tuberous sclerosis - orrin devinsky, md

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Tuberous Sclerosis: Update in Diagnosis and Treatment


1. Tuberous Sclerosis Complex: From Genes to Therapeutics Orrin Devinsky, MD NYU Tuberous Sclerosis & Epilepsy Centers 2. TSC Facts ~1 in 6,000 live births ~1 in 9,000 in the general population ~50,000 Americans have TSC >1 million worldwide Neurological manifestations often most devastating affecting almost all individuals with TSC in some manner, from mild to severe 3. Remarkable Progress TSC1 and TSC2 genes identified -1990s TSC1/2 complex in cell growth, cell size and proliferation discovered - 2002 Uncovering role of TSC1/2 complex in regulating mTOR First clinical trial in 2005 Approval of first treatment specifically for TSC in 2010 (Everolimus (Affinitor)) 4. Data from TS Alliance, CDMRP and NIH 5. Data derived from PubMed at 6. Data derived from PubMed at 7. NIH Funding for mTOR Research 8. Where are we now? From bedside to bench and back to bedside All components of TSC research are still critical to progress Basic research signaling pathway, roles of mTORC1 and mTORC2, how specific gene mutations lead to specific manifestations of disease Translational research identifying new drug targets, testing new compounds, drugs and combination therapies in animal models of TSC Clinical research moving basic and translational research findings into clinical studies and clinical trials 9. Genetics of TSC Mutations in TSC1 and TSC2 genes found in ~85% of individuals with clinical diagnosis of TSC No mutation identified in 10% to 20% of individuals with TSC ?New gene ?Regulatory DNA outside of exome Mosaicism is not the answer 10. Function of TSC1/2 Genes Drosophila (Fruit Fly) provided first clues to function of TSC1/2 in regulation of cell growth and cell size Pointed to involvement in regulation of mTOR 11. mTOR Signaling Pathway TSC1 mTOR mTOR = m ammalian T arget o f R apamycin TSC2 12. mTOR Signaling Pathway mTOR Rheb TSC2 TSC1 13. mTOR Signaling Pathway mTORC1 Rheb mTORC2 Sirolimus (Rapamycin) Temsirolimus (CCI-779) Everolimus (Afinitor) TSC1 TSC2 14. mTOR Pathway RTK PIP2 PIP3 AMP Energy Stress Serum Nutrient Hypoxia Actin Organization mTORC1 mTORC2 Translation off 40S Scanning Akt/PKB Translation On Secondary Structure Unwinding VEGF Pathway Akt Signaling PMA PC PA DAG AUG AUG C Rictor 4EBP G L TSC2 Raptor AMPK DGK PI3K Redd1 eIF4B eIF3 PKC p70S6K mTOR eIF4G eIF4A eIF4E Rheb eIF3 eIF4B eIF4G eIF4A eIF4E eIF4B G L mTOR eIF4E 4EBP VEGF eIF4G eIF4A eIF4E Growth Factors Insulin Receptor P PDK-1 40S RPS6 TSC1 PP2A FKBP12 Rho HIF1 PKC Rac PLD PKC LKB1 Akt Ras RSK MAPK IRS1 Insulin 2009 15. Rapamycin Prevents and Treats Epilepsy in a Mouse Model of Tuberous Sclerosis Complex Early treatment with rapamycin prevented the development of epilepsy and premature death Tsc1(GFAP)CKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1(GFAP)CKO mice that had already developed epilepsy. Rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1(GFAP)CKO mice. Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1(GFAP)CKO mice. International, multicenter Phase 3 clinical trial being planned by Novartis Oncology. Zeng, Xu, Gutmann, Wong (2008) Ann Neurol63:444453 16. Anti-epileptogenesis in TSC Referral of all infants with cardiac rhabdomyomas or TSC at birth Monthly EEG and monitoring Treat with vigabatrin when first identify abnormal EEG (prior to first clinical seizure) Significantly reduced incidence of infantile spasms Seizures that do occur are not refractory Significantly improved cognitive outcomes Do we need to shift our mindset to preventing seizures rather than trying to treat them once they manifest? In other words, should all individuals with TSC receive an EEG at diagnosis and at follow-up? Should we treat the EEG and not wait for clinical seizures to appear? NINDS to issue RFP for anti-epileptogenesis Center Without Walls in 2012 Unpublished observations, Sergiusz Jozwiak, MD, PhD, Warsaw, Poland 17. Distribution of IQ in TSC 20 100 Global Intellectual Ability (IQ) in TSC Normal Distribution (ND) TSC phenotype Profound (P) TSC phenotype 70 Normal distribution in the general population Prather & de Vries, JCN 2004, de Vries & Prather, NEJM, 2007 18. Reversal of Learning Deficits in a Tsc2+/ Mouse Model of Tuberous Sclerosis Deficits observed in learning in mouse model of TSC. