METHODS AND KITS FOR TREATING AND CLASSIFYING INDIVIDUALS AT RISK OF OR SUFFERING FROM TRAP1 CHANGE-OF-FUNCTION

• US 20160186264A1
• Filed: 06/11/2014
• Published: 06/30/2016
• Est. Priority Date: 06/11/2013
• Status: Active Grant

• Current Assignee: Medicinal Genomics Corporation (Courtagen Life Sciences, Inc.)
• Original Assignee: Courtagen Life Sciences, Inc.
• Inventors: McKernan, Kevin, Boles, Richard
• Granted Patent: US 9,670,545 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The present disclosure provides methods and kits for treating and classifying individuals at risk of or suffering from a neurological and/or mitochondrial dysfunction or disorder. In general, the individuals are treated and/or classified based on the presence of a change-of-function mutation in nuclear DNA that encodes TNF receptor-associated protein 1 (TRAP1). Treatment involves the administration of a therapeutically effective amount of an antioxidant.

Claims

1. A method of treating an individual at risk of or suffering from a neurological and/or mitochondrial dysfunction or disorder, the method comprising administering to the individual a therapeutically effective amount of an antioxidant, wherein DNA of the individual that encodes a TNF receptor-associated protein 1 (TRAP1) gene product includes a change-of-function mutation, wherein said change-of-function mutation is a loss-of-function mutation or a gain-of-function mutation.

2. The method of claim 1, wherein, prior to administration, the individual has been determined to possess the change-of-function mutation.

3. The method of claim 1, further comprising determining that the individual possesses the change-of-function mutation.

4. The method of claim 2, wherein the change-of-function mutation is in the ATPase domain or the C-terminal HSP90-like domain.

6. The method of claim 2, wherein the neurological and/or mitochondrial dysfunction or disorder is selected from the group consisting of functional gastrointestinal disorders, chronic pain disorders, chronic fatigue syndrome, intermittent encephalopathy, dementia and combinations thereof.

7. The method of claim 2, wherein the change-of-function mutation causes a changed ATPase activity of a TRAP 1 gene product, wherein the ATPase activity is reduced or increased.

8. The method of claim 2, wherein the change-of-function mutation is or comprises a mutation selected from:

(i) the group consisting of 165Q>

E, 192E>

K, 216E>

*, 253I>

V, and combinations thereof;

or

(ii) the group consisting of 266S>

R, 340R>

H, 388R>

Q, 444Y>

N, 445G>

S, 457E>

K, 469R>

H, 535T>

S, 685D>

N, and combinations thereof.

10. The method of claim 2, wherein the change-of-function mutation is heterozygous.

11. The method of claim 2, wherein the change-of-function mutation is homozygous.

12. The method of claim 2, wherein the antioxidant is selected from the group comprising Vitamin E, N-acetyl cysteine, Coenzyme Q10, alpha-tocopherol, alpha-tocotrienol (EPI-743), Idebenone and pharmaceutically acceptable salts thereof.

85. The method of claim 3, wherein determining that the individual possesses the change-of-function mutation comprises requesting sequencing of at least a portion of nuclear DNA that encodes a TRAP 1 gene product.

86. The method of claim 3, wherein determining that the individual possesses the change-of-function mutation comprises sequencing at least a portion of nuclear DNA that encodes a TRAP 1 gene product.

87. The method of claim 3, wherein determining that the individual possesses the change-of-function mutation comprises requesting genotyping of at least a portion of nuclear DNA that encodes a TRAP 1 gene product.

88. The method of claim 3, wherein determining that the individual possesses the change-of-function mutation comprises genotyping at least a portion of nuclear DNA that encodes a TRAP 1 gene product.

5. (canceled)

9. (canceled)

13. (canceled)

14. A method of aiding in the selection of a therapy for an individual at risk of or suffering from a neurological and/or mitochondrial dysfunction or disorder, the method comprising:

obtaining a sample of DNA from the individual;

processing the sample to determine whether the individual possesses a change-of-function mutation in DNA that encodes a TNF receptor-associated protein 1 (TRAP

     1) gene product, wherein the ATPase activity is reduced or increased; and

classifying the individual as one that could benefit from therapy with an antioxidant if the step of processing determines that the individual possesses a change-of-function mutation in DNA that encodes a TRAP 1 gene product.

15-30. -30. (canceled)

31. A method of classifying an individual at risk of or suffering from a neurological and/or mitochondrial dysfunction or disorder, the method comprising:

obtaining a sample of DNA from the individual;

processing the sample to determine whether the individual possesses a mutation in DNA that encodes a TNF receptor-associated protein 1 (TRAP

     1) gene product; and

classifying the individual as one that does or does not possess a mutation in DNA that encodes a TRAP 1 gene product.

32-45. -45. (canceled)

46. A kit for classifying an individual at risk of or suffering from a neurological and/or mitochondrial dysfunction or disorder, the kit comprising primers for amplifying a target region of DNA that encompasses part or all of the codon for (i) amino acids 165, 192, 216, and/or 253 of a TNF receptor-associated protein 1 (TRAP 1) gene product or (ii) amino acids 266, 340, 388, 444, 445, 457, 469, 535 and/or 685 of a TRAP 1 gene product.

47. (canceled)

48. A kit for classifying an individual at risk of or suffering from a neurological and/or mitochondrial dysfunction or disorder, the kit comprising primers for amplifying a target region of DNA encompassing a region of a TNF receptor-associated protein 1 (TRAP 1) gene, wherein said region includes one or more sites of change-of-function mutations that correspond to (i) amino acids 165, 192, 216, and/or 253 of a TRAP 1 gene product or (ii) amino acids 266, 340, 388, 444, 445, 457, 469, 535 and/or 685 of a TRAP 1 gene product, wherein said change-of-function mutations comprise a loss-of-function mutation or a gain-of-function mutation.

49-79. -79. (canceled)

80. A non-transitory computer readable medium containing executable instructions that when executed cause a processor to perform operations comprising:

(a) receiving an individual'"'"'s genotype for a panel of TRAP 1 polymorphisms, where said panel comprises TRAP 1 amino acids 165, 192, 216, 253, 266, 340, 388, 444, 455, 457, 469, 535 and/or 685;

(b) determining whether the individual possesses a change-of-function mutation in DNA that encodes a TRAP 1 gene product, wherein said change-of-function mutation is a loss-of-function mutation or a gain-of-function mutation;

(c) classifying the individual as one that could benefit from therapy with an antioxidant if the individual possesses a change-of-function mutation in DNA that encodes a TRAP 1 gene product.

81-84. -84. (canceled)