# US 10,246,681 B2 · Reprogramming of human wharton's jelly cells to produce hair cells

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- Number: US 10,246,681 B2
- Document ID: US10246681B2
- Status: Granted
- Kind: B2
- Application number: 15/353,244
- Filed: 2016-11-16
- Published: 2017-03-09
- Granted: 2019-04-02
- Earliest claimed: 2014-04-28
- Assignees: University of Kansas
- Applicants: The University of Kansas
- Inventors: Adam J Mellott; Michael Detamore; Hinrich Staecker
- Web page: https://patentgrep.com/patent/US10246681B2

## CPC

- C12N 5/062: {Sensory transducers, e.g. photoreceptors; Sensory neurons, e.g. for hearing, taste, smell, pH, touch, temperature, pain}
- A61K 35/30: Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/51: in polymeric form, e.g. multimers, concatemers
- C12N 2506/025: from extra-embryonic cells, e.g. trophoblast, placenta
- C12N 2510/00: Genetically modified cells
- C12N 2533/90: Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)

## Abstract

A method of transforming human cells into mechanosensory hair cells (MHCs), such as inner hear hair cells in the cochlea and vestibular organs, can include: causing human Wharton's jelly cells (hWJCs) to increase expression of or biological function of HATH1 so as to transform the hWJCs into MHCs. The method can include; administering a nucleic acid that encodes HATH1 to the hWJCs; causing inhibited expression of or biological function of HES1 and/or HES5 in the hWJCs; administering a nucleic acid that inhibits HES1 and/or a nucleic acid that inhibits HES5 to the hWJCs; causing inhibited expression of or biological function of HES1 and/or HES5 in the WJCs by administering a nucleic acid that inhibits HES1 and/or a nucleic acid that inhibits HES5; nucleic acids are administered includes a sequence of SEQ ID NO: 2, SEQ ID NO: 3, and/or SEQ ID NO: 4.

## Claims

### Claim 1

A cell culture system comprising:
a decellularized cochlea; and
mechanosensory hair cells (MHCs) growing on and/or inside the decellularized cochlea, wherein the MHCs have an exogenous nucleic acid that encodes HATH1 and a promoter operably linked with the encoded HATH1.

### Claim 2 (depends on 1)

The cell culture system of claim 1, comprising one or more test substances in the MHCs, the one or more test substances are not native to Wharton's jelly cells (WJCs) or MHCs and are present in an amount to screen for biological activity thereof.

### Claim 3 (depends on 2)

The cell culture system of claim 2, comprising the MHCs having a nucleic acid that inhibits HES1.

### Claim 4 (depends on 2)

The cell culture system of claim 2, comprising the MHCs having a nucleic acid that inhibits HES5.

### Claim 5 (depends on 2)

The cell culture system of claim 2, comprising the MHCs having a nucleic acid that inhibits HES1 and a nucleic acid that inhibits HES5.

### Claim 6 (depends on 1)

The cell culture system of claim 1, wherein the exogenous nucleic acid that encodes HATH1 includes a sequence of SEQ ID NO: 2.

### Claim 7 (depends on 3)

The cell culture system of claim 3, wherein the nucleic acid that inhibits HES1 includes a sequence of SEQ ID NO: 3.

### Claim 8 (depends on 4)

The cell culture system of claim 4, wherein the nucleic acid that inhibits HES5 includes a sequence of SEQ ID NO: 4.

### Claim 9 (depends on 2)

The cell culture system of claim 2, wherein the decellularized cochlea is shaped as a cochlea.

### Claim 10 (depends on 2)

The cell culture system of claim 2, comprising the MHCs devoid of a nucleic acid that encodes MATH1.

### Claim 11 (depends on 2)

The cell culture system of claim 2, comprising human Wharton's jelly cells (WJCs).

### Claim 12 (depends on 2)

The cell culture system of claim 2, wherein at least one of the one or more test substances is toxic to the MHCs so as to be capable of causing hearing and/or balance loss.

### Claim 13 (depends on 2)

The cell culture system of claim 2, wherein at least one of the one or more test substances is therapeutic for treatment of hearing and/or balance loss.

### Claim 14 (depends on 2)

The cell culture system of claim 2, wherein at least one of the one or more test substances is ototoxic.

### Claim 15 (depends on 2)

The cell culture system of claim 2, wherein at least one of the one or more test substances promote formation of the MHCs.

### Claim 16 (depends on 2)

The cell culture system of claim 2, further comprising neuron-like cell types.

### Claim 17 (depends on 1)

The cell culture system of claim 1, wherein the exogenous nucleic acid is a plasmid DNA.