A5019835767- RNA Interference and Gene Delivery
- Immune cells in cancer
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Phagocytosis and Immune Regulation
- Ubiquitin and proteasome pathways
- Cell Adhesion Molecules Research
- Immunotherapy and Immune Responses
- MicroRNA in disease regulation
- Ferroptosis and cancer prognosis
- Virus-based gene therapy research
- Epigenetics and DNA Methylation
- Fibroblast Growth Factor Research
- CRISPR and Genetic Engineering
- Nanoparticle-Based Drug Delivery
- Lipid Membrane Structure and Behavior
- Advanced Drug Delivery Systems
- Chemokine receptors and signaling
- Monoclonal and Polyclonal Antibodies Research
- Autophagy in Disease and Therapy
- Sirtuins and Resveratrol in Medicine
- Protease and Inhibitor Mechanisms
- Viral gastroenteritis research and epidemiology
- Calcium signaling and nucleotide metabolism
- Cancer Immunotherapy and Biomarkers
Massachusetts Institute of Technology
2014-2023
RaNA Therapeutics (United States)
2022-2023
Allen Institute
2016-2021
Koch Institute for Integrative Cancer Research At MIT
2016-2017
IIT@MIT
2016
The Ohio State University
2011-2012
Intracellular delivery of messenger RNA (mRNA) has the potential to induce protein production for many therapeutic applications. Although lipid nanoparticles have shown considerable promise small interfering RNAs (siRNA), their utility as agents mRNA only recently been investigated. The most common siRNA formulations contain four components: an amine-containing or lipid-like material, phospholipid, cholesterol, and lipid-anchored polyethylene glycol, relative ratios which can profound...
Abstract Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic‐acid‐based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal dose‐dependent control encoded protein expression. Inhaled IVT‐mRNA not yet been demonstrated requires development safe effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized enable...
Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors safe and effective delivery. Synthetic nanoparticle composed poly(β-amino esters) (PBAEs) have previously demonstrated potential utility local delivery applications. To expand this to include systemic mRNA, hybrid polymer-lipid nanoformulations lungs were developed. Through coformulation PBAEs with lipid-polyethylene glycol (PEG), mRNA formulations developed increased serum stability in vitro...
Significance The effectiveness of nucleic acid drugs is limited by inefficient delivery to target tissues and cells unwanted accumulation in off-target organs. Although thousands chemically distinct nanoparticles can be synthesized, designed deliver acids vivo were first tested cell culture, yielding poor predictions for vivo. To facilitate testing many vivo, we optimized a high-throughput DNA barcoding system simultaneously measure mediated dozens single mouse. This nano-barcoding used...
B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T-cell activation; moreover, cell misregulation is implicated in autoimmune disorders cancers such as multiple sclerosis non-Hodgkin's lymphomas. The delivery messenger RNA (mRNA) into cells can be used to modulate study these biological functions by means inducing functional protein expression a dose-dependent time-controlled manner. However, current vivo mRNA systems fail transfect...
Thousands of human diseases could be treated by selectively controlling the expression specific proteins in vivo. A new series alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable delivering mRNA with unprecedented levels vivo efficacy is demonstrated. This study highlights importance utilizing synthesis tools tandem biological inspiration to understand and improve nucleic acid delivery
Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting secondary ischemic complications high mortality. We show that, ApoE(-/-) with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression adhesion molecules. To counteract the arterial recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key Simultaneously...
mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority progress in delivery has been confined to liver. Previously, we demonstrated that poly(β-amino esters), class degradable polymers, are capable systemic lungs mice when formulated into nanoparticles with poly(ethylene glycol)–lipid conjugates. Using experimental design, statistical approach optimization reduces...
Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent risk factor in CKD. We explored the potential impact of on proinflammatory activation macrophages and its underlying mechanisms.We examined vitro effects clinically relevant concentrations responses roles organic anion transporters transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics,...
DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) potential provide for transient production of proteins, without need nuclear and risk insertional mutagenesis. Here we describe sustained proteins in vivo both rodents non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated lipids lipid-like materials were developed two separate mRNA transcripts encoding either human...
Abstract RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies deliver remains important for realizing full clinical potential. Here, we develop lipid nanoparticle formulations that can short interfering (for gene silencing) or messenger upregulation). Specifically, study how tail length, geometry, linker spacing in diketopiperazine materials influences LNP potency with siRNAs mRNAs....
Autophagy is a homeostatic process critical for cellular survival, and its malfunction implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity tissue degeneration, but the mechanistic understanding this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) embryonic stem cells (hESCs), from which established neuronal platform investigate how loss affects survival. ATG5−/− neurons exhibit basal accompanied by metabolic...
In the field of drug delivery, pH-sensitive polymeric microparticles can be used to release therapeutic payloads slowly in extracellular conditions (pH 7.4) and faster more acidic areas vivo, such as sites inflammation, tumors, or intracellular conditions. Our group currently uses is further developing polymer acetalated dextran (Ac-DEX), which a biodegradable with highly tunable degradation kinetics. Ac-DEX has displayed enhanced delivery vaccine components immune other cells, making it an...
mRNA therapeutics hold promise for the treatment of diseases requiring intracellular protein expression and use in genome editing systems, but must transfect desired tissue cell type to be efficacious. Nanoparticle vectors that deliver are often evaluated using encoding reporter genes such as firefly luciferase (FLuc); however, single-cell resolution cannot generally achieved with FLuc, and, thus, transfected populations determined without additional steps or experiments. To more rapidly...
We propose the use of a new biopolymer, acetalated dextran (Ac-DEX), to synthesize porous microparticles for pulmonary drug delivery. Ac-DEX is derived from polysaccharide and, unlike polyesters, has tunable degradation days months and pH neutral products. fabricated through emulsion techniques were optimized using variety postprocessing enhance respirable fraction Tangential flow filtration resulted in maximum 37% microparticles, compared 10% poly(lactic-co-glycolic acid) (PLGA)...
Abstract Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors safe and effective delivery. Synthetic nanoparticle composed poly(β‐amino esters) (PBAEs) have previously demonstrated potential utility local delivery applications. To expand this to include systemic mRNA, hybrid polymer–lipid nanoformulations lungs were developed. Through coformulation PBAEs with lipid–polyethylene glycol (PEG), mRNA formulations developed increased serum stability in...
V-set immunoglobulin domain-containing 4 (VSIG4) is a B7 family protein with known roles as C3 fragment complement receptor involved in pathogen clearance and negative regulator of T cell activation by an undetermined mechanism. VSIG4 expression specific for tumor-associated select tissue-resident macrophages. Increased has been associated worse survival multiple cancer indications. Based upon computational analysis transcript data across thousands tumor normal tissue samples, we...