In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.

@article{Musunuru2021InVC,
  title={In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.},
  author={Kiran Musunuru and Alexandra C. Chadwick and Taiji Mizoguchi and S. P{\'e}rez Garc{\'i}a and Jamie E. DeNizio and Caroline W Reiss and Kui Wang and Sowmya Iyer and Chaitali Dutta and Victoria Clendaniel and Michael Amaonye and Aaron Beach and Kathleen Berth and Souvik Biswas and Maurine C Braun and Huei-Mei Chen and Thomas V. Colace and John Ganey and Soumyashree A. Gangopadhyay and Ryan Garrity and Lisa N. Kasiewicz and Jennifer Lavoie and James A. Madsen and Yuri Matsumoto and Anne Marie Mazzola and Yusuf Nasrullah and Joseph Nneji and Huilan Ren and Athul Sanjeev and Madeleine Shay and Mary R. Stahley and Steven H.Y. Fan and Ying K. Tam and Nicole M. Gaudelli and Giuseppe Ciaramella and Leslie E. Stolz and Padma Malyala and Christopher J. Cheng and Kallanthottathil G Rajeev and Ellen Rohde and Andrew M. Bellinger and Sekar Kathiresan},
  journal={Nature},
  year={2021},
  volume={593 7859},
  pages={
          429-434
        }
}
Gene-editing technologies, which include the CRISPR-Cas nucleases1-3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes… 
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94 Citations
Highly Influential Citations
5
Background Citations
22
Methods Citations
6
Results Citations
1

94 Citations

In vivo prime editing of a metabolic liver disease in mice
TLDR
A proof-of-principle in vivo prime editing strategy corrects phenylketonuria in mice and allows for more versatile and precise editing than CRISPR-based strategies but is still challenging to apply in vivo.
Gene Therapy Targeting PCSK9
TLDR
Use of the CRISPR/Cas system enables precise genome editing down to single-nucleotide changes and has the potential to fundamentally change current concepts of cardiovascular prevention.
Treatment of a metabolic liver disease by in vivo prime editing in mice
TLDR
This study demonstrates in vivo prime editing in the liver with high precision and editing rates sufficient to treat a number of metabolic liver diseases, emphasizing the potential of prime editing for future therapeutic applications.
CRISPR Gene Editing in Lipid Disorders and Atherosclerosis: Mechanisms and Opportunities
TLDR
An overview of CRISPR technology is provided, with a particular focus on recent studies with relevance to its potential use in atherosclerotic cardiovascular disease.
Outsmarting Delivery Barriers In Vivo: Base Editing via Next-Generation Virus-Like Particles
TLDR
Key foundational reports stopped short of robust in vivo genome editing, potentially because the VLPs lacked sufficient potency, so potent upgrades to a virus-like platform that embodies some of the best characteristics of both viral and nonviral technologies are described.
mRNA-mediated delivery of gene editing tools to human primary muscle stem cells
Adenine Base Editing in vivo with a Single Adeno-Associated Virus Vector
TLDR
In vivo delivery of Nme2-ABE and its guide RNA by a single-AAV vector can efficiently edit mouse genomic loci and revert the disease mutation and phenotype in an adult mouse model of tyrosinemia.
Innovations in CRISPR-Based Therapies
  • G. Kesavan
  • Biology, Medicine
    Molecular Biotechnology
  • 2021
TLDR
This mini-review assesses the status of CRISPR-based therapies, both in vivo and ex vivo, and the challenges associated with clinical translation and the safety, affordability, and feasibility ofCRISPR therapies.
The use of new CRISPR tools in cardiovascular research and medicine
TLDR
How these novel CRISPR tools are used to investigate biological processes and disease pathophysiology for cardiovascular research and medicine and the prospect of therapeutic genome editing by CRISpr tools to cure genetic cardiovascular diseases are described.
In vivo somatic cell base editing and prime editing.
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References

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Permanent Alteration of PCSK9 With In Vivo CRISPR-Cas9 Genome Editing
TLDR
Genome editing with the CRISPR–CRISPR-associated 9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice, which may have therapeutic potential for the prevention of cardiovascular disease in humans.
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing.
Treatment of a metabolic liver disease by in vivo genome base editing in adult mice
TLDR
AAV-mediated base editing corrects an autosomal recessive mutation in the Pahenu2 gene and ameliorates molecular deficits in a mouse model of metabolic liver disease and suggests that targeting genetic diseases in vivo using AAV-mediated delivery of base-editing agents is feasible.
Long-term Stable Reduction of Low-density Lipoprotein in Nonhuman Primates Following In Vivo Genome Editing of PCSK9.
Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing
TLDR
This work identifies regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and develops an optimal set of chemical modifications for in vivo applications, and shows that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver.
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TLDR
The results of this proof-of-concept work demonstrate the possibility of efficiently performing gene editing before birth, pointing to a potential new therapeutic approach for selected congenital genetic disorders.
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TLDR
The ability to precisely introduce therapeutically relevant nucleotide variants into the genome in somatic tissues in adult mammals is demonstrated, highlighting a potentially safer alternative to therapeutic genome editing.
Adenine base editing in an adult mouse model of tyrosinemia
TLDR
It is shown in a mouse model of tyrosinaemia that hydrodynamic tail-vein injection of plasmid DNA encoding the adenine base editor (ABE) and a single-guide RNA (sgRNA) can correct an A>G splice-site mutation.
Non-viral Delivery of Zinc Finger Nuclease mRNA Enables Highly Efficient In Vivo Genome Editing of Multiple Therapeutic Gene Targets.
In vivo cytidine base editing of hepatocytes without detectable off-target mutations in RNA and DNA
TLDR
The findings support the feasibility of therapeutic cytidine base editing to treat genetic liver diseases via adeno-associated viruses or lipid nanoparticles delivered to the liver of mice with phenylketonuria and lead to detectable off-target edits in the RNA and DNA of hepatocytes.
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