Teleconference on Tuberous Sclerosis Complex (TSC) Research October 28 th, 2008 and November 11 th, 2008

Transcription

1 Wong 1 Teleconference on Tuberous Sclerosis Complex (TSC) Research October 28 th, 2008 and November 11 th, 2008 Sponsored by the Tuberous Sclerosis Alliance Faculty Participants: Elizabeth Henske, MD, Brigham and Women s Hospital, Harvard Medical School, Boston, MA Vicky Whittemore, PhD, Tuberous Sclerosis Alliance, Silver Spring, MD Michael Wong, MD, PhD, Washington University, St. Louis, MO A. Introduction 1. Acknowledgements 2. Purpose/goals of the teleconference Outline of Teleconference B. Overview of Biomedical Research (See Exhibit 1) 1. Goal of biomedical research 2. Types of biomedical research C. Clinical Manifestations and Problems in TSC (See Exhibit 2) 1. Typical tumors of TSC 2. Typical clinical symptoms of TSC 3. Typical treatments for tumors and symptoms of TSC 4. Limitations of current treatments for TSC D. Basic Research in TSC 1. Timeline of scientific discoveries in TSC (See Exhibit 3) 2. Focus on the mtor pathway (See Exhibit 4) 3. Effect of rapamycin in TSC animal models E. Clinical Trials of Rapamycin in People with TSC 1. Tumor trials 2. Neurological trials F. Questions and Answers

2 Wong 2 Goals of Biomedical Research: Exhibit 1: Overview of Biomedical Research To gain new knowledge about a human disease that can ultimately help develop treatments or a cure for the disease, or otherwise improve the lives of people affected by the disease. Types of Biomedical Research: Basic research: the study of fundamental principles of biology or medicine, usually in a reduced or simplified form ( experimental or model systems ). Examples of experimental systems in basic biomedical research include: Biochemical reactions in a test tube Cells cultured in a petri dish Computer simulations Animal models Clinical research: the direct study of patients (people with a disease). Examples of clinical research include: Epidemological studies of large populations of patients Development of new diagnostic techniques Clinical drug trials

3 Wong 3 Typical Tumors of TSC: Exhibit 2: Clinical Features and Problems of TSC Different types of tumors and other lesions can be found in various organs in TSC. The most typical types, constituting Major Features in the diagnostic criteria for TSC include: 1. Facial angiofibromas (raised red marks on the face) 2. Ungual or periungual fibroma (fibrous growths along the finger- and toenails) 3. Hypomelanotic macules (lightly pigmented spots on the skin) 4. Shagreen patch (raised, roughly-textured patches of skin) 5. Retinal nodular hamartomas (small tumors of the retina of the eye) 6. Cortical tuber (focal, abnormally-developed areas of the outer layer of the brain/cortex) 7. Subependymal nodule (small bumps along the lining of the ventricles/central cavities of the brain) 8. Subependymal giant cell astrocytoma (brain tumors that can grow in the ventricles of the brain) 9. Cardiac rhabdomyoma (heart tumors) 10. Lymphangiomyomatosis (tumor-like disease causing destruction of the lungs) 11. Renal angiomyolipoma (kidney tumors) Most patients with TSC will not have all these major features. Documentation of at least two of the above major features is sufficient for a definite diagnosis of TSC. Typical Clinical Symptoms of TSC: Symptoms in TSC are usually related to the tumors/lesions in various organs, although often the tumors can be asymptomatic: Neurological/brain: epilepsy, developmental delay, learning disabilities, behavioral problems, autism Renal/kidneys: high blood pressure, pain, bleeding Cardiac/heart: often asymptomatic; arrhythmias, heart failure/fatigue/difficulty breathing (usually in infancy) Lung: difficulty breathing (usually in adult women) Eye: often asymptomatic; visual impairment/loss Skin: lightly pigmented spots (hypopigmented macules); course, raised patches of skin (Shagreen patch); raised red bumps on face (angiofibromas); growths along the finger or toenails (periungual fibromas) Typical Treatments for Tumors and Symptoms of TSC: Removal of tumor growths in specific organs may be indicated in some situations, but in many cases asymptomatic tumors do not necessarily need to be treated and are just followed with periodic radiographic tests. There are a number of treatments available for the various symptoms of TSC; for example: medications for seizures, high blood pressure, and arrhythmias; behavioral therapy and educational adaptations for autism and learning disabilities; brain surgery for intractable epilepsy; laser therapy for facial angiofibromas. However, most currently-available treatments only improve the symptoms of TSC, but do not correct the underlying problems causing TSC and do not cure the disease. Biomedical research provides hope that more effective therapies for TSC can be developed in the future.

4 Wong 4 Exhibit 3: Timeline of Major Scientific Discoveries in TSC Late 1800 s Desire-Magloire Bourneville, a French neurologist, described clinical and pathological features of TSC based on an autopsy of a patient, and coined the term, Tuberous Sclerosis. Other researchers further studied the abnormal pathological characteristics of tumors in various organs in TSC Early 1900 s TSC is recognized as a genetic disorder, based on observation of multiple family members affected by the disease s/1980 s Invention of advanced radiographic techniques (CT and MRI scans) allows detailed imaging of tumors in living TSC patients The TSC2 gene, with its gene product, tuberin, is identified The TSC1 gene, with its gene product, hamartin, is identified Hamartin and tuberin are found to function by inhibiting the mammalian target of rapamycin (mtor) signaling pathway Rapamycin is reported to inhibit renal tumor growth in animal models of TSC Rapamycin is reported to prevent or reverse epilepsy and learning deficits in animal models of TSC Initial clinical trials in people indicate that rapamycin is effective against kidney tumor growth and pulmonary symptoms in patients with TSC. Initial clinical trials to test rapamycin for neurological symptoms in TSC are underway or in planning.

5 Exhibit 4: Focus on the mtor Pathway Wong 5