Samuel R. Hildebrand

Chemically Modified Oligonucleotide Sequencing Barcodes Enable High-Throughput In Vivo Screening Of a Tissue-Targeting Conjugate Library

Samuel R. Hildebrand

Chemically modified oligonucleotides are a therapeutic modality with immense potential. They are a mechanistically diverse class of molecules which could be transformative for many unmet medical needs. One of the main impediments to the development of oligonucleotides as drugs is the difficulty …

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Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington’s disease pathogenesis in mice

Jillian Belgrad, Ashley Summers, Christian Landles, Jonathan R. Greene et autres

Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Despite multiple clinical trials, huntingtin (HTT)-lowering strategies have yet to show meaningful clinical benefit. Both somatic expansion and toxic HTT species are key molecular drivers of HD, yet therapeutic strategies …

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Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model

Vignesh Narayan Hariharan, Ashley Summers, Amy E. Clipperton‐Allen, Jillian Caiazzi et autres

MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett …

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Mismatch repair dissection by in vivo RNAi reveals dose-dependent modulators of somatic instability and proteome remodeling in Huntington's disease

Jillian Belgrad, Todd M. Greco, Ellen Sapp, Ashley Summers et autres

Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs

Hassan H Fakih, Clemens Lochmann, Rosemary Gagnon, Ashley Summers et autres

Small interfering RNAs (siRNAs) hold promise for treating cardiac and muscular diseases, but robust and scalable delivery remains a hurdle. While biologic-siRNA conjugates (e.g. antibodies) are in clinical development, their manufacturing is complex. Lipophilic siRNAs are readily chemically synthesized at scale and …

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Blocking somatic repeat expansion and lowering huntingtin via RNA interference synergize to prevent Huntington’s disease pathogenesis in mice

Jillian Belgrad, Ashley Summers, Christian Landles, Jonathan R. Greene et autres

Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Two major molecular drivers-somatic expansion of inherited CAG repeats and toxic mutant HTT (mHTT) variants-lead to neuronal dysfunction. Despite multiple trials, HTT-lowering strategies have not shown meaningful clinical benefit. Using …

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Systematic analysis of siRNA and mRNA features impacting fully chemically modified siRNA efficacy

Sarah M. Davis, Samuel R. Hildebrand, Hannah J. MacMillan, Kathryn R. Monopoli et autres

Chemically modified small interfering RNAs (siRNAs) are a promising drug class that silences disease-causing genes via mRNA degradation. Both siRNA-specific features (e.g. sequence, modification pattern, and structure) and target mRNA-specific factors contribute to observed efficacy. Systematically defining the relative contributions of siRNA …

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Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality for one year in an MECP2 duplication mouse model

Vignesh Narayan Hariharan, Ashley Summers, Amy E. Clipperton‐Allen, Jillian Caiazzi et autres

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Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality for one year in an MECP2 duplication mouse model

Vignesh Narayan Hariharan, Ashley Summers, Amy E. Clipperton‐Allen, Jillian Caiazzi et autres

MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing effective therapies for MDS is particularly challenging due to the variability in MECP2 expression among patients and the potential risk …

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Potent and durable gene modulation in heart and muscle with chemically defined siRNAs

Hassan H. Fakih, Clemens Lochmann, Rosemary Gagnon, Ashley Summers et autres

ABSTRACT Small interfering RNA (siRNAs) hold immense promise for treating cardiac and muscular diseases, but robust and scalable delivery to these tissues remains a challenge. Recent advances in delivery strategies to muscle include conjugation of biologics (antibody/antibody fragments, peptides), which are currently …

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Enhancing siRNA efficacy in vivo with extended nucleic acid backbones

Ken Yamada, Vignesh Narayan Hariharan, Jillian Caiazzi, Rachael Miller et autres

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Phosphatidylcholine head group chemistry alters the extrahepatic accumulation of lipid-conjugated siRNA

Vignesh Narayan Hariharan, Takahiro Nakamura, Minwook Shin, Qi Tang et autres

Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge. Conjugating lipids (e.g., docosanoic acid [DCA]) to siRNA supports extrahepatic delivery, but tissue accumulation remains lower than that achieved in liver by …

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