Daniel G. Anderson

A system for controlling an electricity supply to a load comprises at least one battery for storing energy. The system also comprises a controller for determining when to switch between a first mode wherein electricity is supplied to the load from a mains electricity circuit; and a discharging mode wherein electricity is supplied from the battery to the load via the mains electricity circuit. The determining is based on information associated with the electricity supply. a

Nanoparticle-based RNA delivery has shown great progress in recent years with the approval of two mRNA vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and a liver-targeted siRNA therapy. Here, we discuss the preclinical and clinical advancement of new generations of RNA delivery therapies along multiple axes. Improvements in cargo design such as RNA circularization and data-driven untranslated region optimization can drive better mRNA expression. New materials discovery research has driven improved delivery to extrahepatic targets such as the lung and splenic immune cells, which could lead to pulmonary gene therapy and better cancer vaccines, respectively. Other organs and even specific cell types can be targeted for delivery via conjugation of small molecule ligands, antibodies, or peptides to RNA delivery nanoparticles. Moreover, the immune response to any RNA …

Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air–liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant …

HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C= C2C [C@@ H](O) CC [C@] 2 (C)[C@@ H] 2 [C@@ H] 1 [C@@ H] 1CC [C@ H]([C@ H](C) CCCC (C) C)[C@@] 1 (C) CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 56

The transplantation of immunoisolated stem cell derived beta cell clusters (SC‐β) has the potential to restore physiological glycemic control in patients with type I diabetes. This strategy is attractive as it uses a renewable β‐cell source without the need for systemic immune suppression. SC‐β cells have been shown to reverse diabetes in immune compromised mice when transplanted as ≈300 µm diameter clusters into sites where they can become revascularized. However, immunoisolated SC‐β clusters are not directly revascularized and rely on slower diffusion of nutrients through a membrane. It is hypothesized that smaller SC‐β cell clusters (≈150 µm diameter), more similar to islets, will perform better within immunoisolation devices due to enhanced mass transport. To test this, SC‐β cells are resized into small clusters, encapsulated in alginate spheres, and coated with a biocompatible A10 polycation coating …

2022-11-29 Assigned to THE CHILDREN'S MEDICAL CENTER CORPORATION, MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment THE CHILDREN'S MEDICAL CENTER CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KHATIB, Nima, KRISHNAN, Siddharth, BOCHENEK, Matthew2022-11-29 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LANGER, ROBERT S., ANDERSON, DANIEL, BOSE, SUMAN

Developing safe and effective nanoparticles for the delivery of messenger RNA (mRNA) is slow and expensive, partly due to the lack of predictive power of in vitro screening methods and the low-throughput nature of in vivo screening. While DNA barcoding and batch analysis present methods for increasing in vivo screening throughput, they can also result in incomplete or misleading measures of efficacy. Here, we describe a high-throughput and accurate method for the screening of pooled nanoparticle formulations within the same animal. The method uses liquid chromatography with tandem mass spectrometry to detect peptide barcodes translated from mRNAs in nanoparticle-transfected cells. We show the method’s applicability by evaluating a library of over 400 nanoparticle formulations with 384 unique ionizable lipids using only nine mice to optimize the formulation of a biodegradable lipid nanoparticle for …

The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR–Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.

2021-06-04 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANDERSON, DANIEL G., KOWALSKI, Piotr S., WESSELHOEFT, Robert Alexander

Provided herein are compounds, such as compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, and compositions, methods, uses, and kits thereof. The compounds provided herein are lipids useful for delivery of polynucleotides, such as mRNA, for the treatment and/or prevention of various diseases and conditions (eg, genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease).

Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference …

2020-03-23 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANDERSON, DANIEL G., JASANOFF, ALAN PRADIP, LANGER, ROBERT S., HAI, AVIAD, SPANOUDAKI, Virginia

The ability to create in vivo genomic medicines for tissues other than the liver has been impeded by difficulties in delivery. Using a high-throughput platform, we developed lipid nanoparticles that can effectively deliver mRNA and CRISPR-Cas9 gene editing tools to the lungs through intratracheal administration, expanding the potential clinical uses of gene editing and mRNA-based technologies.

