What I know best: Tuberous Sclerosis Complex

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1 What I know best: Tuberous Sclerosis Complex Prof Petrus de Vries Sue Struengmann Professor of Child & Adolescent Psychiatry University of Cape Town South Africa

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4 Red Cross War Memorial Children s Hospital, Cape Town

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6 Conflicts of interest Study Steering Group for EXIST-1, EXIST-2 and EXIST-3 trials funded by Novartis Co-PI on 2 phase II studies part-funded by Novartis Advisory Board Member/Working Committee of TOSCA Registry, funded by Novatis All honoraria received donated to SSBP, BDT or Universities of Cambridge/Cape Town

7 Outline Update on TSC Current status of clinical trials of mtor inhibitors Revised Diagnostic Criteria Revised Surveillance and monitoring guidelines TSC-Associated Neuropsychiatric Disorders (TAND)

8 Tuberous Sclerosis Complex (TSC)

9 Tuberous Sclerosis Complex (TSC) Bourneville, 1880 & 1881 Archives of Neurology Paris Encephalite ou sclerose tubereuse des circonvolutions cerebrales

10 Rayer s Atlas. 1835

11 Tuberous Sclerosis Complex (TSC) Incidence 1:6, million people worldwide 70% sporadic cases 30% familial (autosomal dominant) M=F Multi-system genetic disorder

12 TSC: a multi-system genetic disorder - skin Facial angiofibroma Shagreen patch White patches Ungual fibromas

13 2+ 3+

14 TSC: a multi-system genetic disorder other organ systems Eye lesions Eye mulberry lesions, achromic patches, other Heart cardiac rhabdomyomas; Wolff Parkinson White Renal angiomyolipomas(aml), cysts, polycystic kidneys Lung lymphangioleiomyomatosis(lam)

15 Krueger et al 2013

16 TSC: a multi-system genetic disorder brain Cortical tubers (CT) Subependymal nodules (SEN) Subependymal giant cell astrocytoma (SEGA)

17 Krueger et al 2013

18 GROUP T UBER DENSI T Y low high high low TSC: a multi-system genetic disorder - brain Widespread white and grey matter deficits over and above CT, SEN, SEGA Ridler et al, 2001, 2004, 2007

19 Age-related expression of manifestations in Tuberous Sclerosis Complex Curatolo et al., Lancet, 2008

20 The genetics of TSC TSC is caused by mutations in one of two genes -TSC1(9q34) or TSC2 (16p13.3) Multiple mutation types and locations have been identified Northrup et al, JCN, 2004 Curatolo et al 2008

21 The TSC1 and TSC2 proteins are multicomponent proteins Serfontein et al., Beh Genet, 2011

22 TSC1 (hamartin) and TSC2 (tuberin) act as an intracellular complex

23 TSC1 and TSC2 act as a molecular switchboard mutations lead to mtor overactivation

24 Knowledge of the molecular mechanisms has helped to understand the physical features of TSC Crino et al, NEJM, 2006 and has led to clinical trials of molecularly targeted treatments

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26 Rapamycinis an mtor inhibitor

27 Rapamycinreduces size of AMLs in kidney In animal modelsof TSC In humanswith TSC AML and LAM (Phase II) USA -Bissler et al., NEJM, 2008 UK -Davies et al., NEJM, 2008 UK Davies et al., CCR, 2011

28 Bissleret al., Lancet, 2013

29 Rapamycinreduces the size of SEGA in the brain Franz et al., 2006, Krueger et al., 2010

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31 Franz, et al., Lancet, 2013

32 Rapamycinalso reduces facial angiofibromas Hofbauer et al, 2008

33 The Neuropsychiatry of TSC I: Behavioural level II: Psychiatric level III: Global Intellectual Abilities IV: Academic/Scholastic Skills V: Neuropsychological level VI: Psycho-social VII: Biological

34 Behavioural and Psychiatric Behavioural level: Very high rates of a range of behavioural abnormalities Psychiatric level: Very high rates of ADHD (>50%) Very high rates of depressive and anxiety disorders in adults Very high rates of Autism spectrum disorders (25% autism + 25% ASD) 1-4% of autism is attributable to TSC TSC is therefore one of the medical conditions MOST HIGHLY associated with autism Bolton et al, 2002; Prather & de Vries, 2004; de Vries et al, 2005; de Vries et al, 2007

35 Intellectual Ability Normal distribution in the general population de Vries & Prather, 2007

36 Intellectual Ability Normal Distribution (ND) TSC phenotype 70% Normal distribution in the general population de Vries & Prather, 2007

37 Intellectual Ability Profound (P) TSC phenotype Normal Distribution (ND) TSC phenotype 30% 70% Normal distribution in the general population de Vries & Prather, 2007

38 Academic or scholastic skills Reading, writing, spelling, mathematics Very limited direct data in TSC Rating scale measures by parents suggest 36% of school-aged children with normal IQ are at high risk of significant scholastic difficulties

