Advances of gene therapy for primary immunodeficiencies.

Fabio Candotti

doi:10.12688/f1000research.7512.1

Abstract

In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. While such progress has widened the choice of therapeutic options in some specific cases of primary immunodeficiency, much remains to be done to extend the geographical availability of such an advanced approach and to increase the number of diseases that can be targeted. At the same time, emerging technologies are stimulating intensive investigations that may lead to the application of precise genetic editing as the next form of gene therapy for these and other human genetic diseases.

Highlights

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of mostly rare genetic diseases comprising over 250 different clinical entities and resulting from a vast variety of aberrations affecting the biological pathways of development and differentiation of the immune system[1]
Based on the notion that genetic correction of autologous hematopoietic stem cells (HSCs) could provide a safer alternative for any patient from whom HSCs can be obtained, gene therapy approaches for PIDs were developed starting in the mid-1980s and were initially based on the use of gene transfer vectors derived from murine gamma-retroviruses[3]
These pioneer clinical protocols made their entry into the clinical arena in the early 1990s and focused on patients affected with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) who derived limited benefit from the genetic correction of either their peripheral blood lymphocytes or

Summary

Introduction

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of mostly rare genetic diseases comprising over 250 different clinical entities and resulting from a vast variety of aberrations affecting the biological pathways of development and differentiation of the immune system[1]. A trial performed in Germany in 2004 using a gamma-retroviral vector expressing gp91phox under the transcriptional control of the spleen focus-forming virus long terminal repeat (LTR) appeared to have achieved superior results in two CGD patients when around 15% of neutrophils were found to be functionally corrected early after treatment This fraction increased due to insertional activation of the PRDM16 and MDS1/EVI1 genes in clonal cell populations that expanded with time. With the aim of avoiding possible toxic effects of gp91phox expression in hematopoietic progenitors, the newer constructs for gene therapy of CGD carry myeloidspecific promoters and/or allow for microRNA-mediated posttranscriptional downregulation of expression in hematopoietic stem/progenitor cells[42,44] Adenosine deaminase deficiency This form of SCID is caused by genetic defects of ADA and presents with extreme reduction of lymphocyte numbers and impairment of immune functions that can lead to early death from infections[45]. I confirm that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Miller AD

Findings

PubMed Abstract