David R. Liu

In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson‐Gilford Progeria Syndrome

Wayne A. Cabral, Caleb M. Grenko, Diana Yeritsyan, Indeevar Beeram et autres

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In …

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Mechanistic machine learning for prediction of prime editing outcomes

Alvin Hsu, Peter J. Chen, Angus Li, Colin Hemez et autres

Prime editing (PE) can make specific local changes to genomic DNA in living systems but its efficient application currently requires extensive optimization of PE guide RNA (pegRNA) sequences. Here we present OptiPrime, a machine learning model of PE efficiency based on current …

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Evolution of botulinum neurotoxin serotype X proteases to induce inflammatory cell death in cancer cells

Julia McCreary, Colin Hemez, Michael H. Raymond, Travis R. Blum et autres

Triggering protease-activated cell death is a promising strategy for cancer treatment. Here, we used phage-assisted evolution to reprogram botulinum neurotoxin serotype X proteases to cleave and activate procaspase-1 and gasdermin D, key effectors of inflammatory cell death. We also developed an efficient …

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AI-redesigned starting points and outcomes enhance protein evolution

N Krasnow, J. Y. Xu, Emily Zhang, Gandhar Mahadeshwar et autres

Abstract Engineered or laboratory-evolved proteins often have suboptimal stability, activity or specificity. Here we applied artificial intelligence (AI)-based protein sequence design to address challenges in experimental enzyme evolution. Using the model ProteinMPNN, we redesigned three distinct botulinum neurotoxin (BoNT) proteases, generating variants …

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Base editing reveals an essential role for NANOG in human embryogenesis

Oliver J. Bower, Ana Elisa Ribeiro Orsi, Riley McMahon, Desislava P. Staneva et autres

Abstract Understanding how the first cell lineages in human development are specified and maintained has fundamental importance and clinical implications for regenerative medicine, infertility and pregnancy loss. Although mouse models have provided valuable insights into transcription factors regulating early development, translating these …

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Base editing reveals an essential role for NANOG in human embryogenesis.

Oliver J. Bower, Ana Elisa Ribeiro Orsi, Riley McMahon, Desislava P. Staneva et autres

Efficient prime editing in vivo and in vitro using lipid nanoparticles

Allen Yujie Jiang, Ana Cristian, Dominique L. Brooks, Emily Feierman et autres

Abstract Prime editing is a versatile clinical genome editing method that enables precise substitutions, small insertions and deletions at specified locations in the genomes of living systems including human cells. Although non-viral lipid nanoparticle (LNP) delivery of RNA in vivo has become …

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Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T cells

Brian Shim, Q. Henry Zhao, Jack A. Queenan, Blake E. Smith et autres

Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfunctional T cell phenotypes. These challenges necessitate technologies to engineer and reprogram endogenous tumor-specific …

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In vivo base editing rescues liver pathophysiology and peroxisome dysfunction in a mouse model of Zellweger spectrum disorder

Xin D. Gao, Maximiliano Presa, Jordyn E. Duby, Jennifer Ryan et autres

Zellweger spectrum disorder (ZSD) is caused by biallelic loss-of-function variants in PEX genes required for peroxisome biogenesis, which is critical for normal cellular metabolism and signalling. The PEX1-p.G843D (c.2528G>A) allele, present in approximately 30% of individuals with ZSD, frequently results in chronic …

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P-2026. Quality Improvement Initiative to Safely Reduce Follow-up Blood Cultures through Diagnostic Stewardship During a National Blood Culture Bottle Shortage

Jeffrey Kubiak, Barbara Ross, S Wang, Regina T Wulff et autres

Abstract Background Blood cultures (BC) are a critical resource to diagnose bloodstream infections. However, over-ordering may lead to antibiotic overuse and increased hospital cost, length of stay, and contamination rates. A national blood culture bottle shortage prompted diagnostic stewardship of follow-up blood …

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Decoupled DMD: CFG Augmentation as the Spear, Distribution Matching as the Shield

Dongyang Liu, Peng Gao, David R. Liu, Rongbao Du et autres

Diffusion model distillation has emerged as a powerful technique for creating efficient few-step and single-step generators. Among these, Distribution Matching Distillation (DMD) and its variants stand out for their impressive performance, which is widely attributed to their core mechanism of matching the …

Prime editing-installed suppressor tRNAs for disease-agnostic genome editing

Sarah E. Pierce, Steven Erwood, Keyede Oye, Meirui An et autres

Abstract Precise genome-editing technologies such as base editing 1,2 and prime editing 3 can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused …

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