# US 10,369,191 B2 · Modulation of epigenetic stress response

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- Number: US 10,369,191 B2
- Document ID: US10369191B2
- Status: Granted
- Kind: B2
- Application number: 15/268,079
- Filed: 2016-09-16
- Published: 2018-03-22
- Granted: 2019-08-06
- Earliest claimed: 2015-03-24
- Applicants: Desmond D. Mascarenhas
- Inventors: Desmond D. Mascarenhas
- Web page: https://patentgrep.com/patent/US10369191B2

## CPC

- A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Stress, such as from physical, metabolic or psychological trauma, is associated with enduring secondary complications leading to morbidity and/or death in subjects that receive the stress insult. The epigenetic oxidative stress response to a stress insult is characterized by (a) global epigenetic events such as changes in DNA methylation and phosphorylation of Ser10 and acetylation of Lys9/14 residues of histone-3 (b) significant systemic elevations in analytes of oxidative stress in body fluids such as blood or urine and (c) deterioration of clinically relevant parameters such as glycemic control, organ function, lean body mass and rate of healing. The applicant teaches a method of counteracting the grave systemic effects of stress insult with reference to the epigenetic oxidative stress response, by daily subcutaneous bolus injections of nephrilin peptide beginning soon after insult and continuing for seven days. These methods of combating epigenetic oxidative stress response are new and have not been described in the prior art. Specifically, the use of nephrilin (acting on its target, Rictor complex) to obviate the epigenetic changes in trauma that result in systemic oxidative stress, is new. Previously disclosed work on nephrilin had not described its effects on epigenetic change (mechanism) or oxidative stress (readout). The relevance of this particular epigenetic-oxidative-stress cascade to clinically relevant outcomes such as loss of organ function, glycemic control or lean body mass was unknown, as was the use of nephrilin molecule to counteract these phenomena. The invention relates to the use of specific therapeutic agents such as nephrilin to ameliorate the epigenetic oxidative stress response, and specifically the above-mentioned clinically relevant parameters.

## Claims

### Claim 1

A method for measuring and treating epigenetic oxidative stress response in a mammal, comprising
(a) obtaining or having obtained a sample of body fluid from the mammal;
(b) measuring the level of a marker of oxidative stress in said body fluid;
(c) administering to the mammal a therapeutically effective dose of nephrilin peptide (SEQ ID NO: 1);
(d) demonstrating
[i] a reduction in the level of said marker of oxidative stress; and
[ii] improvement of one or more clinically relevant parameters selected from the group consisting of glycemic control, eGFR, lean body mass, fat mass or wound healing in the mammal;
thereby mitigating the effects of the epigenetic oxidative stress response in the mammal.

### Claim 2 (depends on 1)

The method of claim 1 wherein the epigenetic oxidative stress response is characterized by an increase in H3S10 phosphorylation and/or H3K9/K14 acetylation.

### Claim 3 (depends on 1)

The method of claim 1, wherein the stress insult is burn injury.

### Claim 4 (depends on 1)

The method of claim 1 wherein the marker of oxidative stress is 8-isoprostane.

### Claim 5 (depends on 1)

The method of claim 1, wherein the clinically relevant parameter is glycemic control.

### Claim 6 (depends on 1)

The method of claim 1, wherein the clinically relevant parameter is eGFR.

### Claim 7 (depends on 1)

The method of claim 1, wherein the clinically relevant parameter is lean body mass.

### Claim 8 (depends on 1)

The method of claim 1, wherein the clinically relevant parameter is fat mass.

### Claim 9 (depends on 1)

The method of claim 1, wherein the clinically relevant parameter is wound healing.

### Claim 10 (depends on 1)

The method of claim 1, wherein the therapeutically effective dose of nephrilin peptide is from about 0.01 mg/kg/day to about 10 mg/kg/day.

### Claim 11 (depends on 1)

The method of claim 1, wherein the body fluid is blood or urine.