A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice
Open accessAbstract
A longstanding goal for the treatment of hemophilia B is the development of a gene transfer strategy that can maintain sustained production of clotting factor IX (F.IX) in the absence of an immune response. To this end, we have sought to use lentiviral vectors (LVs) as a means for systemic gene transfer. Unfortunately, initial evaluation of LVs expressing F.IX from hepatocyte-specific promoters failed to achieve sustained F.IX expression in hemophilia B mice due to the induction of an anti-F.IX cellular immune response. Further analysis suggested that this may be a result of off-target transgene expression in hematopoietic-lineage cells of the spleen. In order to overcome this problem, we modified our vector to contain a target sequence for the hematopoietic-specific microRNA, miR-142-3p. This eliminated off-target expression in hematopoietic cells, and enabled sustained gene transfer in hemophilia B mice for more than 280 days after injection. Treated mice had more than 10% normal F.IX activity, no detectable anti-F.IX antibodies, and were unresponsive to F.IX immunization. Importantly, the mice survived tail-clip challenge, thus demonstrating phenotypic correction of their bleeding diathesis. This work, which is among the first applications to exploit the microRNA regulatory pathway, provides the basis for a promising new therapy for the treatment of hemophilia B.
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miRNAs have been used to inhibit transgene expression in antigen-presenting cells (APCs) with miR-142-3p.
“Others have used miRNAs to inhibit transgene expression in antigen-presenting cells (APCs) with miR-142-3p [146].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [146]
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- Authors
- Brown, B. D., Cantore, A., Annoni, A., Sergi, L. S., Lombardo, A., Della Valle, P., D'Angelo, A., & Naldini, L.
- Affiliations
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Coagulation Service and Thrombosis Research Unit, Fondazione Centro San Raffaele Del Monte Tabor Istituto dì Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Hospital, Milan; and
- Vita-Salute San Raffaele University (IT)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-12-15
- Volume
- 110
- Issue
- 13
- Pages
- 4144-4152
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2044474105
- Cited by
- 252
- References
- 54
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 1 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 12 · 2015: 17 · 2014: 11 · 2013: 25 · 2012: 26
- FWCI
- 14.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- hemophilia B, lentiviral vectors, microRNA, miR-142-3p, clotting factor IX, gene therapy, off-target expression, hematopoietic cells, sustained transgene expression, bleeding tendency, transgenic mice
- MeSH terms
- Animals, Antibodies, Blood Cells, Hemophilia B, Factor IX, Genetic Vectors, Genetic Therapy, Lentivirus, Gene Transfer Techniques, MicroRNAs, Mice
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