Compositions comprising nucleic acids and methods of using the same

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 …

Nature nanotechnology

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

Small

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

Nature Biomedical Engineering

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 …

2020-10-27 Assigned to THE BRIGHAM AND WOMEN'S HOSPITAL, INC. reassignment THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALEXIS, FRANK, FAROKHZAD, OMID C.

Nature biotechnology

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).

Proceedings of the National Academy of Sciences

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

Nature biomedical engineering

Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment …

NATURE BIOTECHNOLOGY

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

Advanced healthcare materials

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 …

Nature Biomedical Engineering

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 …

A method for the systemic delivery of a polypeptide within a subject is provided by creating genetically modified skin cells via topical introduction of a genetically engineered virus which delivers a nucleic acid encoding a therapeutic polypeptide for expression by the skin cells, wherein the expressed therapeutic polypeptide is secreted by the skin cells and is introduced into the circulatory system of the subject.