Translate Bio, Inc.

Transkaryotic Therapies, Inc.

Shire Human Genetic Therapies, Inc.

Ethris Gmbh

Massachusetts Institute of Technology

Rana Therapeutics, Inc.

Other

Takeda Pharmaceutical Company Limited

Synageva Biopharma Corporation

Michael W Heartlein

Frank DeRosa

Braydon Charles Guild

Shrirang Karve

Anusha Dias

Douglas A Treco

Richard F Selden

Lianne Smith

Zarna Patel

Jonathan Abysalh

Daniel Crawford

Michael F Concino

Carsten Rudolph

Christian Plank

Yi Zhang

Daniel Griffith Anderson

Yizhou Dong

Jerry Chi Zhang

Bettina Strack-Logue

Jeffrey F Lemontt

Ashish Sarode

Yi Lin Zhang

Darshan Parekh

Ferenc L Boldog

Dennis Keefe

Serene Josiah

Ann Barbier

Christian Cobaugh

Rebecca L Goldman

Jou-Ku Chung

Sara J Dunaj

Jeffrey S Dubins

Frank Derosa

Thomas McCauley

Kim Askew

Rebecca Powell

Erik Held

Travis Jeannotte

Kimberly Gillis

Joseph Parella

Brian R Bettencourt

Pericles Calias

Paolo Martini

Muthuraman Meiyappan

Lawrence Charnas

Andrea Ballabio

Jan Powell

Peter Francis Daniel

Alla Romashko

Saswata Karmakar

Brian Felice

Natalia Vargas Montoya

Priyal Patel

Shirang Karve

Zarna Bhavsar

Brian M Hauge

Jonathan Cherry

Paula Lewis

Susan Wood

Maria Pia Cosma

Thomas Dierks

Bernhard Schmidt

Kurt Von Figura

Nancy Savioli

Brian Pescatore

Chi-Sung Chiu

Caroline J Woo

Alan Kimura

Peter F Daniel

The present invention provides, among other things, methods of quantitating mRNA capping efficiency, particularly mRNA synthesized in vitro. In some embodiments, methods according to the present invention comprise providing an mRNA sample containing capped and uncapped mRNA, providing a cap specific binding substance under conditions that permit the formation of a complex between the cap specific binding substance and the capped mRNA, and quantitatively determining the amount of the complex as compared to a control, thereby quantifying mRNA capping efficiency.

Quantitative assessment for cap efficiency of messenger RNA

The present invention relates, in part, to methods for large-scale purification of mRNA. The method includes, at least, a step of centrifuging an mRNA suspension in a centrifuge comprising a porous substrate at a speed sufficient to remove process contaminants and to precipitate purified mRNA composition onto the porous substrate.

Methods for purification of messenger RNA

Disclosed are cationic polymers comprising monomers such as those described in Formula (I), Such polymers can be useful for the preparation of therapeutic compositions (e.g., compositions comprising nucleic acids such as mRNA). Additionally, therapeutic compositions comprising these cationic, biodegradable polymers can have improved properties and reduced toxicity.

Cationic polymers

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.

Composition and methods for treatment of primary ciliary dyskinesia

The present invention provides, among other things, methods and compositions of formulating nucleic acid-containing nanoparticles for efficient delivery of payload in vivo such that the method and compositions can be used to generate mRNA vaccines.

Messenger RNA vaccines and uses thereof

Disclosed herein are novel compounds, pharmaceutical compositions comprising such compounds and related methods of their use. The compounds described herein are useful, e.g., as liposomal delivery vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and subsequent transfection of said target cells, and in certain embodiments are characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids.

Ionizable cationic lipids

The present invention provides, among other things, compositions and methods of formulating nucleic acid-containing nanoparticles comprising no more than three distinct lipids components, one distinct lipid component being a sterol-based cationic lipid. In some embodiments, the present invention provides compositions and methods in which the lipid nanoparticles further comprise helper lipids and PEG-modified lipids. The resulting formulation comprises a high encapsulation percentage for nucleic acids.

Lipid nanoparticle formulations for delivery of MRNA

The compounds disclosed herein (e.g., compounds having a structure according to Formula (I/(II)/(III)/(IV), and (V)) are polymers wherein an organic polymeric segment (e.g., a polyethylene glycol (PEG) group) comprises covalent attachments to two or more lipid substructures, and each lipid substructure independently comprises a hydrophobic moiety and a hydrophilic moiety. The compounds 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.

PEG lipidoid compounds

The present invention provides, among other things, methods of treating ornithine transcarbamylase deficiency, including administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbamylase protein at a low dose and at an administration interval such that at least one symptom or feature of the OTC deficiency is reduced.

Composition and methods for treatment of ornithine transcarbamylase deficiency

Disclosed are messenger RNA molecules and related compositions incorporating a 4'-thio modification in the furanose ring of at least one nucleotide residue, and methods of using these mRNAs to produce an encoded therapeutic protein in vivo and to treat or prevent diseases or disorders. In certain embodiments, the 4′-thio modified mRNA provides for enhanced stability and/or reduced immunogenicity in in vivo therapies.

Ribonucleic acids with 4'-thio-modified nucleotides and related methods

Disclosed are cationic lipids comprising a vitamin substructure and an ionizable nitrogen-containing group. 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.

Vitamin cationic lipids

The present invention provides, among other things, methods of purifying messenger RNA (mRNA) including the steps of subjecting an impure preparation comprising in vitro synthesized rnRNA to a denaturing condition, and purifying the rnRNA from the impure preparation from step (a) by tangential flow filtration, wherein the mRNA purified from step (b) is substantially free of prematurely aborted RNA sequences and/or enzyme reagents used in in vitro synthesis.

The present invention provides, among other things, methods of treating ornithine transcarbamylase (OTC) deficiency, including administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbamylase (OTC) protein at an effective dose and an administration interval such that at least one symptom or feature of the OTC deficiency is reduced in intensity, severity, or frequency or has delayed onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids.

Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency

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.

Treatment of cystic fibrosis by delivery of nebulized mRNA encoding CFTR

The present invention provides an improved compositions and processes for preparing mRNA-loaded lipid nanoparticles (mRNA-LNPs). In some embodiments, the present invention provides mRNA-LNPs with exceptional stability and is particularly useful in cases where LNPs comprising low or no PEG-modified lipids are desired.

Stable compositions of MRNA-loaded lipid nanoparticles and processes of making

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Boxborough, MA, United States of America

Michael W Heartlein