Circular RNA and transfer vehicles, along with related compositions and methods are described herein. In some embodiments, the inventive circular RNA comprises group I intron fragments, spacers, an IRES, duplex forming regions, and an expression sequence. In some embodiments, the expression sequence encodes a chimeric antigen receptor (CAR). In some embodiments, circular RNA of the invention has improved expression, functional stability, immunogenicity, ease of manufacturing, and/or half-life when compared to linear RNA. In some embodiments, inventive methods and constructs result in improved circularization efficiency, splicing efficiency, and/or purity when compared to existing RNA circularization approaches.

C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturatedC07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton

Self‐regulated insulin delivery that mimics native pancreas function has been a long‐term goal for diabetes therapies. Two approaches towards this goal are glucose‐responsive insulin delivery and islet cell transplantation therapy. Here, biodegradable, partially oxidized alginate carriers for glucose‐responsive nanoparticles or islet cells are developed. Material composition and formulation are tuned in each of these contexts to enable glycemic control in diabetic mice. For injectable, glucose‐responsive insulin delivery, 0.5 mm 2.5% oxidized alginate microgels facilitate repeat dosing and consistently provide 10 days of glycemic control. For islet cell transplantation, 1.5 mm capsules comprised of a blend of unoxidized and 2.5% oxidized alginate maintain cell viability and glycemic control over a period of more than 2 months while reducing the volume of nondegradable material implanted. These data show the …

To elicit optimal immune responses, messenger RNA vaccines require intracellular delivery of the mRNA and the careful use of adjuvants. Here we report a multiply adjuvanted mRNA vaccine consisting of lipid nanoparticles encapsulating an mRNA-encoded antigen, optimized for efficient mRNA delivery and for the enhanced activation of innate and adaptive responses. We optimized the vaccine by screening a library of 480 biodegradable ionizable lipids with headgroups adjuvanted with cyclic amines and by adjuvanting the mRNA-encoded antigen by fusing it with a natural adjuvant derived from the C3 complement protein. In mice, intramuscular or intranasal administration of nanoparticles with the lead ionizable lipid and with mRNA encoding for the fusion protein (either the spike protein or the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) increased the titres of …

Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg–1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells.

Provided herein are compounds of Formula (I), and salts thereof, wherein each instance of R L is independently optionally substituted C 6-C 40 alkenyl. Further provided are compositions comprising a compound of Formula (I) and an agent. Further provided are methods and kits using the compositions for delivering an agent to a subject or cell and for treating and/or preventing a range of diseases. Further provided are methods of preparing compounds of Formula (I) and precursors thereof.

Fibroblast growth factors (FGFs) are key regulators of the remarkable regenerative capacity of the liver. Mice lacking FGF receptors 1 and 2 (Fgfr1 and Fgfr2) in hepatocytes are hypersensitive to cytotoxic injury during liver regeneration. Using these mice as a model for impaired liver regeneration, we identified a critical role for the ubiquitin ligase Uhrf2 in protecting hepatocytes from bile acid accumulation during liver regeneration. During regeneration after partial hepatectomy, Uhrf2 expression increased in an FGFR-dependent manner, and Uhrf2 was more abundant in the nuclei of liver cells in control mice compared with FGFR-deficient mice. Hepatocyte-specific Uhrf2 knockout or nanoparticle-mediated Uhrf2 knockdown caused extensive liver necrosis and impaired hepatocyte proliferation after partial hepatectomy, resulting in liver failure. In cultured hepatocytes, Uhrf2 interacted with several chromatin …

Provided herein are lipidoid compounds of Formulae (I) and (II), and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive lipidoid compounds, compositions, or formulations for treating and/or preventing diseases (eg, genetic disease, proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, metabolic disorder, long-term medical condition, inflammatory disease, autoinflammatory disease, liver disease, lung disease, spleen disease, familial amyloid neuropathy, cardiovascular disease, viral infection, infectious disease, fibrotic condition, or autoimmune disease) in a subject, methods for synthesizing the compounds described herein, and compounds described herein synthesized by the …

