National Institutes of Health, Public Health Service, HHS.
The technology identifies a new form of Cushing Syndrome, “isolated micronodular adrenocortical disease” (iMAD), classified as a rare disease, as well as the role of PDE11A gene in this disease. We have identified particular sequence variants of the PDE11A gene causing abnormal or altered function of this gene; these variants are present in higher proportion in patients with iMAD, as well as in patients with other adrenal tumors. Additionally, we suggest that PDE11A can be a potential novel drug target for the treatment of bilateral adrenal hyperplasia, and possibly other endocrine tumors.
Phosphodiesterases (PDEs) are a family of cyclic AMP (cAMP) and/or cyclic GMP (cGMP)-hydrolyzing enzymes that cleave 3′, 5′-cyclic nucleotide monophosphates to 5′-nucleotide monophosphates. The PDE superfamily is large and complex, containing 11 highly related and structurally related gene families and over 60 distinct isoforms. PDE family members hydrolyze exclusively cAMP (PDE4, PDE7, and PDE8), exclusively cGMP (PDE5, PDE6, and PDE9), or both cAMP and cGMP (PDE1, PDE2, PDE3, PDE10, and PDE11). Specifically, PDE11A is a dual-specificity phosphodiesterase and is expressed in several endocrine tissues including the adrenal cortex. Members of the PDE family differ in tissue distribution, inhibitor specificity, and in mode of regulation. The side effects of the PDE inhibitors are contributed by the cross-reactivity of the inhibitors to other isoforms of the PDE.
The invention is the discovery that the PDE 11A gene has statistically significant linkage to “isolated micronodular adrenocortical disease” (iMAD), an inherited form of Cushing Syndrome. Patients suffering from the disease have high cortisol levels and infants with this disease may die from related complications, e.g., malignant hypertension or immunosuppression. So far the inventors have identified 3 inactivating mutations of an isoform of the PDE 11A gene, PDE11A4 linked to this particular form of Cushing syndrome; they have also identified several sequence polymorphisms of this gene that may be associated with a variety of adrenal and other conditions. One of these polymorphic variations of the sequence that have been identified leads to an alternate protein product of the PDE11A4 isoform. Such polymorphisms may have important implications for drugs that depend that depend on PDEs functions.
The invention can be separated into three categories:
1. Clinical identification of a new disease termed “isolated micronodular adrenocortical disease” (iMAD), an inherited form of Cushing Syndrome.
2. Identification of PDE11A gene and sequence variants for the diagnosis of “isolated micronodular adrenocortical disease” (iMAD) a form of Cushing Syndrome and endocrine tumors, i.e. as diagnostic genetic biomarker.
3. Identification of PDE11A as a potential novel drug target for the treatment of bilateral adrenal hyperplasia and other endocrine and Start Printed Page 7896non-endocrine tumors and malignancies.
The inventor is continuing work on the development and functional characterization of the PDE11A and its variants in relation to iMAD and other tumors and malignancies of the endocrine system.
Competitive Advantage of Our Technology
Cushing Syndrome occurs in 5 to 10 per 15 million every year and 27,000 new cases of endocrine tumors are diagnosed every year. Our technology identifies a functional role of PDE11A in a new form of Cushing Syndrome and its possible role in endocrine tumors and/or other cancers. PDE inhibitors have been successfully used in the treatment of erectile dysfunction. Currently, there are three products in the market, which inhibit the different forms of PDEs for the treatment of erectile dysfunction: Sildeafil (Viagra®), Vardenafil (Levitra®) and Tadalafil (Cialis®) manufactured by Pfizer, GlaxoSmithkline/Bayer/Schering-Plough and Lily Icos respectively.
Among the marketed PDE inhibitors, Cialis® targets PDE11A and PDE5A. Most interestingly, Cialis® has no known effects on the adrenal gland and endocrine system and no PDE gene has ever been reported to be associated with endocrine or other human tumor development. Our invention of the variants of PDE11A genes and subsequent new protein PDE11A4 from one of the genetic variants have opened up the possibility of the development of new drugs for iMAD, adrenal hyperplasia and other endocrine tumors and malignancies targeting these proteins.
The three marketed PDE inhibitors mentioned above have exceeded individual worldwide sales figures of 1 billion dollars each in 2007 and have been projected to grow steadily in the next few years. Additionally, the endocrine drug market has been projected to grow to more than 40 billion dollars in the next 5 years. New PDE inhibitors and the ones in the market are all in clinical trials for several diseases such as erectile dysfunction, neurological diseases and cardiovascular diseases.
Our technology suggests that drugs that modulate PDE function can be used in treating iMAD, a rare genetic form of Cushing Syndrome with fatal implications in children. The new PDE11A gene variants that have been identified have diagnostic and therapeutic implications. PCR-based diagnostic tools can be developed to diagnose iMAD and novel antagonists targeting these PDE11A variants can be identified and developed as drugs.
This technology consists of U.S. Provisional Applications Serial No. 60/761,446 entitled “PDE11A mutations in Adrenal Diseases” filed January 24, 2007. A PCT application has also been filed.
Next Step: Teleconference
There will be a teleconference where the principal investigator will explain this technology. Licensing and collaborative research opportunities will also be discussed. If you are interested in participating in this teleconference please call or e-mail Mojdeh Bahar; (301) 435-2950; firstname.lastname@example.org. OTT will then e-mail you the date, time and number for the teleconference.Start Signature
Dated: February 13, 2007.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.
[FR Doc. E7-2884 Filed 2-20-07; 8:45 am]
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