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Expanding Adeno-Associated Viral Capsid Engineering to Multiple Variable Regions for Diversified Tropism


Goertsen, David Gerald (2023) Expanding Adeno-Associated Viral Capsid Engineering to Multiple Variable Regions for Diversified Tropism. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/7x3a-g504.


Adeno-associated virus research is critical for the advancement of gene therapy and treatment of myriad debilitating genetic disorders. Targeted delivery of genetic components to a tissue or cell population remains a bottleneck for gene therapy, but the selection of AAV capsids through directed evolution can yield vectors that target desired tissues or cells. This thesis details the engineering of the AAV capsid to acquire desired tropism, namely reduction in liver transduction or increased transduction of the lung. Chapter I chronicles the history of AAV engineering, provides useful information about the AAV capsid proteins, and describes how AAV has been engineered for altered tropism in works preceding this thesis. Chapter II describes the development of AAV9.452sub.LUNG1, an AAV variant that is enriched in the lung of mice after systemic injection. Chapter III details the engineering of variants with attenuated tropism in the liver while maintaining previously acquired brain transduction after systemic injection. Two of these variants, AAV.CAP-B10 and AAV.CAP-B22, display similar tropism in the marmoset after systemic injection. Chapter IV describes the parallel engineering of prominent variable regions of the AAV capsid. Overall, the work presented in this thesis expands the toolbox available for gene therapy and represents an advancement of methods for AAV capsid engineering.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Directed evolution; Viral engineering; Capsid engineering; AAV; Tool development; Neuroscience; Non-human primate translation; Gene delivery; Gene therapy
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Bioengineering
Awards:Natural Sciences and Engineering Research Council of Canada, PGSD3, 2020
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Gradinaru, Viviana
Thesis Committee:
  • Van Valen, David A. (chair)
  • Bois, Justin S.
  • Wang, Kaihang
  • Gradinaru, Viviana
Defense Date:21 April 2023
Non-Caltech Author Email:davidgoertsen (AT)
Record Number:CaltechTHESIS:05172023-011031610
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 2 adapted for Chapter 3
Goertsen, David Gerald0000-0001-7138-1697
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15184
Deposited By: David Goertsen
Deposited On:22 May 2023 19:45
Last Modified:30 May 2023 15:19

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