Matthew Hassler
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View article: Complex Dynamics in Circular and Deformed Bilayer Graphene-Inspired Billiards with Anisotropy and Strain
Complex Dynamics in Circular and Deformed Bilayer Graphene-Inspired Billiards with Anisotropy and Strain Open
While billiard systems of various shapes have been used as paradigmatic model systems in the fields of nonlinear dynamics and quantum chaos, few studies have investigated anisotropic billiards. Motivated by the tremendous advances in using…
View article: Complex dynamics in circular and deformed bilayer graphene inspired billiards with anisotropy and strain
Complex dynamics in circular and deformed bilayer graphene inspired billiards with anisotropy and strain Open
While billiard systems of various shapes have been used as paradigmatic model systems in the fields of nonlinear dynamics and quantum chaos, few studies have investigated anisotropic billiards. Motivated by the tremendous advances in using…
View article: Divalent siRNA for prion disease
Divalent siRNA for prion disease Open
Pharmacologic lowering of PrP expression is efficacious against prion disease in animal models and is now being tested clinically. 50% lowering of PrP increases both survival time and healthy life in prion-infected mice, but does not preve…
View article: Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs
Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs Open
A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficien…
View article: RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice
RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice Open
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neuron…
View article: Silencing <i>Apoe</i> with divalent‐siRNAs improves amyloid burden and activates immune response pathways in Alzheimer's disease
Silencing <i>Apoe</i> with divalent‐siRNAs improves amyloid burden and activates immune response pathways in Alzheimer's disease Open
INTRODUCTION The most significant genetic risk factor for late‐onset Alzheimer's disease (AD) is APOE4 , with evidence for gain‐ and loss‐of‐function mechanisms. A clinical need remains for therapeutically relevant tools that potently modu…
View article: A combinatorial approach for achieving CNS-selective RNAi
A combinatorial approach for achieving CNS-selective RNAi Open
RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture ar…
View article: Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors
Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors Open
View article: Challenges of Assessing Exon 53 Skipping of the Human <i>DMD</i> Transcript with Locked Nucleic Acid-Modified Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
Challenges of Assessing Exon 53 Skipping of the Human <i>DMD</i> Transcript with Locked Nucleic Acid-Modified Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy Open
Antisense oligonucleotide (AON)-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy (DMD) patients to restore dystrophin expression by reframing the disrupted open reading frame of the DMD tran…
View article: Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in rodent and swine photoreceptors
Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in rodent and swine photoreceptors Open
Inherited retinal dystrophies caused by dominant mutations in photoreceptor-expressed genes, are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. …
View article: Humeral Tissue Remodeling in Contact with Pyrocarbon Interposition Implant
Humeral Tissue Remodeling in Contact with Pyrocarbon Interposition Implant Open
View article: Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo
Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo Open
View article: Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy<i>in vivo</i>
Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy<i>in vivo</i> Open
Metabolic stabilization of therapeutic oligonucleotides requires both sugar and backbone modifications, where phosphorothioate (PS) is the only backbone chemistry used in the clinic. Here, we describe the discovery, synthesis, and characte…
View article: Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models
Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models Open
Small interfering RNAs are a new class of drugs, exhibiting sequence-driven, potent, and sustained silencing of gene expression in vivo. We recently demonstrated that siRNA chemical architectures can be optimized to provide efficient deliv…
View article: Chemical engineering of therapeutic siRNAs for allele-specific gene silencing<i>in vivo</i>in CNS
Chemical engineering of therapeutic siRNAs for allele-specific gene silencing<i>in vivo</i>in CNS Open
Small interfering RNAs (siRNAs) are a new class of drugs, exhibiting sequence-driven, potent, and sustained silencing of gene expression in vivo . We recently demonstrated that siRNA chemical architectures can be optimized to provide effic…
