[Federal Register Volume 72, Number 34 (Wednesday, February 21, 2007)]
[Notices]
[Pages 7895-7896]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-2884]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Public Teleconference Regarding Licensing and Collaborative 
Research Opportunities for: PDE11A as a Novel Therapeutic Target for 
Inherited Form of Cushing Syndrome and Endocrine Tumors; Dr. 
Constantine A. Stratakis et al. (NICHD)

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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Technology Summary

    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.

Technology Description

    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

[[Page 7896]]

non-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[supreg]), Vardenafil 
(Levitra[supreg]) and Tadalafil (Cialis[supreg]) manufactured by 
Pfizer, GlaxoSmithkline/Bayer/Schering-Plough and Lily Icos 
respectively.
    Among the marketed PDE inhibitors, Cialis[supreg] targets PDE11A 
and PDE5A. Most interestingly, Cialis[supreg] 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.

Patent Estate

    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; [email protected]. OTT will then e-mail you 
the date, time and number for the teleconference.

    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]
BILLING CODE 4140-01-P