Gene therapy for regulating smooth muscle tone

Abstract

The present invention is directed towards a method of regulating smooth muscle tone, comprising the introduction, into smooth muscle cells of a subject, of a DNA sequence encoding a protein involved in the regulation of smooth muscle tone, and expression of the DNA sequence in a sufficient number of smooth muscle cells of the subject to regulate smooth muscle tone in the subject. Specifically, the invention provides methods of gene therapy for treating erectile dysfunction, bladder dysfunction, and other smooth muscle disorders. The present invention also provides recombinant viral and non-viral vectors comprising DNA encoding a protein involved in the regulation of smooth muscle tone. Further provided by the present invention is a smooth muscle cell which expresses a gene encoding a protein involved in the regulation of smooth muscle tone.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 09 / 531,969, filed Mar. 21, 2000, now U.S. Pat. No. 7,030,096 B1, which is a continuation-in-part of U.S. application Ser. No. 08 / 799,144, filed Feb. 13, 1997, now U.S. Pat. No. 6,150,338, and a continuation-in-part of U.S. application Ser. No. 09 / 135,849, filed Aug. 18, 1998, now abandoned, the contents of all of which are hereby incorporated by reference in their entireties.BACKGROUND OF THE INVENTION [0002] There are many physiological dysfunctions or disorders which are caused by the deregulation of smooth muscle tone. Included among these dysfunctions and disorders are: asthma; benign hyperplasia of the prostate gland (BHP); coronary artery disease (infused during angiography); erectile dysfunction; genitourinary dysfunctions of the bladder, endopelvic fascia, prostate gland, ureter, urethra, urinary tract, and vas deferens; irritable bowel syndrome; migraine hea...

AI Technical Summary

Benefits of technology

[0017] The present invention further provides methods of gene therapy, wherein the DNA sequence which encodes a protein involved in the regulation of smooth muscle tone encodes a protein which modulates contraction of smooth muscle. Such a protein will enhance smooth muscle contraction, thereby restoring smooth muscle tone.

[0018] The present invention also provides methods of gene therapy, wherein the DNA sequence which encodes a protein involved in the regulation of smooth muscle tone encodes a protein which modulates relaxation of smooth muscle. Such a protein will enhance smooth-muscle relaxation, thereby restoring smooth muscle tone.

Problems solved by technology

However, all currently-available therapies are either nonspecific (e.g., hormonal therapy), of limited overall success (e.g., vacuum erection devices), invasive (e.g., intracorporal injection therapy), or non-reversible and expensive (e.g., penile prosthetic implant surgery).

Studies have documented that altered corporal smooth muscle tone, resulting in either heightened contractility or impaired relaxation, is a proximal cause of erectile dysfunction in a large proportion of impotent men.

Abnormal bladder function is another common problem which significantly affects the quality of life of millions of men and women in the United States.

The atonic bladder has diminished capacity to empty its urine contents because of ineffective contractility of the detrusor smooth muscle (the outer smooth muscle of the bladder wall).

Thus, it is not surprising that pharmacological modulation of smooth muscle tone is insufficient to correct the underlying problem.

As such, treatment of the atonic bladder ameliorates the symptoms of disease, but does not correct the underlying cause.

Conversely, the hyperreflexic, or uninhibited, bladder contracts spontaneously; this may result in urge incontinence, where the individual is unable to control the passage of urine.

The hyperreflexic bladder is a more difficult problem to treat.

Medications that have been used to treat this condition are usually only partially effective, and have severe side effects that limit the patient's use and enthusiasm.

Given the central importance of these two pathways in the cellular functioning of many organ systems in the body, such therapeutic strategies are not only crude methods for modulating bladder smooth muscle tone; rather, because of their very mechanism(s) of action, they are also virtually guaranteed to have significant and undesirable systemic effects.

Pharmacological therapy for treating bladder hyperreflexia typically involves frequent intravesical instillations, a treatment that patients often find inconvenient or otherwise undesirable.

In short, frequent intravesical instillations to restore bladder myocyte function are undesirable, and systemic medications still lack tolerable specificity.

Such vectors, however, present certain problems which have not been resolved to date.

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