دورية أكاديمية
Genomic Designs of rAAVs Contribute to Pathological Changes in the Livers and Spleens of Mice.
| العنوان: | Genomic Designs of rAAVs Contribute to Pathological Changes in the Livers and Spleens of Mice. |
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| المؤلفون: | Mulcrone PL; Herman B Wells Center for Pediatric Research, Indiana University, USA.; Department of Pediatrics, Indiana University, USA., Zhang J; Herman B Wells Center for Pediatric Research, Indiana University, USA.; Department of Pediatrics, Indiana University, USA., Pride PM; Herman B Wells Center for Pediatric Research, Indiana University, USA., Lam AK; Herman B Wells Center for Pediatric Research, Indiana University, USA.; Department of Pediatrics, Indiana University, USA., Frabutt DA; Herman B Wells Center for Pediatric Research, Indiana University, USA.; Department of Microbiology & Immunology, Indiana University, Indianapolis, IN, USA., Ball-Kell SM; Department of Biology, Bradley University, Peoria, IL, USA., Xiao W; Herman B Wells Center for Pediatric Research, Indiana University, USA. |
| المصدر: | Advances in cell and gene therapy [Adv Cell Gene Ther] 2022; Vol. 2022. Date of Electronic Publication: 2022 Mar 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley Country of Publication: United States NLM ID: 101731783 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2573-8461 (Electronic) Linking ISSN: 25738461 NLM ISO Abbreviation: Adv Cell Gene Ther Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Hoboken, NJ : Wiley |
| مستخلص: | Recombinant AAV (rAAV) gene therapy is being investigated as an effective therapy for several diseases including hemophilia B. Reports of liver tumor development in certain mouse models due to AAV treatment and genomic integration of the rAAV vector has raised concerns about the long-term safety and efficacy of this gene therapy. To investigate whether rAAV treatment causes cancer, we utilized two mouse models, inbred C57BL/6 and hemophilia B Balb/C mice (HemB), to test if injecting a high dose of various rAAV8 vectors containing or lacking hFIX transgene, a Poly-A sequence, or the CB or TTR promoter triggered liver fibrosis and/or cancer development over the course of the 6.5-month study. We observed no liver tumors in either mouse cohort regardless of rAAV treatment through ultrasound imaging, gross anatomical assessment at sacrifice, and histology. We did, however, detect differences in collagen deposition in C57BL/6 livers and HemB spleens of rAAV-injected mice. Pathology reports of the HemB mice revealed many pathological phenomena, including fibrosis and inflammation in the livers and spleens across different AAV-injected HemB mice. Mice from both cohorts injected with the TTR-hFIX vector demonstrated minimal adverse events. While not tumorigenic, high dose of rAAVs, especially those with incomplete genomes, can influence liver and spleen health negatively that could be problematic for cementing AAVs as a broad therapeutic option in the clinic. Competing Interests: Conflicts of Interest The authors declare that they have no conflicts of interest. |
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| معلومات مُعتمدة: | R01 HL130871 United States HL NHLBI NIH HHS; T32 HL007910 United States HL NHLBI NIH HHS; U54 HL142019 United States HL NHLBI NIH HHS |
| تواريخ الأحداث: | Date Created: 20221212 Latest Revision: 20230224 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9730939 |
| DOI: | 10.1155/2022/6807904 |
| PMID: | 36507314 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2573-8461 |
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| DOI: | 10.1155/2022/6807904 |