INTRODUCTION OVER THE PAST 30 years, the National Heart, Lung, and Blood Institute (NHLBI) has been a leader in gene therapy research and has proactively provided investigators with research resources through various programs. One such program, the NHLBI Gene Therapy Resource Program (GTRP), was first launched in June 2007 and is now in its third iteration, which runs through December 2023. To develop the next generation gene therapy resource and support program, NHLBI sought input from the research community. Therefore, the NHLBI convened a 2-day virtual workshop entitled,‘‘Future Directions and Resource Needs for NHLBI Gene Therapy Research’’on March 15 and 16, 2022. The purpose of this workshop was to bring together experts in the basic science, preclinical, translational, and clinical aspects of gene therapy to evaluate the current, near, and future directions of the field of gene …

Aims Components of bone morphogenetic protein (BMP) signalling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP type 2 receptor in these processes has been extensively analysed. However, the contribution of BMP type 1 receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be down-regulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH. Methods and results We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of …

Provided herein are, in various embodiments, methods and compositions comprising polynucleotides (eg, mRNA) for eliciting an immune response. In certain embodiments, the disclosure provides for methods and compositions for enhancing efficacy of infectious disease treatment (eg, mRNA vaccines). In still further embodiments, the disclosure provides methods and compositions for enhancing one or more vaccines, such as SARS-CoV-2 mRNA vaccines.

Decades of oncologic clinical use have demonstrated that cancer immunotherapy provides unprecedented therapeutic benefits. Tragically, only a minority of patients respond to existing immunotherapies. RNA lipid nanoparticles have recently emerged as modular tools for immune stimulation. Here, we discuss advancements in RNA-based cancer immunotherapies and opportunities for improvement.

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5−/− neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5−/− neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5−/− neurons. Our findings …

Biomedical devices comprise a major component of modern medicine, however immune-mediated fibrosis and rejection can limit their function over time. Here, we describe a humanized mouse model that recapitulates fibrosis following biomaterial implantation. Cellular and cytokine responses to multiple biomaterials were evaluated across different implant sites. Human innate immune macrophages were verified as essential to biomaterial rejection in this model and were capable of cross-talk with mouse fibroblasts for collagen matrix deposition. Cytokine and cytokine receptor array analysis confirmed core signaling in the fibrotic cascade. Foreign body giant cell formation, often unobserved in mice, was also prominent. Last, high-resolution microscopy coupled with multiplexed antibody capture digital profiling analysis supplied spatial resolution of rejection responses. This model enables the study of human …

Provided herein are branched poly (beta-amino esters)(PBAE) useful as vehicles for the delivery of therapeutic agents, such as nucleic acids. The disclosed polymers form stable compositions, and are suitable for the delivery of therapeutic agents via nebulization. Compositions of the disclosed polymers are capable of delivering therapeutic agents such as mRNA to lung epithelial cells.

The immune isolation of cells within devices has the potential to enable long-term protein replacement and functional cures for a range of diseases, without requiring immune suppressive therapy. However, a lack of vasculature and the formation of fibrotic capsules around cell immune-isolating devices limits oxygen availability, leading to hypoxia and cell death in vivo. This is particularly problematic for pancreatic islet cells that have high O2 requirements. Here, we combine bioelectronics with encapsulated cell therapies to develop the first wireless, battery-free oxygen-generating immune-isolating device (O2-Macrodevice) for the oxygenation and immune isolation of cells in vivo. The system relies on electrochemical water splitting based on a water-vapor reactant feed, sustained by wireless power harvesting based on a flexible resonant inductive coupling circuit. As such, the device does not require pumping …

The present disclosure relates to improvements in the selection and formulation of PBAE polymers using a design of experiment approach, in which statistical methods are used to limit possible experimental conditions. The present disclosure relates to improved PBAE polymers and formulations.

Twenty-seven individually tile drained one-quarter-acre plots were established at Iowa State University’s Agricultural and Biosystems Engineering Research Farm in spring 2021. Nine system treatments were assigned in triplicate to the research plots (Figure 1). The site was designed for comparison of litter and land management practices, with immediate and ongoing goals of evaluating crop yield response to poultry litter application timing and cover crops, and water quality impacts with reduced tillage practices.

Covalently modified alginate polymers, possessing enhanced biocompatibility and tailored physiochemical properties, as well as methods of making and use thereof, are disclosed herein. The covalently modified alginates are useful as a matrix for the encapsulation and transplantation of cells. Also disclosed are high throughput methods for the characterizing the biocompatibility and physiochemical properties of modified alginate polymers.

