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Pre-Clinical Modeling of Cell and Gene Therapy of Fanconi Anemia / Suying Liu.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Liu, Suying, author.
- Language:
- English
- Subjects (All):
- Biology.
- Cellular biology.
- Molecular biology.
- Genetics.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Biology.
- Cellular biology.
- Molecular biology.
- Genetics.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (127 pages)
- Contained In:
- Dissertations Abstracts International 85-12B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- Language Note:
- English
- Summary:
- Fanconi anemia (FA) is a rare genetic disorder manifested as bone marrow failure, physical anomalies, and increased cancer risk. While it has long been recognized that FA patients exhibit compromised hematopoiesis and have reduced frequencies of immunophenotype-defined hematopoietic stem and progenitor cells (HSPCs), the number of functional stem cells within the impaired HSPC population remains unknown. Additionally, it is unclear whether current gene therapy approaches, aimed at correcting FA hematological defects by gene transfer to FA HSPCs, utilize a sufficient number of functional HSPCs to support hematopoiesis following transfusion of corrected stem cells. To better understand the number of functional stem cells in FA, I optimized a method to quantify active stem cells based on variance of fluorescence markers under the assumption of binomial distribution. This method enables the comprehensive assessment of active HSPCs across the dynamic range in mice. Applying this method to a FA mouse model, Fancc-/- mice, I revealed that these mice maintain normal levels of precursor cells despite repopulation defects post-transplantation. The only exception was in recipients transplanted with bone marrow from aging Fancc-/- mice, which displayed slightly reduced lymphocyte precursor cell numbers. Consequently, the repopulation defects of Fancc-/- HSPCs primarily stem from inherent defects in cell proliferation rather than a depletion of active stem cells, a concern for gene therapy. Exploring alternative therapeutic options for FA patients, prenatal interventions were investigated as FA have potential prenatal stem cell defects. In utero hematopoietic stem cell therapy in Fancc-/- mice showed higher donor engraftment post-IUHCT, supporting its potential therapeutic utility. In utero gene therapy was conceptually tested in vivo with a BFP expressing lentivirus, showing low but detectable transgene expression, and in vitro with a vector expressing the FANCC cDNA that effectively compensates Fancc-/- cells. These results collectively deepen the understanding of FA pathophysiology and support the design of next generation gene and cell therapy for FA.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- Advisors: Kurre, Peter; Committee members: Shin, Sunny; Speck, Nancy; Johnson, F. Bradley; Tong, Wei.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2024.
- Local Notes:
- School code: 0175
- ISBN:
- 9798382830698
- Access Restriction:
- Restricted for use by site license.
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