Stem Cell Collection and Gene Transfer in Fanconi Anemia

Abstract

Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive bone marrow failure (BMF), congenital anomalies, and a predisposition to malignancy. Successful gene transfer into hematopoietic stem cells (HSCs) could reverse BMF in this disease. We developed clinical trials to determine whether a sufficient number of CD34(+) stem cells could be collected for gene modification and to evaluate the safety and efficacy of HSC-corrective gene transfer in FA genotype A (FANCA) patients. Here, we report that FA patients have significant depletion of their BM CD34(+) cell compartment even before severe pancytopenia is present. However, oncoretroviral-mediated ex vivo gene transfer was efficient in clinical scale in FA-A cells, leading to reversal of the cellular phenotype in a significant percentage of CD34(+) cells. Re-infusion of gene-corrected products in two patients was safe and well tolerated and accompanied by transient improvements in hemoglobin and platelet counts. Gene correction was transient, likely owing to the low dose of gene-corrected cells infused. Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials.

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

“…To overcome these limitations, FA gene therapy clinical trials are in progress [85]. Difficulties in collecting sufficient blood progenitor cells from patients with FA and inefficient transduction protocols with first-generation retroviral vectors led to unsuccessful initial clinical trials [86][87][88].…”

Integration of functional bacterial artificial chromosomes into human cord blood-derived multipotent stem cells

“…Clinical trials using gene-modified hematopoietic stem cells have been undertaken to assess treatment of a number of Integration of a genomic locus into human stem cells F Zaibak et al hematological conditions. [22][23][24][25][26][27][28] Recent preclinical studies using in vitro cultured gene-modified mesenchymal stem cells have also shown promise. [29][30][31][32][33] However, in the majority of these studies, which use viral delivery of small vectors, random integration at multiple sites per cell and different sites between cells was documented, along with variegated expression and transcriptional silencing.…”

Hematopoietic stem cell transplantation in patients with Fanconi anemia: the experience of the Russian Children's Clinical Hospital and the Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology

“…Основной про-блемой данного подхода явилось то, что эффективность трансфекции гемопоэтических стволовых клеток ре-тровирусным вектором, содержащим нативный ген, была низкой и недостаточной для значимого улучше-ния гемопоэза [11]. Недавно было опубликовано не-сколько исследований [12,13], основным вопросом которых явился поиск оптимального клеточного суб-страта для воздействия.…”