BackgroundThere are various techniques for intraocular lens (IOL) placement in patients without adequate zonular or capsular support. Some of these include anterior chamber IOL (ACIOL) with flexible open-looped haptics, anterior or posterior iris claw lenses, posterior iris sutured intraocular lenses, and sclerally-fixated posterior chamber IOLs (PCIOLs). ACIOLs with flexible open-looped haptics are one of the most frequently utilized lenses for this clinical situation.

The following entry provides an overview of the topic by identifying four components of moral character that enable people to act morally: moral sensitivity, moral deliberation, moral motivation, and self-control. All four components undergo significant changes over the course of individuals’ development. It is argued that effective moral character education requires an adequate understanding of how these four components develop. Moral sensitivity refers to the capacity to understand and appreciate the needs and wellbeing of others. Moral sensitivity is grounded in the development of empathy. Moral deliberation derives from an individual’s capacity to consider potentially conflicting claims and coordinate them in their moral judgments. This capacity benefits from engagement in constructive moral dialogues. Moral motivation is needed for prioritizing moral goals over potentially conflicting interests and desires. It …

2018-01-30 Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), US DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), US GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), US DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), US GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: MASSACHUSETTS INSTITUTE OF TECHNOLOGY

Neurological implants whose surfaces have been chemically and covalently modified to impart beneficial properties to the neurological implants are described. The neurological implants possess improved biocompatibility compared to a corresponding neurological implant that lacks the chemical modification. Following implantation in a subject, the sur face-modified neurological implants induce a lower-foreign body response, compared to a corresponding unmodified product. a

This special issue, guest edited by Yizhou Dong (The Ohio State University) and Dan Anderson (MIT), focuses on recent advances in mRNA-based therapeutics, which have shown great promise for preventing or treating diverse diseases including infectious diseases, genetic disorders, and cancers. The topics include the following aspects: chemistry of delivery materials, mRNA translation and engineering, cellular trafficking of mRNA formulations, RNA immunogenicity, manufacturing of mRNA formulations, and therapeutic indications of mRNA. Because the topics are approached from multiple perspectives in this fast-growing field, we feel that this issue will be informative for readers of Accounts of Chemical Research including chemists, biomedical scientists, biologists, material scientists, and pharmaceutical researchers in both academia and industry and will be of significant benefit to not only experts in the field …

RNA nanomedicines present a promising class of therapeutics, with broad applications in protein replacement therapy, gene editing, immunotherapy, and vaccines, owing to their versatility and precise nature. Although recent years have seen dramatic improvements in the safety and efficacy of RNA-based therapies, their functional delivery to target tissues and cells in vivo remains challenging. Here, we discuss many of these challenges, as well as the methods and materials that have been developed to overcome them, with a focus on polymeric and lipid-based nanoscale delivery systems. In addition, we provide an overview of recent clinical and pre-clinical developments in RNA nanomedicines that have been made possible by advances in delivery.

Kim, et al.,“Generation of core-shell microcapsules with three dimensional focusing device for efficient formation of cell spher oid”, Lab Chip, 11 (2): 246-52 (2011). King, et al.,“Microencapsulation of islets of Langerhans: impact of cellular overgrowth”, Upsala Journal of Medical Sciences, 106 (3): 161 174 (2001). Kvist, et al.,“Biocompatibility of electrochemical glucose sensors implanted in the subcutis of pigs”, Diabetes Technol., 8 (4): 463-75 (2006). Linetsky, et al.,“Improved human islet isolation using a new enzyme blend, liberase”, Diabetes 46: 1120 (1997). Ma, et al.,“Core-shell hydrogel microcapsules for improved islets encapsulation”, Adv Healthc Mater., 2 (5): 667-72 (2013). Ma, et al.,“Development of cationic polymer coatings to regulate foreign-body responses”, Adv. Mater. 23 (24): H189-94 (2011).Orive, et al.,“Cell encapsulation: promise and progress”, Nat. Med., 9 (1): 104-7 (2003). Park, et al …

