2. Academic Validation
  3. Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease

Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease

  • ACS Nano. 2023 Jul 17. doi: 10.1021/acsnano.3c02268.
Rohan Palanki 1 2,  Sourav K Bose 2,  Apeksha Dave 2,  Brandon M White 2,  Cara Berkowitz 2,  Valerie Luks 2,  Fazeela Yaqoob 3,  Emily Han 1,  Kelsey L Swingle 1,  Pallavi Menon 2,  Emily Hodgson 2,  Arijit Biswas 4,  Margaret M Billingsley 1,  Li Li 5,  Fan Yiping 4,  Marco Carpenter 2,  Alexandra Trokhan 2,  Julie Yeo 4,  Nuryanti Johana 4,  Tan Yi Wan 4,  Mohamad-Gabriel Alameh 6,  Frederick Chris Bennett 3,  Phillip B Storm 7,  Rajan Jain 6 5,  Jerry Chan 4 8,  Drew Weissman 6,  Michael J Mitchell 1 9 10 5 11,  William H Peranteau 2 12
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 2 Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States.
  • 3 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 4 Duke-NUS Graduate Medical School, Singapore, 169547, Singapore.
  • 5 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 6 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 7 Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States.
  • 8 Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, 229899, Singapore.
  • 9 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 10 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 11 Institute for Regenerative Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.
  • 12 Division of General, Thoracic, and Fetal Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States.
PMID: 37458484 DOI: 10.1021/acsnano.3c02268
Abstract

Delivery of mRNA-based therapeutics to the perinatal brain holds great potential in treating congenital brain diseases. However, nonviral delivery platforms that facilitate nucleic acid delivery in this environment have yet to be rigorously studied. Here, we screen a diverse library of ionizable lipid nanoparticles (LNPs) via intracerebroventricular (ICV) injection in both fetal and neonatal mice and identify an LNP formulation with greater functional mRNA delivery in the perinatal brain than an FDA-approved industry standard LNP. Following in vitro optimization of the top-performing LNP (C3 LNP) for codelivery of an adenine base editing platform, we improve the biochemical phenotype of a lysosomal storage disease in the neonatal mouse brain, exhibit proof-of-principle mRNA brain transfection in vivo in a fetal nonhuman primate model, and demonstrate the translational potential of C3 LNPs ex vivo in human patient-derived brain tissues. These LNPs may provide a clinically translatable platform for in utero and postnatal mRNA therapies including gene editing in the brain.

Keywords

congenital brain disease; fetal gene therapy; gene editing; ionizable lipid nanoparticles; mRNA delivery.

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