MODIFIED mRNA ENCODING A URIDINE DIPHOPSPHATE GLUCURONOSYL TRANSFERASE AND USES THEREOF

• US 20190307857A1
• Filed: 12/09/2016
• Published: 10/10/2019
• Est. Priority Date: 12/09/2015
• Status: Active Application

• Current Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Original Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Inventors: Lasaro, Melissa, Osterman, David, Vasavada, Haren, Cobaugh, Christian
• Application Number:
  US15/781,881
• Publication Number:
  US 20190307857A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 38/45 Transferases (2)
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C12N 15/52 Genes encoding for enzymes or proenzymes
• CPC Class Codes: C12Y 204/01017 Glucuronosyltransferase (2.4.1.17)

Abstract

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

Claims

1. A method of treating a disease or disorder associated with a uridine diphosphate glucuronosyltransferase family 1 deficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a modified mRNA molecule encoding a uridine diphosphate glucuronosyltransferase family 1A1 (UGT1A1) polypeptide comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:

4, wherein the modified mRNA molecule comprises N1-methyl pseudouridine.

4. The method of claim 1, wherein the amino acid sequence is at least 85% identical to SEQ ID NO:

4.

5. The method of claim 1, wherein the amino acid sequence is at least 90% identical to SEQ ID NO:

4.

6. The method of claim 1, wherein the amino acid sequence is at least 95% identical to SEQ ID NO:

4.

7. The method of claim 1, wherein the amino acid sequence is identical to SEQ ID NO:

4.

13. The method of claim 1, wherein the uridine diphosphate glucuronosyltransferase family 1 deficiency is type 1 Crigler-Najjar syndrome, kernicterus or hyperbilirubinemia.

15. The method of claim 1, wherein the modified mRNA molecule comprises a poly(A) tail, a Kozak sequence, a 3′

untranslated region, a 5′

untranslated region or any combination thereof.

2-3. -3. (canceled)

8-12. -12. (canceled)

14. (canceled)

16. A pharmaceutical composition comprising a therapeutically effective amount of a modified mRNA molecule encoding a uridine diphosphate glucuronosyltransferase family 1A1 (UGT1A1) polypeptide comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:

4, wherein the modified mRNA molecule comprises N1-methyl pseudouridine, and a pharmaceutically acceptable carrier, diluent or excipient.

17. A pharmaceutical composition comprising a therapeutically effective amount of a modified mRNA molecule encoding a uridine diphosphate glucuronosyltransferase family 1A1 (UGT1A1) polypeptide comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:

4, wherein the modified mRNA molecule comprises N1-methyl pseudouridineor active fragment thereof formulated in a lipid nanoparticle carrier.

18. A method of reducing unconjugated bilirubin levels in a subject comprising administering to the subject a therapeutically effective amount of a modified mRNA molecule encoding a uridine diphosphate glucuronosyltransferase family 1A1 (UGT1A1) polypeptide comprising an amino acid sequence that is at least 80% identical to SEQ ID NO:

4, wherein the modified mRNA molecule comprises N1-methyl pseudouridine.

21. The method of claim 18, wherein the amino acid sequence is at least 85% identical to SEQ ID NO:

4.

22. The method of claim 18, wherein the amino acid sequence is at least 90% identical to SEQ ID NO:

4.

23. The method of claim 18, wherein the amino acid sequence is at least 95% identical to SEQ ID NO:

4.

24. The method of claim 18, wherein the amino acid sequence is identical to SEQ ID NO:

4.

19-20. -20. (canceled)