Abstract: The present disclosure provides optimized mRNAs encoding a site-directed endonuclease for use in a CRISPR/Cas system. Also provided herein are delivery systems for use of the CRISPR/Cas system in methods of in vivo and ex vivo genome editing.

Abstract: The present invention provides, among other things, methods and compositions for cancer treatment. The methods and compositions disclosed herein are particularly effective in reducing the size/volume of a tumor and inhibiting tumor growth.

Abstract: The present disclosure provides optimized mRNAs encoding a site-directed endonuclease for use in a CRISPR/Cas system. Also provided herein are delivery systems for use of the CRISPR/Cas system in methods of in vivo and ex vivo genome editing.

Abstract: The present invention provides, among other things, methods and compositions for cancer treatment. The methods and compositions disclosed herein are particularly effective in reducing the size/volume of a tumor and inhibiting tumor growth.

Abstract: Described herein are fusion proteins that include a fragment of factor H and an Fc receptor binding domain, as well as the use of such proteins in methods of treatment for diseases mediated by alternative complement pathway dysregulation.

Abstract: mRNAs containing an exogenous open reading frame (ORF) flanked by a 5? untranslated region (UTR) and a 3? UTR is provided, wherein the 5? and 3? UTRs are derived from a naturally abundant mRNA in a tissue. Also provided are methods for identifying the 5? and 3? UTRs, and methods for making and using the mRNAs.

Abstract: The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal heavy chain 5 (DNAH5) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAH5 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

Abstract: The present invention provides, among other things, methods and compositions for treating methylmalonic academia (MMA) based on mRNA therapy. The compositions used in treatment of MMA comprise an mRNA comprising a methymalonyl-CoA mutase (MUT) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of MMA is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized MUT coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

Abstract: mRNAs containing an exogenous open reading frame (ORF) flanked by a 5? untranslated region (UTR) and a 3? UTR is provided, wherein the 5? and 3? UTRs are derived from a naturally abundant mRNA in a tissue. Also provided are methods for identifying the 5? and 3? UTRs, and methods for making and using the mRNAs.

Abstract: The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal heavy chain 5 (DNAH5) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAH5 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

Abstract: mRNAs containing an exogenous open reading frame (ORF) flanked by a 5? untranslated region (UTR) and a 3? UTR is provided, wherein the 5? and 3? UTRs are derived from a naturally abundant mRNA in a tissue. Also provided are methods for identifying the 5? and 3? UTRs, and methods for making and using the mRNAs.

Abstract: The invention is based on the discovery that unmodified mRNA encapsulated in a liposome that is preferentially directed to the liver is particularly effective at inducing immune tolerance in a subject and avoids the need for co-administering an immune regulator (either separately or in form of an mRNA encoding the immune regulator). The invention therefore provides methods for inducing immune tolerance to one or more peptides, polypeptides or proteins in a subject in need thereof, wherein said method comprises administering to the subject one or more mRNAs, each mRNA comprising a 5?UTR, a coding region and a 3?UTR, wherein the one or more coding regions of the one or more mRNAs encode the one or more peptides, polypeptides or proteins, wherein said one or more mRNAs are encapsulated in one or more liposomes, wherein upon administration the one or more liposomes are preferentially delivered to the liver of the subject, wherein the nucleotides of the one or more mRNAs are unmodified.

Abstract: The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal heavy chain 5 (DNAH5) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAH5 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

Abstract: Described herein are fusion proteins that include two fragments of factor H, a fragment of factor H and an Fc domain, or a fragment of factor H, a fragment of CR2, and an Fc domain. The use of such proteins in methods of treatment for diseases mediated by alternative complement pathway dysmegulation.

Abstract: The present disclosure provides optimized mRNAs encoding a site-directed endonuclease for use in a CRISPR/Cas system. Also provided herein are delivery systems for use of the CRISPR/Cas system in methods of in vivo and ex vivo genome editing.

Abstract: The present invention provides, among other things, methods and compositions for selective degradation of proteins. In some aspects, messenger RNAs (mRNAs) are described that encode a ubiquitin pathway moiety and a binding peptide that binds a target protein, wherein the mRNA is encapsulated within a lipid nanoparticle. Also provided herein are mRNAs that encode at least two binding peptides, wherein a first binding peptide binds a ubiquitin pathway moiety and a second binding peptide binds a target protein, and wherein the mRNA is encapsulated within a lipid nanoparticle.

Abstract: The present invention provides, among other things, methods and compositions for cancer treatment. The methods and compositions disclosed herein are particularly effective in reducing the size/volume of a tumor and inhibiting tumor growth.

Abstract: The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal heavy chain 5 (DNAH5) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAH5 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

Abstract: The invention relates to methods and compositions for treating a UDP glucuronosyltransferase family 1 deficiency based on mRNA therapy.

Abstract: mRNAs containing an exogenous open reading frame (ORF) flanked by a 5? untranslated region (UTR) and a 3? UTR is provided, wherein the 5? and 3? UTRs are derived from a naturally abundant mRNA in a tissue. Also provided are methods for identifying the 5? and 3? UTRs, and methods for making and using the mRNAs.