View article: Silencing of <i>ApoE</i> with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer’s Disease
Silencing of <i>ApoE</i> with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer’s Disease Open
The most common genetic risk factor for late-onset Alzheimer’s disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function mechanisms. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due t…
View article: PK-modifying anchors significantly alter clearance kinetics, tissue distribution, and efficacy of therapeutics siRNAs
PK-modifying anchors significantly alter clearance kinetics, tissue distribution, and efficacy of therapeutics siRNAs Open
View article: Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep
Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep Open
siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman pri…
View article: An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis
An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis Open
View article: Structurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificity
Structurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificity Open
Oligonucleotides is an emerging class of chemically-distinct therapeutic modalities, where extensive chemical modifications are fundamental for their clinical applications. Inter-nucleotide backbones are critical to the behaviour of therap…
View article: Cell Type Impacts Accessibility of mRNA to Silencing by RNA Interference
Cell Type Impacts Accessibility of mRNA to Silencing by RNA Interference Open
RNA interference (RNAi) is a potent mechanism that silences mRNA and protein expression in all cells and tissue types. RNAi is known to exert many of its functional effects in the cytoplasm, and thus, the cellular localization of target mR…
View article: Development of Novel Class of Therapeutic Oligonucleotides Based on Small Molecule Screening
Development of Novel Class of Therapeutic Oligonucleotides Based on Small Molecule Screening Open
Highly inefficient transit of oligonucleotides from outside cells to the intracellular compartments where functional activity of oligonucleotides takes place is the most serious limitation to the practical realization of a full potential o…
View article: 2′-O-Methyl at 20-mer Guide Strand 3′ Termini May Negatively Affect Target Silencing Activity of Fully Chemically Modified siRNA
2′-O-Methyl at 20-mer Guide Strand 3′ Termini May Negatively Affect Target Silencing Activity of Fully Chemically Modified siRNA Open
View article: Serum Deprivation of Mesenchymal Stem Cells Improves Exosome Activity and Alters Lipid and Protein Composition
Serum Deprivation of Mesenchymal Stem Cells Improves Exosome Activity and Alters Lipid and Protein Composition Open
Exosomes can serve as delivery vehicles for advanced therapeutics. The components necessary and sufficient to support exosomal delivery have not been established. Here we connect biochemical composition and activity of exosomes to optimize…
View article: Pyrocarbon versus cobalt-chromium in the context of spherical interposition implants: an in vitro study on cultured chondrocytes
Pyrocarbon versus cobalt-chromium in the context of spherical interposition implants: an in vitro study on cultured chondrocytes Open
In the context of shoulder surgical replacement, a new generation of spherical interposition implants has been developed, with the implant being a mobile spacer rubbing against the glenoid cartilage and humeral bone cavity. The aim of the …
View article: Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways
Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways Open
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…
View article: Diverse lipid conjugates for functional extra-hepatic siRNA delivery <i>in vivo</i>
Diverse lipid conjugates for functional extra-hepatic siRNA delivery <i>in vivo</i> Open
Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen l…
View article: Heavily and fully modified RNAs guide efficient SpyCas9-mediated genome editing
Heavily and fully modified RNAs guide efficient SpyCas9-mediated genome editing Open
RNA-based drugs depend on chemical modifications to increase potency and to decrease immunogenicity in vivo. Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as well. Cas9 orthologs are RN…
View article: Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles
Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles Open
Extracellular vesicles are promising delivery vesicles for therapeutic RNAs. Small interfering RNA (siRNA) conjugation to cholesterol enables efficient and reproducible loading of extracellular vesicles with the therapeutic cargo. siRNAs a…
View article: Heavily and Fully Modified RNAs Guide Efficient SpyCas9-Mediated Genome Editing
Heavily and Fully Modified RNAs Guide Efficient SpyCas9-Mediated Genome Editing Open
RNA-based drugs depend on chemical modifications to increase potency and nuclease stability, and to decrease immunogenicity in vivo . Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as we…