedale Pediatrico Bambino, Gesù Rome, Catholic University of the Sacred Heart Rome Italy

4. Vertex Pharmaceuticals Incorporated Boston Massachusetts USA

5. Department of Pediatrics UCSF Benioff Children's Hospital Oakland Oakland California USA

Abstract

Abstractβ‐thalassemia is a monogenic disease that results in varying degrees of anemia. In the most severe form, known as transfusion‐dependent β‐thalassemia (TDT), the clinical hallmarks are ineffective erythropoiesis and a requirement of regular, life‐long red blood cell transfusions, with the development of secondary clinical complications such as iron overload, end‐organ damage, and a risk of early mortality. With the exception of allogeneic hematopoietic cell transplantation, current treatments for TDT address disease symptoms and not the underlying cause of disease. Recently, a growing number of gene addition and gene editing‐based treatments for patients with TDT with the potential to provide a one‐time functional cure have entered clinical trials. A key challenge in the design and evaluation of these trials is selecting endpoints to evaluate if these novel genetic therapies have a curative versus an ameliorative effect. Here, we present an overview of the pathophysiology of TDT, review emerging gene addition or gene editing therapeutic approaches for TDT currently in clinical trials, and identify a series of endpoints that can quantify therapeutic effects, including a curative outcome.

Funder

Vertex Pharmaceuticals

Publisher

Wiley

Subject

Hematology

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