دورية أكاديمية
Natural variations in AAVHSC16 significantly reduce liver tropism and maintain broad distribution to periphery and CNS
العنوان: | Natural variations in AAVHSC16 significantly reduce liver tropism and maintain broad distribution to periphery and CNS |
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المؤلفون: | Laura J. Smith, Lindsay A. Schulman, Samantha Smith, Laura Van Lieshout, Carmen M. Barnes, Liana Behmoiras, Meghan Scarpitti, Monicah Kivaa, Khanh L. Duong, Ludo O. Benard, Jeff L. Ellsworth, Nancy Avila, Deiby Faulkner, April Hayes, Jason Lotterhand, Jose Israel Rivas, Arnold V. Sengooba, Alec Tzianabos, Albert B. Seymour, Omar L. Francone |
المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 26, Iss , Pp 224-238 (2022) |
بيانات النشر: | Elsevier, 2022. |
سنة النشر: | 2022 |
المجموعة: | LCC:Genetics LCC:Cytology |
مصطلحات موضوعية: | gene therapy, adeno-associated virus, AAV, tropism/biodistribution, glycan binding, structure-function relationship, Genetics, QH426-470, Cytology, QH573-671 |
الوصف: | Adeno-associated viruses derived from human hematopoietic stem cells (AAVHSCs) are naturally occurring AAVs. Fifteen AAVHSCs have demonstrated broad biodistribution while displaying differences in transduction. We examine the structure-function relationships of these natural amino acid variations on cellular binding. We demonstrate that AAVHSC16 is the only AAVHSC that does not preferentially bind to terminal galactose. AAVHSC16 contains two unique amino acids, 501I and 706C, compared with other AAVHSCs. Through mutagenesis, we determined that residue 501 contributes to the lack of galactose binding. Structural analysis revealed that residue 501 is in proximity to the galactose binding pocket, hence confirming its functional role in galactose binding. Biodistribution analysis of AAVHSC16 indicated significantly less liver tropism in mice and non-human primates compared with other clade F members, likely associated with overall binding differences observed in vitro. AAVHSC16 maintained robust tropism to other key tissues in the peripheral and central nervous systems after intravenous injection, including to the brain, heart, and gastrocnemius. Importantly, AAVHSC16 did not induce elevated liver enzyme levels in non-human primates after intravenous injection at high doses. The unique glycan binding and tropism of AAVHSC16 makes this naturally occurring capsid an attractive candidate for therapies requiring less liver tropism while maintaining broad biodistribution. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 2329-0501 |
Relation: | http://www.sciencedirect.com/science/article/pii/S2329050122000924; https://doaj.org/toc/2329-0501 |
DOI: | 10.1016/j.omtm.2022.06.013 |
URL الوصول: | https://doaj.org/article/7732422524634ae684ab6a55ab50be2f |
رقم الأكسشن: | edsdoj.7732422524634ae684ab6a55ab50be2f |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 23290501 |
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DOI: | 10.1016/j.omtm.2022.06.013 |