Modernatx, Inc.

Fundacion Para La Investigacion Medica Aplicada

Iain McFadyen

Vladimir Presnyak

Kerry Benenato

Stephen G Hoge

Ellalahewage Sathyajith Kumarasinghe

Ailin Bai

Joshua P Frederick

Susannah Hewitt

Paolo Martini

Staci Sabnis

Lin Tung Guey

Ding An

Xuling Zhu

Athanasios Dousis

Zhinan Xia

Barry Ticho

Nadege Briancon-Eris

Seymour De Picciotto

Jingsong Cao

Amy E Rabideau

Pedro Berraondo Lopez

Antonio Fontanellas Roma

David Mauger

Lei Jiang

Matias Antonio Avila Zaragoza

The invention relates to mRNA therapy for the treatment of Acute Intermittent Porphyria (AIP). mRNAs for use in the invention, when administered in vivo, encode human porphobilinogen deaminase (PBGD), isoforms thereof, functional fragments thereof, and fusion proteins comprising PBGD. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to affect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of PBGD expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient PBGD activity in subjects, namely porphobilinogen and aminolevulinate (PBG and ALA).

Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria

The invention relates to mRNA therapy for the treatment of galactosemia type 1 (Gal-1). mRNAs for use in the invention, when administered in vivo, encode human galactose-1-phosphate uridylyltransferase (GALT), isoforms thereof, functional fragments thereof, and fusion proteins comprising GALT. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of GALT expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient GALT activity in subjects, namely galactose-1-phosphate (Gal-1-P).

Polynucleotides encoding galactose-1-phosphate uridylyltransferase for the treatment of galactosemia type 1

The invention relates to mRNA therapy for the treatment of Citrullinemia Type 2 ('CTLN2'). mRNAs for use in the invention, when administered in vivo, encode human Citrin, isoforms thereof, functional fragments thereof, and fusion proteins comprising Citrin. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of Citrin expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of biomarkers associated with deficient Citrin activity in subjects, namely ammonia and/or triglycerides.

Polynucleotides encoding Citrin for the treatment of Citrullinemia type 2

The invention relates to mRNA therapy for the treatment of Alagille syndrome (ALGS), mRNAs for use in the invention, when administered in vivo, encode JAGGED 1 (JAG1), isoforms thereof functional fragments thereof, and fusion proteins comprising JAG1, mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of JAG1 expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient JAG1 activity in subjects.

Polynucleotides encoding JAGGED1 for the treatment of Alagille syndrome

The invention relates to mRNA therapy for the treatment of hyperlipidemia. mRNAs for use in the invention, when administered in vivo, encode human lipoprotein lipase (LPL), isoforms thereof, functional fragments thereof, and fusion proteins comprising LPL. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto, mRNA therapies of the invention increase and/or restore deficient levels of LPL expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of triglycerides associated with deficient LPL activity in subjects.

Polynucleotides encoding lipoprotein lipase for the treatment of hyperlipidemia

The invention relates to mRNA therapy for the treatment of fibrosis and/or cardiovascular disease. mRNAs for use in the invention, when administered in vivo, encode human relaxin, isoforms thereof, functional fragments thereof, and fusion proteins comprising relaxin. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of relaxin expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient relaxin activity in subjects.

Polynucleotides encoding relaxin

The present disclosure provides methods and compositions for high fidelity in vitro transcription reactions.

High fidelity in vitro transcription

The invention relates to mRNA therapy for the treatment of cystic fibrosis. mRNAs for use in the invention, when administered in vivo, encode cystic fibrosis transmembrane conductance regulator (CFTR), isoforms thereof, functional fragments thereof, and fusion proteins comprising CFTR. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of CFTR expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient CFTR activity in subjects.

Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis

The present disclosure relates to the use of nucleic acid (e.g., mRNA) combination therapies for the treatment of cancer. The disclosure provides compositions, and methods for their preparation, manufacture, and therapeutic use, wherein those compositions comprise at least two polynucleotides (e.g., mRNAs) in combination wherein the at least two polynucleotides are selected from the group consisting of (i) a polynucleotide encoding an immune response primer (e.g., IL23), (ii) a polynucleotide encoding an immune response co-stimulatory signal (e.g., OX40L), (iii) a polynucleotide encoding a checkpoint inhibitor (e.g., an anti CTLA-4 antibody), and, (iv) a combination thereof. The therapeutic methods disclosed herein comprise, e.g., the administration of a combination therapy disclosed herein for the treatment of cancer, e.g., by reducing the size of a tumor or inhibiting the growth of a tumor, in a subject in need thereof. In some aspects, the combination therapies disclosed herein disclosed are administered intratumorally.

mRNA combination therapy for the treatment of cancer

The invention relates to mRNA therapy for the treatment of Fabry disease. mRNAs for use in the invention, when administered in vivo, encode human the &#x3b1;-galactosidase A (GLA), isoforms thereof, functional fragments thereof, and fusion proteins comprising GLA. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of GLA expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient GLA activity in subjects, namely Gb3 and lyso-Gb3.

Polynucleotides encoding &#x3b1;-galactosidase A for the treatment of Fabry disease

The disclosure relates to compositions and methods for the preparation, manufacture and therapeutic use of combinations of immunomodulatory polynucleotides (e.g., mRNAs) encoding an immune response primer polypeptide (e.g., an interleukin 23 (IL-23) polypeptide or an interleukin 36&#x3b3; (IL-36-gamma) polypeptide), and an immune response co-stimulatory signal polypeptide (e.g., an OX40L polypeptide).

Combinations of mRNAs encoding immune modulating polypeptides and uses thereof

The present disclosure relates to polynucleotides comprising an open reading frame of linked nucleosides encoding human interleukin-12 (IL12), functional fragments thereof, and fusion proteins comprising IL12. In some embodiments, the open reading frame is sequence-optimized. In particular embodiments, the disclosure provides sequence-optimized polynucleotides comprising nucleotides encoding the polypeptide sequence of human IL12, or sequences having high sequence identity with those sequence optimized polynucleotides.

Polynucleotides encoding interleukin-12 (IL12) and uses thereof

The disclosure relates to polynucleotides comprising an open reading frame of linked nucleosides encoding human methylmalonyl-CoA mutase precursor, human methylmalonyl-CoA mutase (MCM) mature form, or functional fragments thereof. In some embodiments, the disclosure includes methods of treating methylmalonic acidemia in a subject in need thereof comprising administering an mRNA encoding an MCM polypeptide.

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Arlington, MA, United States of America

Iain McFadyen