Safe and Effective Gene Therapy for Murine Wiskott-Aldrich Syndrome Using an Insulated Lentiviral Vector
Open accessAbstract
Wiskott-Aldrich syndrome (WAS) is a life-threatening immunodeficiency caused by mutations within the WAS gene. Viral gene therapy to restore WAS protein (WASp) expression in hematopoietic cells of patients with WAS has the potential to improve outcomes relative to the current standard of care, allogeneic bone marrow transplantation. However, the development of viral vectors that are both safe and effective has been problematic. While use of viral transcriptional promoters may increase the risk of insertional mutagenesis, cellular promoters may not achieve WASp expression levels necessary for optimal therapeutic effect. Here we evaluate a self-inactivating (SIN) lentiviral vector combining a chromatin insulator upstream of a viral MND (MPSV LTR, NCR deleted, dl587 PBS) promoter driving WASp expression. Used as a gene therapeutic in Was −/− mice, this vector resulted in stable WASp + cells in all hematopoietic lineages and rescue of T and B cell defects with a low number of viral integrations per cell, without evidence of insertional mutagenesis in serial bone marrow transplants. In a gene transfer experiment in non-human primates, the insulated MND promoter (driving GFP expression) demonstrated long-term polyclonal engraftment of GFP + cells. These observations demonstrate that the insulated MND promoter safely and efficiently reconstitutes clinically effective WASp expression and should be considered for future WAS therapy.
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Gene transfer using LVVs into CD34+ HSCs has been used to treat several genetic diseases, including b-thalassemia, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and Wiskott-Aldrich Syndrome.
“Gene transfer using LVVs into CD34 þ HSCs has been used to treat several genetic diseases, including b-thalassemia, 100 X-linked adrenoleukodystrophy, 101 metachromatic leukodystrophy, 102 and Wiskott-Aldrich Syndrome.103”
From Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges (2020) · cites this paper as [103]
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- Authors
- Singh, S., Khan, I., Khim, S., Seymour, B., Sommer, K., Wielgosz, M., Norgaard, Z., Kiem, H.-P., Adair, J., Liggitt, D., Nienhuis, A., & Rawlings, D. J.
- Affiliations
- Seattle Children's Research Institute (US)
- St. Jude Children's Research Hospital (US)
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Corresponding author
- Rawlings, David J.
- ORCID
- Venue
- Molecular Therapy - Methods & Clinical Development
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 4
- Pages
- 1-16
- ISSN
- 2329-0501 (ISSN-L)
- PMC
- PMC5363182
- OpenAlex
- W2565961003
- Cited by
- 13
- References
- 63
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 1
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- NIH (R01-AI071163, P01-HL053749, P01-AI097100)
- Fred Hutchinson Cancer Research Center
- Seattle Children’s Hospital Program for Cell and Gene Therapy
- Topics
- 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
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- Wiskott-Aldrich syndrome, gene therapy, lentiviral vectors, chromatin insulators, self-inactivating lentivirus, insertional mutagenesis, viral integration, hematopoietic recovery, mouse model
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