The remarkable speed of vaccine development to address the SARS-CoV-2 coronavirus pandemic has highlighted the unique potential of mRNA therapy. In March 2020, only 10 weeks after the identification of the SARS-CoV-2 sequence, a phase I clinical trial was initiated. In December 2020, two lipid nanoparticle (LNP)− mRNA formulations obtained Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA). Meanwhile, mRNA-based vaccines are also being developed against an array of human diseases such as respiratory syncytial virus (RSV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), influenza, and even cancer. mRNA-based drugs have broad potential applications and hold promise as vehicles for cancer therapy, as rare disease treatment, and even as enabling tools for in vivo genome editing.These breakthroughs are built upon several generations of …

2019-10-14 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANDERSON, DANIEL G., LANGER, ROBERT S., VEISEH, OMID2019-10-14 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY, THE CHILDREN'S MEDICAL CENTER CORPORATION reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VEGAS, ARTURO J., DOLOFF, JOSHUA C., MA, MINGLIN

2021-10-12 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LOVE, KEVIN THOMAS, ANDERSON, DANIEL GRIFFITH, LEVINS, CHRISTOPHER G., Mahon, Kerry Peter, LANGER, ROBERT S., WHITEHEAD, KATHRYN ANN

Background Atrial fibrillation (AF) has become a global epidemic. Early catheter ablation and therapies modifying risk factors (RF) have been shown to improve outcomes of AF ablation. However, the time invested in pursuing risk factor modification may delay ablation, which could negate the procedural benefit. Purpose This study sought to investigate the prevalence and impact of potentially modifiable RF among AF patients undergoing catheter ablation in clinical practice. Methods This retrospective study included 724 consecutive patients undergoing AF ablation at a tertiary care center from 2012–2019. Pre-specified modifiable risks were examined, including the time from AF diagnosis to ablation, fluctuation/increase in BMI >5% prior to ablation, mean systolic/diastolic blood pressure >125/80 mmHg, obstructive sleep apnea with CPAP noncompliance …

The emergency use authorizations (EUAs) of two mRNA-based severe acute respiratory syndrome coronavirus (SARS-CoV)-2 vaccines approximately 11 months after publication of the viral sequence highlights the transformative potential of this nucleic acid technology. Most clinical applications of mRNA to date have focused on vaccines for infectious disease and cancer for which low doses, low protein expression and local delivery can be effective because of the inherent immunostimulatory properties of some mRNA species and formulations. In addition, work on mRNA-encoded protein or cellular immunotherapies has also begun, for which minimal immune stimulation, high protein expression in target cells and tissues, and the need for repeated administration have led to additional manufacturing and formulation challenges for clinical translation. Building on this momentum, the past year has seen clinical …

Objective:1. Examine the proportion of patients with obesity represented in contemporary RCTs of catheter ablation for treatment of AF 2. Examine potential risks associated with underrepresentation of obese participants

A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, eg COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL

Circular RNAs are garnering increasing interest as potential regulatory RNAs and a format for gene expression. The characterization of circular RNA using analytical techniques commonly employed in the literature, such as gel electrophoresis, can, under differing conditions, yield different results when attempting to distinguish circular RNA from linear RNA of similar molecular weights. Here, we describe circular RNA migration in different conditions, analyzed by gel electrophoresis and high-performance liquid chromatography (HPLC). We characterize key parameters that affect the migration pattern of circular RNA in gel electrophoresis systems, which include gel type, electrophoresis time, sample buffer composition, and voltage. Finally, we demonstrate the utility of orthogonal analytical tests for circular RNA that take advantage of its covalently closed structure to further distinguish circular RNA from linear RNA …

PP 7.3 – 00010 Virion Immunocapture Reveals Low-level Myeloid-derived HIV Expression in Semen under INSTI-based Therapy is Disparate from Circulating Seminal and Blood Proviral Sequences Food and Agriculture Organization of the United Nations Discover About FAO News Multimedia Main topics Statistics Members Publications English العربية Español Français Русский 中文 AGRIS - International System for Agricultural Science and Technology About AGRIS Contribute Acceptable use policy facebook linkedin twitter weibo Close Advanced Search PP 7.3 – 00010 Virion Immunocapture Reveals Low-level Myeloid-derived HIV Expression in Semen under INSTI-based Therapy is Disparate from Circulating Seminal and Blood Proviral Sequences 2022 J. Johnson | JF Li | J. Politch | J. Lipscomb | J. Defelice | M. Gelman | K. Mayer | D. Anderson AGROVOC Keywords microbiology Bibliographic information …

