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Method of detecting and treating tuberous sclerosis complex associated disorders

Method of detecting and treating tuberous sclerosis complex associated disorders description/claims

This application is a Continuation under 37 C.F.R. 1.53(b) of U.S. Ser. No. 10/016,253, filed Dec. 10, 2001, which is incorporated by reference in its entirety.

The invention relates to methods of detecting and treating Tuberous Sclerosis Complex (TSC) associated disorders.

The phakomatoses, or ‘neuro-cutaneous disorders’, are a group of three Mendelian autosomal dominantly inherited diseases that present with phenotypes affecting multiple organ systems in affected individuals. Neuro-cutaneous disorders include for example, Neurofibromatosis (NF), Tuberous Sclerosis (TSC) and Von Hippel-Lindau (VHL). These diseases all produce both neurological and dermatological symptoms.

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome, characterized by development of distinctive benign tumors (hamartomas) and malformations (hamartias) in multiple organ systems. The brain, skin, heart, and kidneys are commonly affected. TSC lesions occurring in the skin and kidney contain smooth muscle cells, endothelial cells, adipocytes, and large neuronal appearing cells. Despite this complex cellular architecture, kidney and other lesions in TSC appear to be clonal in nature, based on clonality and loss of heterozygosity (LOH) analyses. In the brain, TSC produces both subependymal tubers that line the ventricular sacs and subcortical hamartomas which serve as foci for epileptic discharges. TSC produces cardiac rhabdomyomas in the fetus/newborn that spontaneously regress in the first year of life. TSC is also associated with renal angiomyolipomas, pulmonary symptoms, and manifestations in other organ systems. In addition, TSC is also associated with multiple dermatological features such as hypomelanotic macules, facial angiofibroma, shagreen patches, and ungual fibromas.

A better understanding of the molecular nature of this disease will provide new therapeutic tools to treat the pathologies associated with TSC complex not only in TSC patients but also in non TSC patients afflicted by similar pathologies.

The present invention is based in part on the discovery of changes in expression patterns of multiple nucleic acid sequences in cells derived from the Tsc2 knockout transgenic mice compared to the expression pattern found in cells derived from Tsc2+/− heterozygote and wild type sibling mice. These differentially expressed nucleic acids include previously undescribed sequences and nucleic acids sequences that, while previously described, have not heretofore been identified as TSC modulated.

In various aspects, the invention includes methods of diagnosing or determining susceptibility to Tuberous Sclerosis Complex (TSC) associated disorder, and methods of treating those disorders. For example, in one aspect, the invention provides a method of diagnosing determining susceptibility to a tuberous sclerosis complex associated disorder by providing a test cell population that includes one or more cells capable of expressing one or more TSC modulated nucleic acids sequences. Levels of expression of one or more sequences, termed TSCX sequences, are then compared to the levels of expression of the corresponding nucleic acids in a reference cell population. The reference cell population contains cells whose tuberous sclerosis complex associated disorder status is known, i.e., the reference cells are known to have or are known not to have a tuberous sclerosis associated disorder.

The invention in another aspect includes a method of identifying a therapeutic agent for treating a tuberous sclerosis complex associated disorder. The method includes providing from the subject a test cell population comprising a cell capable of expressing one or more TSCX nucleic acids sequences, contacting the test cell population with the therapeutic agent, and comparing the expression of the nucleic acids sequences in the test cell population to the expression of the nucleic acids sequences in a reference cell population.

The invention in a further aspect includes a method of selecting an individualized therapeutic agent appropriate for a particular subject. The method includes providing from the subject a test cell population comprising a cell capable of expressing one or more TSCX nucleic acids sequences, contacting the test cell population with the therapeutic agent, and comparing the expression of the nucleic acids sequences in the test cell population to the expression of the nucleic acids sequences in a reference cell population.

Also provided are novel nucleic acids, as well as their encoded polypeptides, which are tuberous sclerosis complex modulated.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

The present invention is based in part on the discovery of changes in expression patterns of multiple nucleic acid sequences in cells derived from the Tsc2 knockout transgenic mice compared to the expression pattern found in cells derived from Tsc2+/− heterozygote and wild type sibling mice.

The change is expression pattern was identified by GeneCalling™ analysis (U.S. Pat. No. 5,871,697; Shimkets et al., 1999 Nature Biotechnology 17:198-803, incorporated herein by reference in their entireties) of neuronal stem cell (NSC) and mouse emroyonic fibroblasts (MEF) cell lines established from 10-11 day embryos from mice of the three genotypes (i.e.)

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