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Nanoparticle Technologies to Cure and Prevent Infectious Diseases

Citation

Hoffmann, Magnus Adrian Gero (2022) Nanoparticle Technologies to Cure and Prevent Infectious Diseases. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/g0w1-rc77. https://resolver.caltech.edu/CaltechTHESIS:10302021-184745797

Abstract

Despite almost 40 years of intensive research, there is still no curative treatment for HIV-1/AIDS. Anti-retroviral therapy (ART) prolongs the life expectancy of HIV-1-infected individuals but is associated with side effects, and multiple drugs need to be given in combination to prevent the development of viral resistance. In addition, treatment must continue for the lifetime of the individual due to the existence of a long-lived latent proviral reservoir. While a "sterilizing" cure remains difficult to achieve due to difficulties associated with identifying and clearing latently-infected cells, recent research has focused on designing a "functional" cure, i.e., a therapeutic strategy that enables long-term suppression of HIV-1 replication and remission of symptoms in the absence of ART. The work presented here describes a new therapeutic direction for the development of a functional cure against HIV-1. This approach is based on the hypothesis that HIV-1 is unable to escape from a nanoparticle (NP)-based decoy that presents clusters of the HIV-1 receptor CD4, because CD4-NPs mimic viral target cells more accurately than soluble CD4-based inhibitors and permit high-avidity interactions with trimeric HIV-1 Env proteins. We demonstrate that CD4-NPs are >10,000-fold more potent than soluble CD4 (sCD4) and prevent viral escape in vitro. AAV-mediated delivery of self-assembling CD4-NPs produced stable CD4-NP serum concentrations in mice that were almost 1,000-fold higher than concentrations required to neutralize HIV-1 in vitro, suggesting that these concentrations could be therapeutic. Viral challenge studies in non-human primates are underway to evaluate the potential of this therapeutic strategy.

As an alternative approach to generate decoys against HIV-1, we generated engineered red blood cells (RBCs) that expressed viral receptors and potently inhibited HIV-1 infection of target cells in vitro. Because RBCs do not contain nuclei or functional organelles required for protein translation, infection of engineered RBCs represents a dead-end for a lentivirus such as HIV-1, which must integrate into the host cell genome as part of its lifecycle. We generated stable erythroid progenitor cell lines that continuously produced HIV-1 receptor-expressing RBCs that could be administered to HIV-1-infected individuals. As RBCs vastly outnumber CD4+ T-cells, HIV-1’s main target cells, and have extended lifetimes, only a fraction of an individual’s RBCs would need to be replaced with the engineered RBC viral traps in order to suppress HIV-1 infection in vivo.

My work on CD4-NP therapeutics against HIV-1 also led to the invention and development of the EBR NP technology that is ideally suited for vaccine design applications. This technology can be used to modify any type of membrane protein to self-assemble into enveloped virus-like NPs without the need for additional proteins. EBR NP assembly is induced by inserting a short amino acid sequence into the cytoplasmic tail of the membrane protein, which was designed to recruit host proteins from the endosomal sorting complex required for transport (ESCRT) pathway. We applied this technology to design protein NP-based vaccines against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which elicited potent serum neutralizing antibody responses in mice. The EBR NP technology is also ideally suited for the development of hybrid vaccine approaches that allow genetic encoding of protein-based NPs, thereby combining attributes of mRNA and protein-based NP vaccines. Pilot studies demonstrated that mRNA and DNA vaccines encoding the self-assembling SARS-CoV-2 spike-EBR construct elicited ~10-fold higher neutralizing antibody responses than mRNA and DNA vaccines encoding the unmodified spike protein. This hybrid approach has the potential to substantially enhance the potency of mRNA vaccines and could become a leading vaccine platform technology. Future applications for the EBR NP technology are discussed, including the development of a universal coronavirus vaccine to prevent future pandemics, and engineering EBR NPs to mRNA vaccines or therapeutic cargoes for efficient and targeted delivery.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Nanoparticles; HIV-1; gene therapy; vaccines; SARS-CoV-2
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Awards:Milton and Francis Clauser Doctoral Prize, 2022. Lawrence L. and Audrey W. Ferguson Prize, 2022.
Thesis Availability:Not set
Research Advisor(s):
  • Bjorkman, Pamela J.
Group:COVID-19
Thesis Committee:
  • Mazmanian, Sarkis K. (chair)
  • Pierce, Niles A.
  • Baltimore, David L.
  • Bjorkman, Pamela J.
Defense Date:26 October 2021
Funders:
Funding AgencyGrant Number
Bill and Melinda Gates FoundationOPP1202246
DeLogi Science and Technology GrantUNSPECIFIED
Kairos Ventures (Gift)UNSPECIFIED
Rothenburg Innovation InitiativeUNSPECIFIED
Rosen Bioengineering Center (Pilot grant)UNSPECIFIED
Center for Environmental Microbiology Interactions (Pilot grant)UNSPECIFIED
Record Number:CaltechTHESIS:10302021-184745797
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:10302021-184745797
DOI:10.7907/g0w1-rc77
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.2010320117DOIArticle adapted for ch. 2
https://doi.org/10.1016/j.omtm.2021.03.003DOIArticle adapted for ch. 4
ORCID:
AuthorORCID
Hoffmann, Magnus Adrian Gero0000-0003-4923-9568
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14413
Collection:CaltechTHESIS
Deposited By: Magnus Hoffmann
Deposited On:12 Nov 2021 20:39
Last Modified:08 Aug 2022 21:52

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