39 Neuropsychological Deficits in TSC The majority of individuals with TSC have some neuropsychological deficits, including those with Normal Intellectual Ability Verbal and Spatial Memory (Recall, not recognition) Executive skills (planning, set-shifting) Attentional skills (particularly dual-tasking) Visuo-constructional skills

40 Psycho-social level Self-esteem Psychological impact of the disorder Self-efficacy Family Stressors Resilience Factors

41 TSC-Associated Neuropsychiatric Disorders (TAND) Together, almost 90% of people with TSC will have some TSC-associated neuropsychiatric disorder Fewer than 20% ever receive appropriate assessment and/or treatment

42 What are the mechanisms for the neuropsychiatric features in TSC? TSC mutation Cortical Tubers? Neurocognitive deficits Seizures? direct molecular route

43 CNS energy sensing and regulation & astrocyte morphology LTP and synaptic plasticity ERK1/2 p38mapk PI3K LKB1 AMPK REDD1? MK2 TSC2- TSC1 Akt GSK3β PTEN myelination CDK1 Rheb Rac1 Rho Actin cytoskeleton Forebrain development mtor Rapamycin eif4e 4E-BP1 S6K1 Cell Growth & Proliferation de Vries & Howe, TIMM, 2007

44 Tsc1 +/- mouse Utrecht No structural brain abnormalities, no seizures Significant spatial learning deficits Significant socialisation deficits Probe day 9 wt Tsc1 +/- Goorden et al, Ann Neurol, 2007

45 Tsc2 +/- mouse UCLA No seizures No structural lesions in brain Significant spatial learning deficits No socialisation deficits Ehninger et al, NMed, 2008

46 TSC2 +/- mice Learning Deficits Rapamycin IP for 5 days Learning deficits reversed to be similar to WT mice Ehningeret al, N Med, 2008

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48 Autism-related behavioursreversed by intraperitonealrapamycin Tsai et al, Nature, 2012

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50 RapamycinPhase II trial (TESSTAL -UK) Open label, multi-centre trial Efficacy and safety Rapamycin(Sirolimus) TSC AML + LAM Selected measures of memory Baseline, 4 months, 12 months Measures selected with parallel versions (reduce practice effects) Neuropsychologist blind to patient status and to hypothesis (reduce expectance effects) Control tasks (recognition) Davies, de Vries et al., CCR 2011

51 Experimental task Control task Improvement in immediate recall memory scores in 7/8 subjects after 12 months on Rapamycin (between 0.5SD and 3SD change) No improvement in recognition memory after 12 months

52 Experimental task Control task Improvement in immediate recall memory scores in 7/8 subjects after 12 months on Rapamycin (between 0.5SD and 3SD change) No improvement in recognition memory after 12 months 4 improved by >1SD

53 Current Status SEGA: Phase III trial completed; Everolimuslicencedby FDA and EMA for SEGA not amenable to surgery Angiomyolipoma: Phase III trial completed; FDA and EMA approved for AML>3cm; 2012 International consensus panel recommended mtorinhibitor as 1 st line treatment for AML>3cm Skin: Phase III trial underway for topical preparation Neuropsychiatric: 2 xphase II trials underway Epilepsy: Phase III underway

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55 Diagnostic Criteria (revised from Roach et al 1998) Roach et al 1998 Krueger et al 2013 Definite/Probable/Possible Definite/Possible Genetic test results Quantification (3+FA or fibrous plaque, 3+HM >0.5cm; 2+UF) Terminology Cortical dysplasias(include CT and migration lines) Angiomyolipomas(2+) Minor features (Rationalization; removal of bone cysts)

56 Baseline evaluations 2013 Krueger et al., Ped Neurol 2013

57 Ongoing monitoring 2013

58 Conclusion TSC has great variability of features Age-related expression of physical features and TAND Revised diagnostic criteria Revised monitoring guidelines mtor inhibitors FDA and EMA approved Global efforts to improve knowledge and treatment for those who live with TSC

59 Europe: Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany,Greece, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom Australasia: Australia Asia: China, Israel, Korea, Taiwan, Thailand, Turkey Eurasia: Russia Africa: South Africa

60 Unanswered Questions: variability Possible predictors of response variability: Pharmacological: dose, duration, trough levels, compliance Molecular: functional consequences of mutations on mtor activation status

61 Bissler et al Lancet 2013

62 Franz et al Lancet2013

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68 Acknowledgements Cambridge: Christopher Howe Jaco Serfontein Kevin Tierney Howard Wong Anna Whiteley Birmingham: Deborah McCartney Cardiff: Julian Sampson TESSTAL and TRON Trial Groups Cape Town: Rehana Effendi Loren Leclezio Heidelberg: Robert Waltereit Bonn: Dan Ehninger UCLA: Alcino Silva Boston: Mustafa Sahin and team Cincinnatti: David Franz Darcy Krueger Anna Byars Funding: TSA, TSAlliance, Autism Speaks, Novartis, UCT, Struengmann Fund