Title:Stem Cell Genetic Therapy for Fanconi Anemia – A New Hope
Volume: 16
Issue: 5
Author(s): Helmut Hanenberg, Katharina Roellecke and Constanze Wiek
Affiliation:
Keywords:
Fanconi anemia, Stem cell genetic therapy, Lentivirus, Somatic reversion, Selective in vivo growth advantage, Insertional
mutagenesis.
Abstract: Fanconi anemia (FA) is a rare inherited DNA disorder clinically characterized by congenital
malformations, progressive bone marrow failure, and cancer susceptibility. Due to a strong survival advantage
of spontaneously corrected ‘normal’ hematopoietic stem cells (HSCs) in a few patients, FA is
considered a model disorder for genetic correction of autologous stem cells, where genetically corrected
stem cells and their progeny have a strong in vivo selective advantage, ultimately leading to normal hematopoiesis.
Despite these apparently ideal circumstances, three HSC gene therapy trials with gammaretroviral
vectors (stage I) designed to cure the hematological manifestation of FA completely failed
to provide long-term clinical benefits for patients, predominantly due to the combination of insufficient
gene transfer technologies and incompletely understood FA HSC pathobiology. Currently, FA gene
therapy is in stage II where, based on an improved understanding of the cellular defects in FA HSCs,
consequently adapted transduction protocols are being used in two phase I/II trials for in vitro genetic
correction of FANCA-deficient hematopoietic stem cells. These results are eagerly awaited. Independent
from the outcome of these studies, technologies are already available that seem highly attractive for
testing in FA. In stage III, this would ultimately include targeted in vivo correction of autologous HSCs
by overexpression of nonintegrating lentiviral vectors with scaffold/matrix attachment region elements
using specific envelopes as pseudotypes. Although currently still challenging, in a few years in vivo genome
editing approaches will be readily available in stage IV, in which the delivery of the editing machinery/
complex is targeted to the autologous FA HSCs by the nonintegrating lentiviral vectors established
in stage III. Even low levels of corrected stem cells will then quickly repopulate the entire hematopoiesis
of the patient. We therefore are sanguine that in the future, genetic therapy can be used clinically
for the correction of FA HSCs in the standard care of FA patients.
