A5101834039- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- MicroRNA in disease regulation
- Amyotrophic Lateral Sclerosis Research
- Cognitive Computing and Networks
- HIV Research and Treatment
- RNA Research and Splicing
- melanin and skin pigmentation
- Genetics and Neurodevelopmental Disorders
- Glycosylation and Glycoproteins Research
- Neurogenetic and Muscular Disorders Research
- Proteoglycans and glycosaminoglycans research
- Pancreatic function and diabetes
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- Enzyme Structure and Function
- Advanced Electron Microscopy Techniques and Applications
- Genetically Modified Organisms Research
- Pharmacological Effects and Toxicity Studies
- Cell death mechanisms and regulation
- Vacuum and Plasma Arcs
- Business Law and Ethics
- Blood properties and coagulation
- Smart Grid Security and Resilience
- Safety Systems Engineering in Autonomy
University of Massachusetts Chan Medical School
2022-2025
Massachusetts Academy of Math and Science
2024
UMass Memorial Medical Center
2024
University of Alabama at Birmingham
2016
National Institute of Standards
2010-2011
National Institute of Standards and Technology
2010-2011
University of Colorado Denver
2011
National Park Service
2001
Diazyme (United States)
1999
University of Pittsburgh
1997
The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring need for a dynamic platform rapid development pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing treatment numerous diseases with unprecedented potency, duration effect, and safety. Through systematic screening hundreds oligonucleotide sequences, we identified fully chemically stabilized siRNAs ASOs that target regions genome conserved in all concern,...
Abstract Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy safety profiles, likely reflecting variable selectivity subtypes. Absolute subtype has not yet been achieved. Here, we rationally design interfering RNAs (siRNAs) that offer sequence-specific gene silencing JAK1, narrowing spectrum action on JAK-dependent cytokine signaling to maintain...
Transcriptional gene silencing (TGS) of mammalian genes can be induced by short interfering RNA (siRNA) targeting promoter regions. We previously reported potent TGS HIV-1 siRNA (PromA), which targets tandem NF-κB motifs within the viral 5'LTR. In this study, we screened a panel with aim identifying novel 5'LTR targets, to provide multiplexing potential enhanced and application toward developing alternate therapeutic strategies. Systematic examination identified target, si143, confirmed...
Lipid conjugation supports delivery of small interfering RNAs (siRNAs) to extrahepatic tissues, expanding the therapeutic potential siRNAs beyond liver indications. However, siRNA silencing efficacy in tissues remains inferior that routinely achieved liver, partially due low rate endosomal escape following internalization. Improving release into cytoplasm is crucial improving lipid-conjugated siRNAs. Given ability ionizable lipids enhance a context lipid nanoparticles (LNP), here, we provide...
Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain IFN-γ receptor (IFNGR1), for modulation signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery all major cell types local injection site, with single dose supporting...
Abstract Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of target gene within central nervous system (CNS). However, an siRNA modality capable simultaneously modulating pairs would be invaluable treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, parameters and scaffold considerations multi-targeting nucleic acid modalities in CNS are undefined. Here, we...
Metastatic melanoma has poor prognosis and is refractory to most conventional chemotherapies. The alkylating agent temozolomide (TMZ) commonly used in treating but a disappointing response rate. Agents that can act cooperatively with TMZ improve its efficacy are thus highly sought after. BH3 mimetic ABT-737, which induce apoptosis by targeting pro-survival Bcl-2 family members, been found enhance the of many chemotherapeutic agents multiple cancers. We combining ABT-737 induced strong...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein toxic motor neurons, making gene lowering promising approach, supported by preclinical data 2023 FDA approval GapmeR ASO targeting SOD1, tofersen. Despite an optimism it brings field, pharmacodynamics pharmacokinetics therapeutic modulation can be improved. Here, we developed...
