Socheata Ly

University of Massachusetts Chan Medical School

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Anastasia Khvorova

University of Massachusetts Chan Medical School

Dimas Echeverria

University of Massachusetts Chan Medical School

Chantal Ferguson

University of Massachusetts Chan Medical School

Neil Aronin

University of Massachusetts Chan Medical School

Marian DiFiglia

Massachusetts General Hospital

Matthew Hassler

Chemnitz University of Technology

Sherwin S. Lehrer

Boston Biomedical Research Institute

Ellen Sapp

Massachusetts General Hospital

Andrew H. Coles

AbbVie (United States)

Bruno M.D.C. Godinho

University of Massachusetts Chan Medical School

Cooperative Institutions

University of Massachusetts Chan Medical School

UMass Memorial Medical Center

Massachusetts Academy of Math and Science

Harvard University

Massachusetts General Hospital

National Institutes of Health

Boston Biomedical Research Institute

UMass Memorial Health Care

Howard Hughes Medical Institute

University of Pittsburgh

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Long-Range Transmission of Structural Instability due to the FHC Mutation E180G in Coiled-Coil Tm is inhibited by an Interchain Disulfide Bond

Biophysical Journal (2013)

David Yampolsky Socheata Ly Sherwin S. Lehrer

Cleavage (geology)

Residue (chemistry)

10.1016/j.bpj.2012.11.2490

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Citations (0)

Structural Instability of Tropomyosin FHC Mutants D175N and E180G Probed by Limited Trypsin Cleavage

Biophysical Journal (2012)

Socheata Ly Robin Maytum Zenon Grabarek Sherwin S. Lehrer

Cleavage (geology)

Tropomyosin

10.1016/j.bpj.2011.11.846

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Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington’s disease

Molecular Therapy (2023)

Daniel O’Reilly Jillian Belgrad Chantal Ferguson Ashley Summers Ellen Sapp

Huntington's disease (HD) is a severe neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify a fully chemically modified short interfering RNA (siRNA) that robustly silences Msh3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of Msh3 effectively blocked CAG-repeat expansion in the striatum of two HD mouse models without affecting tumor-associated microsatellite instability or mRNA expression of other MMR genes. Our findings establish a promising treatment approach for patients with HD and other repeat expansion diseases.

10.1016/j.ymthe.2023.05.006

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Citations (34)

Long-Range Effects of Familial Hypertrophic Cardiomyopathy Mutations E180G and D175N on the Properties of Tropomyosin

Biochemistry (2012)

Socheata Ly Sherwin S. Lehrer

Cardiac α-tropomyosin (Tm) single-site mutations D175N and E180G cause familial hypertrophic cardiomyopathy (FHC). Previous studies have shown that these mutations increase both Ca2+ sensitivity and residual contractile activity at low Ca2+ concentrations, which causes incomplete relaxation during diastole resulting in hypertrophy and sarcomeric disarray. However, the molecular basis for the cause and the difference in the severity of the manifested phenotypes of disease are not known. In this work we have (1) used ATPase studies using reconstituted thin filaments in solution to show that these FHC mutants result in an increase in Ca2+ sensitivity and an increased residual level of ATPase, (2) shown that both FHC mutants increase the rate of cleavage at R133, ∼45 residues N-terminal to the mutations, when free and bound to actin, (3) shown that for Tm-E180G, the increase in the rate of cleavage is greater than that for D175N, and (4) shown that for E180G, cleavage also occurs at a new site 53 residues C-terminal to E180G, in parallel with cleavage at R133. The long-range decreases in dynamic stability due to these two single-site mutations suggest increases in flexibility that may weaken the ability of Tm to inhibit activity at low Ca2+ concentrations for D175N and to a greater degree for E180G, which may contribute to differences in the severity of FHC.

Tropomyosin

Cleavage (geology)

10.1021/bi3006835

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Citations (44)

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Nucleic Acids Research (2018)

Maire F. Osborn Andrew H. Coles Annabelle Biscans Reka A. Haraszti Loïc Roux

Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.

