7 results on '"Kauffman, Kevin"'
Search Results
2. Customizable Lipid Nanoparticle Materials for the Delivery of siRNAs and mRNAs.
- Author
-
Fenton, Owen S., Kauffman, Kevin J., McClellan, Rebecca L., Kaczmarek, James C., Zeng, Manhao D., Andresen, Jason L., Rhym, Luke H., Heartlein, Michael W., DeRosa, Frank, and Anderson, Daniel G.
- Subjects
- *
LIPIDS , *SMALL interfering RNA , *MESSENGER RNA , *GENE silencing , *DIKETOPIPERAZINES - Abstract
Abstract: RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid materials influences LNP potency with siRNAs and mRNAs. Eight lipid materials are synthesized, and 16 total formulations are screened for activity in vitro; the lead material is evaluated with mRNA for in vivo use and demonstrates luciferase protein expression in the spleen. In undertaking this approach, not only do we develop synthetic routes to delivery materials, but we also reveal structural criteria that could be useful for developing next‐generation delivery materials for RNA therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
3. Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo.
- Author
-
Kauffman, Kevin J., Mir, Faryal F., Jhunjhunwala, Siddharth, Kaczmarek, James C., Hurtado, Juan E., Yang, Jung H., Webber, Matthew J., Kowalski, Piotr S., Heartlein, Michael W., DeRosa, Frank, and Anderson, Daniel G.
- Subjects
- *
DRUG efficacy , *MESSENGER RNA , *PSEUDOURIDINE , *LIPIDS , *CYTOKINES , *IN vivo studies - Abstract
mRNA has broad potential for treating diseases requiring protein expression. However, mRNA can also induce an immune response with associated toxicity. Replacement of uridine bases with pseudouridine has been postulated to modulate both mRNA immunogenicity and potency. Here, we explore the immune response and activity of lipid nanoparticle-formulated unmodified and pseudouridine-modified mRNAs administered systemically in vivo . Pseudouridine modification to mRNA had no significant effect on lipid nanoparticle physical properties, protein expression in vivo , or mRNA immunogenicity compared to unmodified mRNA when delivered systemically with liver-targeting lipid nanoparticles, but reduced in vitro transfection levels. Indicators of a transient, extracellular innate immune response to mRNA were observed, including neutrophilia, myeloid cell activation, and up-regulation of four serum cytokines. This study provides insight into the immune responses to mRNA lipid nanoparticles, and suggests that pseudouridine modifications may be unnecessary for therapeutic application of mRNA in the liver. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
4. Materials for non-viral intracellular delivery of messenger RNA therapeutics.
- Author
-
Kauffman, Kevin J., Webber, Matthew J., and Anderson, Daniel G.
- Subjects
- *
MESSENGER RNA , *CANCER immunotherapy , *GENE transfection , *BIOCHEMICAL mechanism of action , *DRUG administration , *GENE delivery techniques - Abstract
Though therapeutics based on messenger RNA (mRNA) have broad potential in applications such as protein replacement therapy, cancer immunotherapy, and genomic engineering, their effective intracellular delivery remains a challenge. A chemically diverse suite of delivery materials with origins as materials for cellular transfection of DNA and small interfering RNAs (siRNAs) has recently been reported to have promise as non-viral delivery agents for mRNA. These materials include covalent conjugates, protamine complexes, nanoparticles based on lipids or polymers, and hybrid formulations. This review will highlight the use of delivery materials for mRNA, with a specific focus on their mechanisms of action, routes of administration, and dosages. Additionally, strategies in which these materials can be adapted and optimized to address challenges specific to mRNA delivery are also discussed. The technologies included have shown varying promise for therapeutic use, specifically having been used to deliver mRNA in vivo or exhibiting characteristics that could make in vivo use a possibility. In so doing, it is the intention of this review to provide a comprehensive look at the progress and possibilities in applying nucleic acid delivery technology specifically toward the emerging area of mRNA therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
5. Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs.
- Author
-
Kaczmarek, James C., Patel, Asha K., Kauffman, Kevin J., Fenton, Owen S., Webber, Matthew J., Heartlein, Michael W., DeRosa, Frank, and Anderson, Daniel G.
