Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 2, Issue 58, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3001522
Keywords
-
Categories
Funding
- Telethon
- EU [FP5LSHB-CT-2004-005242 CONSERT]
- ERC [249845]
- Fondazione CARIPLO (NOBEL)
- Italian Ministry of Health
- National Tay-Sachs and Allied Disease Association
- ELA Foundation [2009-00515]
- Stem Cell Network of Canada National Centres of Excellence
- Canadian Cancer Society and the Terry Fox Foundation
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research, province of Ontario
- Leukemia and Lymphoma Society
- Canadian Institutes for Health Research
- Canada Research Chair
- European Research Council (ERC) [249845] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
Globoid cell leukodystrophy (GLD; also known as Krabbe disease) is an invariably fatal lysosomal storage disorder caused by mutations in the galactocerebrosidase (GALC) gene. Hematopoietic stem cell (HSC)-based gene therapy is being explored for GLD; however, we found that forced GALC expression was toxic to HSCs and early progenitors, highlighting the need for improved regulation of vector expression. We used a genetic reporter strategy based on lentiviral vectors to detect microRNA activity in hematopoietic cells at single-cell resolution. We report that miR-126 and miR-130a were expressed in HSCs and early progenitors from both mice and humans, but not in differentiated progeny. Moreover, repopulating HSCs could be purified solely on the basis of miRNA expression, providing a new method relevant for human HSC isolation. By incorporating miR-126 target sequences into a GALC-expressing vector, we suppressed GALC expression in HSCs while maintaining robust expression in mature hematopoietic cells. This approach protected HSCs from GALC toxicity and allowed successful treatment of a mouse GLD model, providing a rationale to explore HSC-based gene therapy for GLD.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available