Preclinical Studies for Designing Rational Therapies for Epilepsy in Tuberous Sclerosis Complex Summit on Drug Discovery in TSC and Related Disorders Washington D.C. July 7, 2011 Michael Wong, MD, PhD Department of Neurology, Pediatrics, and Anatomy & Neurobiology Washington University School of Medicine Saint Louis, MO
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Preclinical Studies for Designing Rational Therapies for Epilepsy in Tuberous Sclerosis Complex
Preclinical Studies for Designing Rational Therapies for Epilepsy in Tuberous Sclerosis Complex Summit on Drug Discovery in TSC and Related Disorders Washington D.C. July 7, 2011. Michael Wong, MD, PhD Department of Neurology, Pediatrics, and Anatomy & Neurobiology - PowerPoint PPT Presentation
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Preclinical Studies for Designing Rational Therapies for Epilepsy in Tuberous Sclerosis Complex
Summit on Drug Discovery in TSC and Related DisordersWashington D.C.
July 7, 2011
Michael Wong, MD, PhDDepartment of Neurology, Pediatrics, and Anatomy &
NeurobiologyWashington University School of Medicine
Saint Louis, MO
Epilepsy in TSC: Clinical Features
• Epilepsy is a very common neurological manifestation of TSC, occurring in up to 90% of patients in some series (Sparagana et al., 2003; Devlin et al., 2006; Chu-Shore et al. 2009).
• Seizures are often severe and disabling, and may be multiple types.• Infantile spasms occur in about one-third of patients with TSC.• Seizures are often intractable to antiepileptic drugs. ~60-80% are
medically-refractory (Sparagana et al., 2003; Chu-Shore et al. 2009), as opposed to ~33% medical intractability rate in the general epilepsy population.
• Seizures are often not amenable to epilepsy surgery, due to multifocal nature of seizures.
• Thus, more effective treatments are needed for epilepsy in TSC, including disease-modifying or antiepileptogenic therapies.
Epileptogenesis in TSC• Circuit Abnormalities: role of tubers; disrupted circuits in “normal”
• Inactivation of Tsc1 in glia achieved with Cre-LoxP technology.• LoxP sites targeted to Tsc1 allele.• Cre recombinase linked to GFAP promoter• Crossing of GFAP-Cre with LoxP-Tsc1 mice results in inactivation
of Tsc1 gene in glia
Uhlmann et al. 2002
LF
RF
RH
LF
RF
RH
5 s
0.5 mV
Uhlmann et al. 2002
Generalized Cortical Onset
Hippocampal Onset
Tsc1GFAPCKO mice: Seizure Localization and Frequency
Erbayat-Altay et al. 2007
• Circuit Physiology (“Epileptic Network”)– “Mass” effect from astrocyte proliferation on existing
Circuit AbnormalitiesSynaptic ReorganizationLoss of Inhibitory Circuits
Epileptogenic/Ictogenicmechanisms
Rapamycin
Ceftriaxone
Early rapamycin treatment prevents glial proliferation and increased brain size in Tsc1GFAPCKO mice .
Zeng et al., 2008
Cont-Veh Cont-Rap KO-Veh KO-Rap
Early rapamycin treatment increases astrocyte Glt-1 expression of Tsc1GFAPCKO mice.
Zeng et al., 2008
Early rapamycin treatment prevents development of epilepsy and prolongs survival of Tsc1GFAPCKO mice .
Zeng et al., 2008
Late rapamycin treatment decreases seizure frequency and prolongs survival of already symptomatic Tsc1GFAPCKO mice .
Zeng et al., 2008
Clinical Implications of Mouse Epilepsy Data• Preventive, “Anti-epileptogenic” Therapy:
Early treatment with rapamycin prevented the development of epilepsy in presymptomatic mice. Since many patients are diagnosed with TSC at a young age due to non-neurological findings or due to a positive family history, and yet 90% of patients may go on to develop epilepsy, it is reasonable to consider a clinical trial testing the ability of rapamycin to prevent epilepsy in TSC patients who have never had a seizure or in patients presenting with their first seizure or with infantile spasms.
• Symptomatic, “Anti-Seizure” Therapy:Late treatment with rapamycin decreased seizure frequency in
symptomatic mice; so one could also consider using rapamycin to decrease progression of seizures in TSC patients that already have epilepsy.
Clinical trials: mTOR inhibition reduces astrocytoma growth and seizure frequency in TSC patients.
Circuit AbnormalitiesSynaptic ReorganizationLoss of Inhibitory Circuits
Epileptogenic/Ictogenicmechanisms
Feedbackinhibition
FOXOs, BAD, p27↓ apoptosis↑ cell proliferation
Dual PI3K/mTORinhibitor
Dual PI3K/mTORinhibitor
Conclusions• The mTOR pathway is critical for epileptogenesis in mouse models of
TSC and mTOR inhibitors may have both early antiepileptogenic and late symptomatic effects on epilepsy in TSC.
• Modulation of downstream mechanisms of epileptogenesis, such as astrocyte glutamate transporters, may also have some, more limited, effectiveness for epilepsy, but could have fewer side effects .
• Future therapies for epilepsy can continue to be designed with better, more selective efficacy and few side effects, based on rationally targeting different mechanistic levels of epileptogenesis.
Wong LabEbru Erbayat-AltayVered GazitLaura JansenYannan OuyangNicholas RensingLin XuLinghui ZengBo Zhang
David Gutmann Kevin EssErik Uhlmann
David HoltzmanJohn CirritoAdam Bero
SupportNINDS/NIH K02 NS045583NINDS/NIH R01 NS056872 Tuberous Sclerosis Alliance Citizens United for Research in Epilepsy (CURE)McDonnell Center