- Subjects
MESSENGER RNA ,DRUG delivery systems ,NUCLEIC acids ,POLYETHYLENE glycol ,LUNG disease treatment - Abstract
Therapeutic nucleic acids hold great promise for the treatment of disease but require vectors for safe and effective delivery. Synthetic nanoparticle vectors composed of poly(β-amino esters) (PBAEs) and nucleic acids have previously demonstrated potential utility for local delivery applications. To expand this potential utility to include systemic delivery of mRNA, hybrid polymer-lipid nanoformulations for systemic delivery to the lungs were developed. Through coformulation of PBAEs with lipid-polyethylene glycol (PEG), mRNA formulations were developed with increased serum stability and increased in vitro potency. The formulations were capable of functional delivery of mRNA to the lungs after intravenous administration in mice. To our knowledge, this is the first report of the systemic administration of mRNA for delivery to the lungs using degradable polymer-lipid nanoparticles. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
6. Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery
- Author
-
Mark W. Tibbitt, Rebecca L. McClellan, J. Robert Dorkin, Robert Langer, Frank Derosa, Owen S. Fenton, Eric A. Appel, Kevin J. Kauffman, Daniel G. Anderson, Michael W. Heartlein, Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Koch Institute for Integrative Cancer Research at MIT, Fenton, Owen S., Kauffman, Kevin John, McClellan, Rebecca L, Appel, Eric, Dorkin, Joseph Robert, Tibbitt, Mark W, Langer, Robert S, and Anderson, Daniel Griffith
- Subjects
0301 basic medicine ,Biological inspiration ,Materials science ,Alcohol ,02 engineering and technology ,Alkenes ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Biomimetic Materials ,In vivo ,Humans ,General Materials Science ,RNA, Messenger ,Erythropoietin ,Drug Carriers ,Messenger RNA ,Mechanical Engineering ,RNA ,021001 nanoscience & nanotechnology ,Amino Alcohols ,Lipids ,030104 developmental biology ,Biochemistry ,chemistry ,Mechanics of Materials ,Drug delivery ,Nucleic acid ,Nanoparticles ,0210 nano-technology ,Drug carrier - Abstract
Thousands of human diseases could be treated by selectively controlling the expression of specific proteins in vivo. A new series of alkenyl amino alcohol (AAA) ionizable lipid nanoparticles (LNPs) capable of delivering human mRNA with unprecedented levels of in vivo efficacy is demonstrated. This study highlights the importance of utilizing synthesis tools in tandem with biological inspiration to understand and improve nucleic acid delivery in vivo., National Science Foundation (U.S.). Graduate Research Fellowship Program, Shire Pharmaceuticals, Wellcome Trust-MIT Postdoctoral Fellowship
- Published
- 2016
7. Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo
- Author
-
Kevin J. Kauffman, Michael W. Heartlein, Daniel G. Anderson, Matthew J. Webber, Piotr S. Kowalski, Juan E. Hurtado, Frank Derosa, Siddharth Jhunjhunwala, James C. Kaczmarek, Faryal F. Mir, Jung H. Yang, Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Kauffman, Kevin John, Mir, Faryal, Jhunjhunwala, Siddharth, Kaczmarek, James Cliff, Hurtado, Juan E., Yang, Jung H, Webber, Matthew, Kowalski, Piotr S, and Anderson, Daniel Griffith
- Subjects
0301 basic medicine ,Surface Properties ,Biophysics ,Gene Expression ,Bioengineering ,Pharmacology ,Biology ,Transfection ,Pseudouridine ,Article ,Biomaterials ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,In vivo ,Extracellular ,Animals ,Humans ,Myeloid Cells ,RNA, Messenger ,Particle Size ,Messenger RNA ,Innate immune system ,Immunogenicity ,Gene Transfer Techniques ,Molecular biology ,Lipids ,Uridine ,Immunity, Innate ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Liver ,Mechanics of Materials ,030220 oncology & carcinogenesis ,Ceramics and Composites ,Cytokines ,Nanoparticles ,Female ,HeLa Cells - Abstract
mRNA has broad potential for treating diseases requiring protein expression. However, mRNA can also induce an immune response with associated toxicity. Replacement of uridine bases with pseudouridine has been postulated to modulate both mRNA immunogenicity and potency. Here, we explore the immune response and activity of lipid nanoparticle-formulated unmodified and pseudouridine-modified mRNAs administered systemically in vivo. Pseudouridine modification to mRNA had no significant effect on lipid nanoparticle physical properties, protein expression in vivo, or mRNA immunogenicity compared to unmodified mRNA when delivered systemically with liver-targeting lipid nanoparticles, but reduced in vitro transfection levels. Indicators of a transient, extracellular innate immune response to mRNA were observed, including neutrophilia, myeloid cell activation, and up-regulation of four serum cytokines. This study provides insight into the immune responses to mRNA lipid nanoparticles, and suggests that pseudouridine modifications may be unnecessary for therapeutic application of mRNA in the liver. Keywords: mRNA, Base modification, Pseudouridine, Lipid nanoparticle, In vivo, Immmune response, Shire Pharmaceuticals
- Published
- 2016
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.