Alternative means of modifying biomolecules that do not rely on covalent bonding are desired; in particular, site-specific non-covalent complexation is an attractive option. Moreover, this concept can be extended beyond biomolecules to aid in the modification of small molecules, diagnostic agents, imaging agents, etc. Supramolecular chemistry utilizes specific, directional, reversible, non-covalent molecular recognition motifs in order to achieve organization of molecules. In particular, supramolecular chemistry can be used to bind agents, such as biomolecules (eg, peptides, proteins, nucleic acids), small molecule drugs, and imaging agents, and diagnostic agents to excipients and other tags. The present invention provides useful supramolecular complexes comprising an agent associated with a tag, wherein the agent is specifically bound to a host via non-covalent guest-host interactions, and wherein the host is …

(52) US Ci. CPC C08B 37/0012 (2013.01); C08B 37/0015 (2013.01); GOIN 33/66 (2013.01); A61K 38/28 (2013.01); A61K 47/6951 (2017.08)(57) ABSTRACT Provided herein are new cyclodextrin-based compounds, and pharmaceutically acceptable salts, stereoisomers, and isotopically labeled derivatives thereof, which are capable of binding sugars (eg, glucose). The compounds provided herein may be conjugated to agents or tags (eg, therapeutic agents such as insulin) to form conjugates. In another aspect, also provided herein are pharmaceutical compositions com prising the compounds and conjugates described herein. The compounds and conjugates described herein are capable of binding glucose; therefore, provided herein are methods of sensing or detecting glucose comprising contacting glucose with the compound or conjugate. In another aspect, also provided herein are methods of treating a …

Background/Introduction Obesity and atrial fibrillation (AF) coexist and share multiple cardiovascular risk factors. Lifestyle modifications can reduce AF burden in obese patients. However, the time invested in pursing lifestyle changes may delay AF ablation, which could negate the procedural benefit. Purpose To examine the effects of lifestyle modifications and the timing of catheter ablation on morbidly obese patients with AF. Methods This retrospective study included 217 consecutive AF patients with a body mass index (BMI) ≥35 kg/m2 undergoing AF ablation at a tertiary care center from 2012 to 2019. Modifiable risks were examined, including the time from AF diagnosis to ablation, fluctuation of BMI >5% or an increase in BMI >3% prior to ablation, mean systolic blood pressure >130 mmHg or diastolic blood pressure >80 mmHg, obstructive sleep apnea …

MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5ʹ- and 3ʹ-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5ʹ Rapid Amplification of cDNA Ends (RACE …

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium’s plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems …

Author Correction: Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates Author Correction: Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates Nat Mater. 2021 Jul;20(7):1038. doi: 10.1038/s41563-021-01023-1. Authors Joshua C Doloff 1 2 3 , Omid Veiseh 1 2 3 4 , Arturo J Vegas 1 2 5 , Hok Hei Tam 1 3 , Shady Farah 1 2 3 , Minglin Ma 1 2 6 , Jie Li 1 2 , Andrew Bader 1 2 , Alan Chiu 1 2 , Atieh Sadraei 1 , Stephanie Aresta-Dasilva 1 2 , Marissa Griffin 1 , Siddharth Jhunjhunwala 1 2 , Matthew Webber 1 3 , Sean Siebert 1 2 , Katherine Tang 1 2 , Michael Chen 1 2 , Erin Langan 1 2 , Nimit Dholakia 1 2 , Raj Thakrar 1 2 , Meirigeng Qi 7 , Jose Oberholzer 7 , Dale L Greiner 8 , Robert Langer 1 2 3 9 10 , Daniel G Anderson 11 12 13 …

The basic principle of mRNA therapeutics involves delivery of in vitro transcribed mRNA into a target cell, where cellular machinery translates the mRNA into a functional protein. In vaccine applications, an mRNA encoding a viral protein will elicit a protective immune response, whereas in therapeutic applications, an mRNA encoding an absent (or dysfunctional) protein in a patient provides functional protein expression. Thus, mRNAs can be widely used in vaccine development, protein replacement therapy, and the treatment of genetic diseases.ADVANTAGES:

Surface-modified cell containing a cell and a conformal coating on the extracellular surface of the cell are described. The conformal coating contains two or more layers contain ing particles (eg nanoparticles) or macromolecules. The cell is an islet cell, a B cell, or a T cell. The macromolecules or particles are formed from zwitterionic polymers. Cova lent linkages are employed to link the particles or macro molecules to a cell surface molecule containing an abiotic functional group, or between macromolecules and/or par ticles in adjacent layers. Also described are methods of making and using a surface-modified cell.

Genomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of new non-coding transcripts deregulated in HCC. We hypothesize that some of these transcripts may be involved in disease progression. Long non-coding RNAs are a large class of non-coding transcripts which participate in the regulation of virtually all cellular functions. However, a majority of lncRNAs remain dramatically understudied. Here, we applied a pooled shRNA-based screen to identify lncRNAs essential for HCC cell survival. We validated our screening results using RNAi, CRISPRi, and antisense oligonucleotides. We found a lncRNA, termed ASTILCS, that is critical for HCC cell growth and is overexpressed in tumors from HCC patients. We …

Background Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discover therapeutic targets for vein graft failure. Methods Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, quantitative polymerase chain reaction, flow cytometry, metabolic assays, and single-cell RNA sequencing on primary human and mouse macrophages. Results We identified changes in the …

2022-03-03 Assigned to MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment MASSACHUSETTS INSTITUTE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEVINS, CHRISTOPHER G., ANDERSON, DANIEL GRIFFITH, DAHLMAN, JAMES E., LANGER, ROBERT S., SCHROEDER, AVRAHAM D.

Compositions and methods for modified dendrimer nanoparticle (“MDNP”) delivery of therapeutic, prophylactic and/or diagnostic agent such as large repRNA molecules to the cells of a subject have been developed. MDNPs efficiently drive proliferation of antigen-specific T cells against intracellular antigen, and potentiate antigen-specific antibody responses. MDNPs can be multiplexed to deliver two or more different repRNAs to modify expression kinetics of encoded antigens and to simultaneous deliver repRNAs and mRNAs including the same UTR elements that promote expression of encoded antigens.

BackgroundPalbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.MethodsPALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6 …

The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S–containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell–derived endothelial cells from Friedreich’s ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency …

Non-viral vectors offer the potential to deliver nucleic acids including mRNA and DNA into cells in vivo. However, designing materials that effectively deliver to target organs and then to desired compartments within the cell remains a challenge. Here we develop polymeric materials that can be optimized for either DNA transcription in the nucleus or mRNA translation in the cytosol. We synthesized poly(beta amino ester) terpolymers (PBAEs) with modular changes to monomer chemistry to investigate influence on nucleic acid delivery. We identified two PBAEs with a single monomer change as being effective for either DNA (D-90-C12-103) or mRNA (DD-90-C12-103) delivery to lung endothelium following intravenous injection in mice. Physical properties such as particle size or charge did not account for the difference in transfection efficacy. However, endosome co-localization studies revealed that D-90-C12-103 …

The present disclosure relates to compositions and methods for modifying a gene sequence, and for systems for deliverying such compositions. For example, the disclosure relates to modifying a gene sequence using a CRISPR-Cas9 or other nucleic acid editing system, and methods and delivery systems for achieving such gene modification, such as viral or non-viral delivery systems.

HighlightsDesign and construction of mobile swine facility on a flat decked trailer for experimentation.Air infiltration evaluation for an experimental building.Theoretical building shell thermal analysis and heat transfer determination.Abstract. Specialized animal environment experiments needing swine facilities calls for novel technology creation to enable unique experimentation without the drawbacks of traditional swine facilities. In a full-scale swine facility, there are challenges with cost, increased travel time to sites, additional labor is required, the facility cannot be fully controlled, and biosecurity becomes a risk. A small-scale, mobile swine confinement laboratory was designed and built to mitigate the challenges faced in a full-scale barn. The mobility of the laboratory enables it to travel to swine farms to obtain fresh animal specimens, which allows the experiments and data collected to be more representative of an …

That the world is awash with resentment poses a genuine question for educators. Here, we will suggest that resentment can be better harnessed for good if we stop focusing on people and tribes and, instead, focus on systems: those invisible norms that often produce locked-in structures of social interaction. A “systems lens” is vast, so fixes will have to be an iterative process of reflection, and revision toward a more just system. Nonetheless, resentment toward the status quo may be an important element in keeping that otherwise tedious process going, with the caveat that resentment is only productive when it is combined with reason, and that, therefore, educators, rather than privileging participant reactive attitudes, ought, instead, to promote participant reactive reasoning, as the latter can be a genuine force for both personal and interpersonal growth, while the former might very well do the reverse.

