Method of early detection of duchenne muscular dystrophy and other neuromuscular disease

• US 20030003052A1
• Filed: 06/19/2002
• Published: 01/02/2003
• Est. Priority Date: 06/19/2001
• Status: Active Grant

• Current Assignee: Mouse Specifics, Inc.
• Original Assignee: Mouse Specifics, Inc.
• Inventors: Hampton, Thomas G.
• Granted Patent: US 6,875,418 B2
• Time in Patent Office: Days
• US Class Current: 424/9.2
• CPC Class Codes: A61B 5/4035 Evaluating the autonomic nervous system
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions

Abstract

The mdx mouse is a model of Duchenne muscular dystrophy. The present invention describes that mdx mice exhibited clinically relevant cardiac phenotypes. A non-invasive method of recording electrocardiograms (ECGs) was used to a study mdx mice (n=15) and control mice (n=15). The mdx mice had significant tachycardia, consistent with observations in patients with muscular dystrophy. Heart-rate was nearly 15% faster in mdx mice than control mice (P<0.01). ECGs revealed significant shortening of the rate-corrected QT interval duration (QTc) in mdx mice compared to control mice (P<0.05). PR interval duration were shorter at baseline in mdx compared to control mice (P<0.05). The muscarinic antagonist atropine significantly increased heart-rate and decreased PR interval duration in C57 mice. Paradoxically, atropine significantly decreased heart-rate and increased PR interval duration in all mdx mice. Pharmacological autonomic blockade and baroreflex sensitivity testing demonstrated an imbalance in autonomic nervous system modulation of heart-rate, with decreased parasympathetic activity and increased sympathetic activity in mdx mice. These electrocardiographic findings in dystrophin-deficient mice provide new bases for diagnosing, understanding, and treating patients with Duchenne muscular dystrophy.

Claims

1. A method of diagnosing or aiding in diagnosing of a perturbation of an autonomic nervous system in a subject, the method comprising the steps of:

a) administering, into a body of the subject, an effective amount of a cholinergic agent or a derivative thereof; and

,

b) determining whether the cholinergic agent or a derivative thereof, elicits a cholinomimetic effect in the subject, as opposed to a cholinergic effect, thereby identifying whether the subject has indications of the perturbation of the autonomic nervous system.

2. The method of claim 1, wherein the perturbation of the autonomic nervous system is determined by detecting a change in heart-rate of the subject in response to the cholinergic agent or a derivative thereof.

3. The method of claim 2, wherein the change in heart rate is measured as a decrease in heart rate activity.

4. The method of claim 2, wherein the change in heart rate is measured as an increase in heart rate activity.

5. The method of claim 2, wherein the change in the heart rate is determined using a detector supplying data associated with electrocardiogram signals and providing an electrocardiogram using an apparatus for interpreting the data associated with electrocardiogram signals of the subject.

6. The method of claim 2, wherein the changes in heart rate activity is detected by a computing apparatus.

7. The method of claim 6, wherein the computing apparatus further comprises a digital processor, a working memory, and a database, which records changes in heart rate in the subject.

8. The method of claim 1, wherein the perturbation is caused by an alteration in property and function of an acetylcholine receptor.

9. The method of claim 1, wherein the perturbation is caused by an alteration in property and function of a cholinergic receptor.

10. The method of claim 9, wherein the cholinergic receptor is a muscarinic receptor.

11. The method of claim 1, wherein the perturbation is caused by a perturbation in acetylcholine concentration.

12. The method of claim 1, wherein the perturbation is caused by perturbation in acetylcholinesterase concentration.

13. The method of claim 1, wherein the perturbation is caused by a deficiency in dystrophin or a dystrophin-associated protein.

14. The method of claim 1, wherein the perturbation of the autonomous nervous system results in a disorder.

15. The method of claim 14, wherein the disorder is selected from a group consisting of:

peripheral nervous system disorder, a neuromuscular disorder;

a neurodegenerative disorder, a cardiovascular disorder, a lateral sclerosis, a diabetic neuropathy, an arteriosclerosis, a tachycardia, a bradycardia, a pressure overload, a hypertension, an atrial fibrillation, an atrial flutter, a dilated cardiomyopathy, an idiopathic cardiomyopathy, a myocardial infarction, a coronary artery disorder, a coronary artery spasm, and an arrhythmia.

16. The method according to claim 1, wherein the cholinergic agent or a derivative thereof, is a muscarinic agent.

17. The method of claim 1, wherein the muscarinic agent is a muscarinic antagonist or a derivative thereof.

18. The method of claim 17, wherein the muscarinic antagonist is selected from a group consisting of, an atropine, a latrotoxin, a scopolamine, a propantheline, a pirezapine, and a derivative thereof.

19. The method of claim 1, wherein the agent is administered intravenously, intraperitonially, ophthalmologically, buccal, intracoronary, intramuscularly, topically, intranasally, rectally, sublingually, orally, subcutaneously, by patch, or inhalation.

20. The method of claim 1, wherein the subject is a human.

21. The method of claim 1, wherein the subject further comprises of one or more of age, sex, and ethnic origin.

22. A method of diagnosing or aiding in diagnosing of Duchenne muscular dystrophy in a subject, the method comprising the steps of:

a) administering, into a body of the subject, an effective amount of a cholinergic agent or a derivative thereof, and,

b) determining whether the cholinergic agent or a derivative thereof, elicits a cholinomimetic effect in the subject, as opposed to a cholinergic effect.

23. The method of claim 22, wherein the cholinergic agent or a derivative thereof, elicits a change in heart rate.

24. The method of claim 23, wherein the change in the heart rate decreases the heart rate of the subject in response to the cholinergic agent or a derivative thereof, thereby indicative of Duchenne muscular dystrophy in the subject.

26. The method of claim 25, wherein the agent is administered intravenously, intraperitonially, ophthalmologically, buccal, intracoronary, intramuscularly, topically, intranasally, rectally, sublingually, orally, subcutaneously, by patch, or inhalation.

27. The method of claim 25, wherein a second effective amount of one of the cholinergic agent, the muscarinic agent, the adrenergic agent, and a derivative thereof, is administered about one, two or three times in a day after administration of a first effective amount of one of the cholinergic agent, the muscarinic agent, the adrenergic agent, and a derivative thereof.

28. The method of claim 25, wherein one or more further effective amounts of one of the cholinergic agent, the muscarinic agent, the adrenergic agent, and a derivative thereof, is added at intervals of one day or more.

30. The method of claim 29, wherein the physiological response is determined by a constriction in the eye.

25. A method for treating a heart-disorder state associated with dystrophin in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of one of a cholinergic agent, a muscarinic agent, an adrenergic agent, and a derivative thereof, such that treatment of heart-disorder state occurs.

29. A method of diagnosing or aiding in diagnosing a subject suffering from a dystrophin-deficient disorder, or at risk of developing a dystrophin-deficient disorder comprising the steps of:

a) administering topically into an eye of the subject an effective amount of one of a cholinergic, a muscarinic agent, and a derivative thereof, to induce a physiological change in the eye;

b) comparing a physiological change in the subject with a response under similar conditions in a normal subject, thereby identifying whether the subject suffers from dystrophin-deficient disorder.