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Brief treatment with the mTOR inhibitor rapamycin in adult mice rescues the behavioral deficits in this animal model of TSC. Results reveal a biological basis for some of the cognitive deficits associated with TSC, and treatment with mTOR inhibitors ameliorates cognitive dysfunction in a mouse model of TSC. Neurocognitive clinical trial starting to recruit study participants in Boston (and Cincinnati once IRB approved); PIs: Mustafa Sahin, MD, PhD, Petrus de Vries, MD, PhD, and David Franz, MD; funded by Novartis Oncology, TS Alliance and Autism Speaks. Ehninger, Han, Shilyansky, Zhou, Li, Kwiatkowski, Ramesh, Silva (2008) Nature Medicine 14(8):843-8 19. Afinitor Approved to Treat SEGA Associated with TSC First medication approved specifically to treat individuals with TSC. Afinitor received conditional approval by FDA on October 29, 2010 for treatment of SEGA associated with TSC At least 30% reduction in size of SEGA in 21 patients (75%) At least 50% reduction in size of SEGA in 9 patients (32%) Marked reductions were seen within 3 months and were sustained In 16 patients who had 24-hour video EEG, seizure frequency decreased in 9 patients, did not change in 6, and increased in 1 patient Krueger et al (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363(19):1801-11 20. Axial T1 +C Axial T1 +C MRI after treatment MRI prior to treatment 21. Rapamycin Afinitor O O O H O O O N O O O O O H O H O O O O H O O O N O O O O O O H O O H Chemical Structure Rapamycin and Everolimus (Afinitor ) 22. VEGF-D Assay V ascular e ndothelial g rowth f actor D (VEGF-D) promotes the growth of blood vessels and lymphatic vessels in the body Elevated in blood of ~70% of women with sporadic lymphangioleiomyomatosis (LAM) and almost all women with TSC + LAM* Used as a diagnostic test for LAM in women with cystic lung disease Increased levels may also correlate with growing renal AMLs in individuals with TSC (and sporadic-LAM??) Further research needed before understand utility in individuals with TSC *Young et al, Chest 2010; 138:674-681 23. Additional Clinical Trials Topical Rapamycin to Treat Facial Angiofibromas; PI: Mary Kay Koenig, MD, University of Texas- Houston; funded by TSCRP Treatment of Renal AMLs and LAM Using Ultrasound-Guided MRI; PI: John Bissler, MD, Cincinnati Childrens Hospital; funded by TS Alliance Rothberg Courage Award VEGF-D as a Biomarker for TSC and LAM 24. TSC Drug Screening Program Goal: To screen potential new compounds and FDA-approved drugs for treatment of TSC Awarded two grants in 2010 Program to be continued and expanded Use to leverage funding for translational studies at NIH and/or clinical trials 25. TSC Natural History Database Project 1,050 study participants now enrolled at 15 sites in the USA and 1 in Belgium First publication including data from database published in 2010 Several additional studies underway Utilized to identify study participants for clinical trials NYU will be analyzing seizure data 26. TSC Research at NYU 25 peer-reviewed papers Pioneered multistage surgery in TSC Recruitment of Delia Talos, MD from Harvard to expand research on human tissue and examine animal models Studies of tuber v. perituberal tissue Stu


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