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Emerging Treatment Strategies for Tuberous Sclerosis Complex

Emerging Treatment Strategies for Tuberous Sclerosis Complex. David Neal Franz, MD Director, Tuberous Sclerosis Clinic Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio. Goals.

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Emerging Treatment Strategies for Tuberous Sclerosis Complex

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  1. Emerging Treatment Strategies for Tuberous Sclerosis Complex David Neal Franz, MD Director, Tuberous Sclerosis ClinicCincinnati Children’s Hospital Medical CenterCincinnati, Ohio

  2. Goals • Describe the manifestations of tuberous sclerosis complex (TSC) in various organ systems and the most frequent causes of neurologic, renal, and pulmonary morbidity and mortality • Review the molecular pathophysiology of TSC and how this forms the basis for novel therapeutic approaches • Compare the rationale and initial clinical trial evidence for emerging treatment approaches for TSC • Summarize ongoing clinical trials evaluating treatment approaches for TSC, including the goals of the trials, patient eligibility criteria, and other key factors

  3. Clinical Manifestations of TSC • Brain: cortical tubers, subependymal nodules, subependymal giant cell astrocytomas • Eye: retinal hamartomas • Heart: cardiac rhabdomyomas • Kidney: benign angiomyolipomas, cysts, malignant angiomyolipomas, renal cell carcinoma • Lung: lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia • Skin: hypomelanotic macules, shagreen patches, periungual or subungual fibromas, facial angiofibromas • Behavior: mental retardation, autism, bipolar disorder Pan D, et al. Trends Cell Biol. 2004;14:78-85.

  4. Clinical Diagnostic Criteria Roach ES, Sparagana SP. J Child Neurol. 2004;19:643-649.

  5. TSC: Onset of Symptoms

  6. Hypopigmented Macule and Shagreen Patch

  7. Facial Angiofibroma

  8. Periungual Fibroma

  9. Dental Pits and Gingival Fibromas

  10. Retinal Hamartomas and Achromic Patches

  11. Cardiac Rhabdomyoma

  12. Lymphangioleiomyomatosis (LAM)

  13. Renal Angiomyolipoma and Renal Cysts

  14. Angiomyolipoma

  15. Cerebral Manifestations of TSC

  16. Cortical Tuber

  17. Subependymal Nodules

  18. Neurologic/Behavioral Manifestations • Seizures (90%) • Mental retardation and learning difficulties (60%-70%) • Sleep disorders (60%) • Autism and behavioral difficulties (30%-50%) • Subependymal giant cell astrocytoma (15%-20%)

  19. Seizures, Infantile Spasms, and Cognitive Outcome • Infantile spasms correlated with increased risk for poor neurologic outcomea aO’Callaghan FJ, et al. Arch Dis Child. 2004;89:530-533. b Goh S, et al. Neurology. 2005;65:235-238.

  20. Infantile Spasms in TSC • Vigabatrin is the treatment of choice in TSC • Risk for adverse effect on peripheral vision • As high as 95% response rate in TSCa • Steroids are second-line treatment (adrenocorticotropic hormone or oral prednisone) • Valproate, topiramate, clonazepam minimally effective as single agents but may have beneficial adjunctive use aHancock EC, Osborne JP. J Child Neurol. 1999;14:71-74.

  21. Epilepsy in TSC • About 90% of patients with TSC experience seizures • Virtually all seizure types have been reported (simple partial, complex partial, generalized tonic-clonic, absence) • Aggressive treatment is necessary to reduce risk for negative neurologic outcome (development, cognition, behavior)

  22. Surgical Outcome of Epilepsy Surgery in TSC • Outcome (Engel’s classification): • Class I (seizure free): 37/69 • Class II (some seizures): 8/69 • Class III (> 90% reduction): 13/69 • Class IV (< 90% reduction): 12/69 Connolly M, et al. Child Nerv Syst. 2006;22:896-908. Madhavan D, et al. Epilepsia. 2007;48:1625-1628.

