Disclosed are cationic lipids which are compounds of Formula (I′). Cationic lipids provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.

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The present invention provides, among other things, an improved method of treating cystic fibrosis (CF) in a human subject. The method comprises administering a composition comprising an mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein at a concentration of 0.5 mg/mL or greater to a human subject via nebulization. The composition is aerosolized using a nebulizer and a nominal dose of the mRNA is administered to the human subject via the nebulizer over a period of time, typically at least 30 minutes, at a suitable nebulization rate, e.g., at least 0.2 mL/minute.

Disclosed herein are circular RNA s and transfer vehicles, along with related compositions and methods of treatment. The circular RNAs can comprise group I intron fragments, spacers, an IRES, duplex forming regions, and/or an expression sequence, thereby having the features of improved expression, functional stability, low immunogenicity, ease of manufacturing, and/or extended half-life compared to linear RNA. Pharmaceutical compositions comprising such circular RNAs and transfer vehicles are particularly suitable for efficient protein expression in immune cells in vivo. Also disclosed are precursor RNAs and materials useful in producing the precursor or circular RNAs, which have improved circularization efficiency and/or are compatible with effective circular RNA purification methods.

The present disclosure provides a method of pulmonarily administering an oligonucleotide to lung cells. In some embodiments, the disclosure provides formulations that comprise an oligonucleotide that is complementary to a target gene in lung cells and a lipid nanoparticle. Methods of the present disclosure are useful in modifying expression of target genes associated with chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis.

The disclosure features methods of treatment comprising systemic administration of mRNA encoding a therapeutic protein and delivered by lipid nanoparticle to human subjects.

Disclosed herein are circular RNAs and transfer vehicles, along with related compositions and methods of treatment. The circular RNAs can comprise group I intron fragments, spacers, an IRES, duplex forming regions, and/or an expression sequence, thereby having the features of improved expression, functional stability, low immunogenicity, ease of manufacturing, and/or extended half-life compared to linear RNA. Pharmaceutical compositions comprising such circular RNAs and transfer vehicles are particularly suitable for efficient protein expression in immune cells in vivo. Also disclosed are precursor RNAs and materials useful in producing the precursor or circular RNAs, which have improved circularization efficiency and/or are compatible with effective circular RNA purification methods.

The present invention provides compositions and methods useful for treating cancers such as glioblastoma. SapC-DOPS was found to be synergistically effective at inducing cell death when administered in conjunction with rampamycin. SapC-DOPS/rapamycin combination therapy allows physicians to give lower doses of each drug and achieve better therapeutic efficacy. The compositions also allow for less toxicity and fewer off-target effects. Related methods and materials are also provided herein.

Lipid formulations that encapsulate messenger RNA (mRNA) are provided herein. The mRNA can be used to express CFTR protein in vitro or in vivo. The lipid formulations can be administered via inhalation to treat cystic fibrosis.

Embodiments of the present invention generally relate to novel immunostimulatory compositions of use to stimulate non-specific immune responses in a subject. In certain embodiments, immunostimulatory compositions disclosed herein can be directed to preventing or treating an infection, cancer or other immunocompromising health condition in the subject. In some embodiments, the immunostimulatory compositions disclosed herein enhance non-specific immune responses systemically or locally in the subject to treat or reduce the risk of onset of a health condition. In some embodiments, immunostimulatory compositions disclosed can be used to induce a non-specific immune response within mucosal surfaces such as the nasopharynx, upper respiratory tract, eye, GI tract, and reproductive tract to induce a non-specific immune response in order to reduce onset of or treat an infection or other health condition.

The disclosure relates to respiratory syncytial vims (RSV) ribonucleic acid (RNA) vaccines, as well as methods of using the vaccines and compositions comprising the vaccines.