Arrhythmia-induced cardiomyopathy secondary to frequent ventricular premature contractions is a well-studied phenomenon; however, there is a paucity of data showing a similar association with frequent atrial premature contractions (APCs). Early recognition and successful APC ablation can reverse left ventricular dysfunction in these patients. (Level of Difficulty: Beginner.)

Glucose-responsive insulin delivery systems have the potential to improve quality of life for individuals with diabetes by improving blood sugar control and limiting the risk of hypoglycemia. However, systems with desirable insulin release kinetics and high loading capacities have proven difficult to achieve. Here, we report the development of electrostatic complexes (ECs) comprised of insulin, a polycation, and glucose oxidase (GOx). Under normoglycemic physiological conditions, insulin carries a slight negative charge and forms a stable EC with the polycation. In hyperglycemia, the encapsulated glucose-sensing enzyme GOx converts glucose to gluconic acid and lowers the pH of the microenvironment, causing insulin to adopt a positive charge. Thus, the electrostatic interactions are disrupted, and insulin is released. Using a model polycation, we conducted molecular dynamics simulations to model these …

Disclosed are methods, compositions, reagents, systems, and kits to prepare and utilize poly (ß-amino ester)(PBAE) polymers, which are synthesized via Michael addition reac tions of diacrylates and amines disclosed herein. Various embodiments utilize lactones and lactone derivatives to generate the diacrylate compounds. The PBAE polymers are shown to be effective biodegradable carriers for the delivery of an agent such as an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, or an immunological agent. Specification includes a Sequence Listing.

An insulin delivery system that self-regulates blood glucose levels has the potential to limit hypoglycemic events and improve glycemic control. Glucose-responsive insulin delivery systems have been developed by coupling glucose oxidase with a stimuli-responsive biomaterial. However, the challenge of achieving desirable release kinetics (i.e., insulin release within minutes after glucose elevation and duration of release on the order of weeks) still remains. Here, we develop a glucose-responsive delivery system using encapsulated glucose-responsive, acetalated-dextran nanoparticles in porous alginate microgels. The nanoparticles respond rapidly to changes in glucose concentrations while the microgels provide them with protection and stability, allowing for extended glucose-responsive insulin release. This system reduces blood sugar in a diabetic mouse model at a rate similar to naked insulin and responds …

Funding Acknowledgements Type of funding sources: None. Introduction Obesity and extreme obesity increase risk of recurrent atrial fibrillation (AF) and perioperative complications following AF ablation. However, long-term outcomes following AF ablation among obese patients is unknown. Purpose To examine long-term cardiovascular (CV) mortality and hospitalization among obese patients undergoing AF ablation Methods This retrospective study included 830 consecutive patients undergoing AF ablation from January 2013 to June 2019 at a tertiary referral medical center. Patients with obesity defined as body mass index (BMI) ≥30-39.9 kg/m2 and a subgroup of patients with extreme obesity with BMI ≥40 kg/m2 were identified. Patients were monitored for mortality and hospitalization during a median follow-up time of 819 days …

Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components 1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites to aid metabolic homeostasis 2. Loss of autophagy in animal models or malfunction of this process in a number of age-related human pathologies, including neurodegenerative and lysosomal storage diseases, contributes to tissue degeneration 3-9. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD+/NADH) levels, which are critical for cellular survival. In respiring cells, loss of autophagy caused hyperactivation of PARP and Sirtuin families of NADases. Uncontrolled depletion of NAD (H) pool by these enzymes resulted in mitochondrial membrane depolarisation and cell death. Supplementation with NAD (H) precursors improved cell viability in autophagy-deficient models including human pluripotent stem cell-derived neurons with autophagy deficiency or patient-derived neurons with autophagy dysfunction. Our study provides a mechanistic link between autophagy and NAD (H) metabolism, and suggests that boosting NAD (H) levels may have therapeutic benefits in human diseases associated with autophagy dysfunction.