  23. Sleep Problems in TSC • Survey of 300 TSC patients (age 0.5-74 years): • 58% with sleep problems in general • Survey of 40 pediatric TSC patients (age 2-15 yrs): Hunt A . J Intellectual Disability Res. 1993;37:41-51. Hunt A , Stores G. Dev Med Child Neurol. 1994;36:108-115.

  24. Subependymal Giant Cell Astrocytoma (SEGA)

  25. Acute Hydrocephalus With SEGA

  26. Serial Monitoring for SEGA

  27. Traditional Surgical Resection of SEGA

  28. Stereotactic Angioplasty Balloon Technique Levine NB, et al. Minim Invasive Neurosurg. 2006;49:317-320.

  29. PKD1 TSC2 (60%-70%) TSC1 (15%-20%) Genetics of TSC Autosomal dominant Near 100% penetrance Variable expression No Mutation Identified (10%-15%) 9 16

  30. TSC1/TSC2 and mTORC1

  31. H O O H O O O O O O H O O O H N N O O O O O O O O O O O H O H O O O O Rapamycin and Everolimus (RAD001) Rapamycin (sirolimus) RAD001 (everolimus)

  32. Everolimus and Sirolimus Comparison of Properties *Varies with formulation, dose, and co-medications. Everolimus has greater bioavailability than sirolimus. **Ratio of drug in blood (ng/mL) and brain (ng/g) following 6 days oral dosing at 3 mg/kg in rats.f a RAD001 Investigators Brochure (6th ed). b Buech G, et al. J Ocul Pharmacol Ther. 2007;23:292. c Formica RN, et al. Transplant Proc. 2004;36(Suppl 25S):495S-499S. d Brattstrom C, et al. Ther Drug Monit. 2000;22:537-544.5. e Kahan BD, et al. Transplantation. 1991;52:185-191. f Serkova N, et al. Br J Pharmacol. 2001;133:875-885.

  33. Rapamycin for Treatment of Angiomyolipoma A B Bissler JJ, et al. N Engl J Med. 2008;358:140-151.

  34. Rapamycin Effect on LAM Bissler JJ, McCormack FX, Young LR, et al. N Engl J Med. 2008;358:140-151.

  35. Rapamycin for the Treatment of SEGA Franz DN, et al. Ann Neurol. 2006;59:490-498.

  36. Everolimus Effect on SEGA in TSC Baseline 6 months RAD001

  37. Cerebellar Tuber Growth

  38. Cerebellar Tuber Before and After Treatment With Rapamycin

  39. RAD001 Effect on SEGA Volume

  40. Angiomyolipoma Before and After Treatment Before Treatment Everolimus x 3 months

  41. Chylothorax in LAM

  42. Current Clinical Trials Related to TSC • EXIST-1: Efficacy and Safety of RAD001 in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC) • EXIST-2: Efficacy and Safety of RAD001 in Patients 18 Years and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) • MILES: Efficacy and Safety of Rapamycin in Patients with Tuberous Sclerosis Complex Lymphangioleiomyomatosis (TSC-LAM) or Sporadic Lymphangioleiomyomatosis (S-LAM) • Long-term Follow-Up for RAD001 Therapy of Angiomyolipomata in Patients With Tuberous Sclerosis Complex (TSC) and Sporadic Lymphangioleiomyomatosis (LAM) • Long-term Follow-Up for RAD001 Therapy of Subependymal Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex (TSC)

  43. Current Clinical Trials Related to TSC (cont) • Efficacy and Safety of Aromatase Inhibition for Tuberous Sclerosis Complex Lymphangioleiomyomatosis (TSC-LAM) or Sporadic Lymphangioleiomyomatosis (S-LAM) • Study of Skin Tumors in Tuberous Sclerosis • Tuberous Sclerosis Complex Natural History Study: Renal Manifestations • Study of the Disease Process of Lymphangioleiomyomatosis • Effect of Fasting on the Size of Abdominal Lymphatic Tumors in Women • Role of Genetic Factors in the Development of Lung Disease

  44. Summary • Tuberous sclerosis is a multiorgan disorder with variable penetrance and severity • Highest disease morbidity is associated with cerebral, renal, and pulmonary manifestations • Molecular-based therapies using mTOR inhibitors are showing promise in treating patients with TSC

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