# US 10,865,252 B2 · Lin28-mediated control of let-7 biogenesis

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- Number: US 10,865,252 B2
- Document ID: US10865252B2
- Status: Granted
- Kind: B2
- Application number: 15/913,323
- Filed: 2018-03-06
- Published: 2018-09-27
- Granted: 2020-12-15
- Earliest claimed: 2011-03-25
- Assignees: Dana-Farber Cancer Institute, Inc.; Children's Medical Center Corporation
- Applicants: Children's Medical Center Corporation; Dana-Farber Cancer Institute, Inc.
- Inventors: Richard I. Gregory; Elena Piskounova; Dimitrios Iliopoulos
- Web page: https://patentgrep.com/patent/US10865252B2

## CPC

- C07K 16/40: against enzymes
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 35/00: Antineoplastic agents
- C07K 2/00: Peptides of undefined number of amino acids; Derivatives thereof
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- C12N 15/115: Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2320/10: in screening processes
- C12N 2320/50: Methods for regulating/modulating their activity
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present embodiments provide for compositions and methods that regulate microRNA-binding protein-mediated miRNA biogensis; for example Lin28-mediated biogenesis of let-7; and in particular Lin28A-recruited 3′ terminal uridylyl transferase (TUTase) uridylation of pre-let-7. A particular embodiment provide compositions and methods for screening for agents that inhibit TUTase-dependent Lin28A-mediated repression of let-7 miRNA.

## Claims

### Claim 1

A method of inhibiting Lin28A-mediated let-7 repression in a cell comprising contacting said cell with an inhibitor of TUTaseU, wherein the cell expresses Lin28A and is in a tissue in a subject, and wherein the amount of let-7 in the tissue is increased in the presence of the inhibitor relative to in the absence of the inhibitor.

### Claim 2

A method of inhibiting tumor growth or preventing tumor or cancer metastasis in a subject in need thereof comprising administering a therapeutically effective amount of an inhibitor of a TUTase and a pharmaceutically acceptable carrier, whereby tumor growth is inhibited in the presence of the inhibitor, wherein the tumor or cancer in the subject expresses Lin28A.

### Claim 3 (depends on 2)

The method of claim 2, further comprising measuring the level of expression of Lin28A in a in a sample of cancerous tissue obtained from the subject prior to administering the TUTase inhibitor.

### Claim 4 (depends on 2)

The method of claim 2, wherein the TUTase is Zcchc11 or Zcchc6.

### Claim 5 (depends on 2)

The method of claim 2, wherein the inhibitor inhibits the expression of Zcchc11 or Zcchc6.

### Claim 6 (depends on 2)

The method of claim 2, wherein the inhibitor inhibits the activity of Zcchc11 or Zcchc6.

### Claim 7 (depends on 2)

The method of claim 2, wherein the inhibitor is selected from the group consisting of an antibody, a RNA interference molecule, a small molecule, a peptide and an aptamer.

### Claim 8 (depends on 7)

The method of claim 7, wherein the inhibitor is a RNA interference molecule.

### Claim 9 (depends on 8)

The method of claim 8, wherein the RNA interference molecule is a short-hairpin RNA.

### Claim 10 (depends on 9)

The method of claim 9, wherein the RNA interference molecule is a short-hairpin RNA directed specifically against the Zcchc11 gene or the Zcchc6 gene.

### Claim 11 (depends on 2)

The method of claim 2, wherein the cancer is colon, breast, ovarian, or prostate cancer.

### Claim 12 (depends on 2)

The method of claim 2, wherein administering the inhibitor of the TUTase increases the expression level of let-7a level in the subject by at least 2-fold.

### Claim 13 (depends on 2)

The method of claim 2, wherein administering the inhibitor of the TUTase increases the expression level of let-7a level in the subject by about 2- to about 10-fold.