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 particularly challenging due to variability in expression among patients and potential risk inducing Rett through excessive pharmacological intervention. Reducing dosage optimize silencing levels often compromises durability necessitates increased dosing frequency. We present here...
MicroRNA (miRNA) mimic therapies act through a broad and complex targetome in disease contexts. However, both the composition of these targetomes impact chemical modifications on them remain poorly understood. In this study, we investigate eight fully chemically modified miRNA scaffolds across three sequences model immune disorder, graft-versus-host-disease (GvHD), which is an off-tumor effect allogeneic T cell therapy. We demonstrate that conventional silencing assays fail to predict...
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 particularly challenging due to variability in expression among patients and potential risk inducing Rett through excessive pharmacological intervention. Reducing dosage optimize silencing levels often compromises durability necessitates increased dosing frequency. We present here...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein toxic motor neurons, making gene suppression promising approach, supported by preclinical data 2023 FDA approval GapmeR ASO targeting SOD1, tofersen. Despite an optimism it brings field, pharmacodynamics pharmacokinetics therapeutic modulation can be improved. Here, we developed...
Chemically modified short interfering RNAs (siRNAs) unequivocally represent a groundbreaking class of drugs. The deliberate chemical modification the natural structure has been pivotal to their resounding success. Specific modifications at certain positions bolster potency, safety, stability, and specificity. In clinical research, 2'-O-methyl 2'-fluoro are most used modifications. effects wide range changes in fully siRNAs have not thoroughly evaluated for tolerability. this study, we...
While an increasing number of siRNA therapies are reaching the market, challenge efficient extra-hepatic delivery continues to limit their full therapeutic potential. Drug vehicles and hydrophobic conjugates being employed overcome bottleneck. Previously, we reported a novel dendritic conjugate that can be appended efficiently oligonucleotides, allowing them bind albumin with nanomolar affinity. Here, explore ability this albumin-binding improve siRNAs in vivo. We demonstrate binds...
Abstract Guide RNAs offer programmability for CRISPR-Cas9 genome editing but also add challenges delivery. Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance stability, distribution, cellular uptake, and safety nucleic acids. Previously, we engineered heavily fully modified SpyCas9 crRNA tracrRNA, showed enhanced stability retained activity when delivered cultured cells in form ribonucleoprotein complex. In this study, report that a short,...
Fibrinolysin (Thrombolysin) has been used in various dosage schedules for thromboembolic disorders, but its clinical value not established. In this study, a single large intravenous dose was given at onset of anticoagulant therapy to 170 patients with thrombophlebitis, pulmonary embolism, or acute myocardial infarction. Only the group treated embolism mortality significantly reduced from that observed receiving only anticoagulants. Toxicity attributable fibrinolysin minor except four who...
Small interfering RNA (siRNAs) hold immense promise for treating cardiac and muscular diseases, but robust scalable delivery to these tissues remains a challenge. Recent advances in strategies muscle include conjugation of biologics (antibody/antibody fragments, peptides), which are currently clinical development. However, the manufacturing biologic-siRNA conjugates is challenging complex process. By contrast, lipophilic siRNAs readily chemically synthesized at scale support sufficient...
Huntington's disease is one of nine neurodegenerative diseases caused by a polyglutamine (polyQ)-repeat expansion. An anti-polyQ antigen-binding fragment, MW1 Fab, was crystallized both on Earth and the International Space Station, microgravity environment where convection limited. Once crystals returned to Earth, number, size morphology all were recorded, X-ray data collected from representative crystals. The results generally agreed with previous crystallization studies. On average,...
Di-valent short interfering RNA (siRNA) is a promising therapeutic modality that enables sequence-specific modulation of single target gene in the central nervous system (CNS). To treat complex neurodegenerative disorders, where pathogenesis driven by multiple genes or pathways, di-valent siRNA must be able to silence simultaneously. Here we present framework for designing unimolecular "dual-targeting" siRNAs capable co-silencing two CNS. We reconfigured - which identical, linked are made...