Tuberous Sclerosis - Orrin Devinsky, MD
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Tuberous Sclerosis Complex: From Genes to Therapeutics
Orrin Devinsky, MDNYU Tuberous Sclerosis & Epilepsy
Centers
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
Remarkable Progress
TSC1 and TSC2 genes identified -1990’s
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))
Data from TS Alliance, CDMRP and NIH
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Number
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Year
TSC Publications
TSC
Data derived from PubMed at http://www.ncbi.nlm.nih.gov/pubmed/
TSC and mTOR Publications
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1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Years
TSC
mTOR
Data derived from PubMed at http://www.ncbi.nlm.nih.gov/pubmed
NIH Funding for mTOR Research
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2000 2010
Number of Projects
Number of Projects
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50000000
100000000
150000000
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2000 2010
Total Funding
Total Funding
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
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
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
TSC1
mTOR
mTOR Signaling Pathway
mTOR = mammalian Target of Rapamycin
TSC2
mTOR
mTOR Signaling Pathway
Rheb
TSC2TSC1
mTORC1
mTOR Signaling Pathway
Rheb
mTORC2
Sirolimus (Rapamycin)Temsirolimus (CCI-779)Everolimus (Afinitor®)
TSC1 TSC2
mTOR Pathway
RTK
Rictor
4EBP
GβL
TSC2
Raptor
AMPK
DGKξ
PI3K
Redd1
eIF4B
eIF3
PIP2PIP3
PKC
p70S6KmTOR
AMP
eIF4GeIF4A
eIF4ERheb
eIF3
eIF4B
eIF4GeIF4A
eIF4EeIF4B
GβLmTOR
eIF4E 4EBPVEGF
eIF4GeIF4AeIF4E
Growth Factors
Insulin Insulin ReceptorReceptorInsulin Insulin
ReceptorReceptor
Energy Energy StressStressSerumSerum NutrientNutrient
HypoxiaHypoxia
Actin Organization
P
PDK-1
mTORC1mTORC1
mTORC2mTORC2
Translation off
40SRPS6
40S
Scanning
Akt/PKB
Translation On
SecondaryStructure
Unwinding
TSC1
PP2A
FKBP12
Rho
HIF1α
VEGFPathway
VEGFPathway
Akt SignalingAkt Signaling
PKC
Rac
PMA
PLD
PKCα
PC
LKB1
Akt
PA
DAG
AUG
Ras
RSK
AUG
MAPK
IRS1
InsulinInsulin 2009ProteinLounge.com 2009ProteinLounge.com
C
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 Neurol63:444–453
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
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
Distribution of IQ in TSC
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
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
Axial T1 Axial T1 +C+C
Axial T1 +CAxial T1 +C
MRI after treatmentMRI after treatmentMRI prior to treatmentMRI prior to treatment
Rapamycin Afinitor®
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N
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O O
OH
OH
O
O O OH
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N
OO
O O
O
OH
O
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Chemical StructureRapamycin and Everolimus (Afinitor®)
VEGF-D Assay
Vascular endothelial growth factor 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
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 Children’s Hospital; funded by TS Alliance Rothberg Courage Award
VEGF-D as a Biomarker for TSC and LAM
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
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
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 Studies of neuroinflammation, mTOR pathway, excitatory neurotransmitters
Animal models of epilepsy & SUDEP in TSC
High field (7T) imaging
Pros High resolution images (excellent
T1 contrast) T2* (T2 star)- excellent
delineation of venous structures, calcifications, blood products
Neg Field inhomogeneities Sensitivity to air/artifacts Long sequences for high
resolution Research magnet, no implants
Human Studies – NYU TSC Ctr
Biopsy tissue from epilepsy surgery cases Immunocytochemical and western blot
analysis (neuroinflammation markers and synaptic proteins)
Standard extracellular and whole-cell patch clamp techniques (LTP/LTD, AMPA/NMDA)
Ex vivo pharmacologic studies
Vimentin/DAPI Vimentin/DAPIVeronique RuppePelin Dilsiz
Cellular Abnormalities in Human TSC
TUBER PERI-TUBER
Altered mTORC1 signaling in human cortical tubers
Veronique RuppePelin Dilsiz
SMI 311/pS6/DAPI Vimentin/pS6/DAPI
Altered mTORC1 signaling in human peri-tuberal cortex
Veronique RuppePelin Dilsiz
SMI 311/pS6/DAPI Vimentin/pS6/DAPI
Animal Model Studies – NYU TSC Ctr
Time course experiments Early life inflammatory /seizure challenge Treatment efficacy
Seizures
Natural history of epilepsy in TSC mouse model
P7 P14
1 month 3 monthsP21
Brain collection
Epidural electrode implantation
Long term video EEG monitoringVideo EEG monitoring at intervals
Repeated subcutaneous electrode placements
Brain collection
Brain collection
Brain collection
Seizures
Early treatment
P7 P14
1 month 3 monthsP21
Epidural electrode implantation
Long term video EEG monitoring
Brain collection
Brain collection
Brain collection
Daily anti-inflammatory drug treatment
Seizures
Late treatments of epilepsy
P14
1 month 2 monthsP21
Epidural electrode implantation
Long term video EEG monitoring
Brain collection
Brain collection
2. Anti-inflammatory drug
1.5 month
1. Conventional AED
3. Combination treatment
Conclusions New research on
genetics of TSC Important to support
basic, translational and clinical research
Bedside to bench to bedside important!
TSC Natural History Database Project
TSC Drug Screening Program
Expanded research and clinical program for TSC at NYU
Dr. Jim Riviello to become new NYU TSC Director
Questions?
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