Internalization

10.1093/nar/gky1232

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Citations (102)

67: Pulmonary Effects of Atropine in Humans

Annals of Emergency Medicine (2009)

Socheata Ly James Lindberg Mark Dershwitz Matthias Walz Romolo Gaspari

Hypoxia

Parasympatholytics

10.1016/j.annemergmed.2009.06.088

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Citations (1)

Visualization of self-delivering hydrophobically modified siRNA cellular internalization

Nucleic Acids Research (2016)

Socheata Ly Deanna M. Navaroli Marie-Cécile Didiot James Cardia Lakshmipathi Pandarinathan

siRNAs are a new class of therapeutic modalities with promising clinical efficacy that requires modification or formulation for delivery to the tissue and cell of interest. Conjugation of siRNAs to lipophilic groups supports efficient cellular uptake by a mechanism that is not well characterized. Here we study the mechanism of internalization of asymmetric, chemically stabilized, cholesterol-modified siRNAs (sd-rxRNAs®) that efficiently enter cells and tissues without the need for formulation. We demonstrate that uptake is rapid with significant membrane association within minutes of exposure followed by the formation of vesicular structures and internalization. Furthermore, sd-rxRNAs are internalized by a specific class of early endosomes and show preferential association with epidermal growth factor (EGF) but not transferrin (Tf) trafficking pathways as shown by live cell TIRF and structured illumination microscopy (SIM). In fixed cells, we observe ∼25% of sd-rxRNA co-localizing with EGF and <5% with Tf, which is indicative of selective endosomal sorting. Likewise, preferential sd-rxRNA co-localization was demonstrated with EEA1 but not RBSN-containing endosomes, consistent with preferential EGF-like trafficking through EEA1-containing endosomes. sd-rxRNA cellular uptake is a two-step process, with rapid membrane association followed by internalization through a selective, saturable subset of the endocytic process. However, the mechanistic role of EEA1 is not yet known. This method of visualization can be used to better understand the kinetics and mechanisms of hydrophobic siRNA cellular uptake and will assist in further optimization of these types of compounds for therapeutic intervention.

Internalization

10.1093/nar/gkw1005

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Citations (117)

Investigating the Role of Mutant Huntingtin mRNA in Huntington’s Disease

Socheata Ly

10.13028/x0ym-8h64

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Novel Cluster and Monomer-Based GalNAc Structures Induce Effective Uptake of siRNAs in Vitro and in Vivo

Bioconjugate Chemistry (2018)

Vivek Sharma Maire F. Osborn Matthew Hassler Dimas Echeverria Socheata Ly

GalNAc conjugation is emerging as a dominant strategy for delivery of therapeutic oligonucleotides to hepatocytes. The structure and valency of the GalNAc ligand contributes to the potency of the conjugates. Here we present a panel of multivalent GalNAc variants using two different synthetic strategies. Specifically, we present a novel conjugate based on a support-bound trivalent GalNAc cluster, and four others using a GalNAc phosphoramidite monomer that was readily assembled into tri- or tetravalent designs during solid phase oligonucleotide synthesis. We compared these compounds to a clinically used trivalent GalNAc cluster both in vitro and in vivo. In vitro, cluster-based and phosphoramidite-based scaffolds show a similar rate of internalization in primary hepatocytes, with membrane binding observed as early as 5 min. All tested compounds provided potent, dose-dependent silencing, with 2–4% of injected dose recoverable from liver after 1 week. The two preassembled trivalent GalNAc clusters showed higher tissue accumulation and gene silencing relative to di-, tri-, or tetravalent GalNAc conjugates assembled via phosphoramidite chemistry.

10.1021/acs.bioconjchem.8b00365

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Citations (38)

Tropomyosin is in a reduced state in rat cardiac muscle

Journal of Muscle Research and Cell Motility (2011)

Sherwin S. Lehrer Socheata Ly Franklin Fuchs

Tropomyosin

Cardiac muscle

10.1007/s10974-011-9254-9

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Citations (10)