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Disease Modification in Epilepsy
Asla Pitkänen, MD, PhDEpilepsy Research Laboratory
A.I.Virtanen Institute for Molecular SciencesUniversity of Eastern Finland (UEF),
Kuopio, FinlandEmail: [email protected]
Content
1. Terminology
2. From Concepts to Study Designs to ProofofPrinciple Experiments
3. The Next Step
Epileptogenesis
Recurrent seizures(epilepsy)insult
epileptogenesis
The development and extension of tissue capable of generating
spontaneous seizures, including
• Development of an epileptic condition
• Progression after the condition is established
NINDS Workshop 8/2010; Pitkänen, Epilepsia 2010:51(Suppl 3):217
Disease or Syndrome Modification
Recurrent seizures(epilepsy)insult
antiepileptogenesis
comorbidity modification
Comorbidity 1
Comorbidity 2
Treatment Treatment
A process that alters the development or progressionof a “disease”
• antiepileptogenesis• comorbidity modification• reversal of pathology (related to either one)
NINDS Workshop 8/2010; Pitkänen, Epilepsia 2010:51(Suppl 3):217
Disease Modifying Treatment (DMT)
DefinitionA treatment or intervention that affects the underlyingpathophysiology of the disease and has a beneficial effecton clinical outcome (natural history)
•finite period of therapy•prevention of signs and symptoms even after
therapy withdrawal
Fox et al., Headache 2008: 48:11691175; Cummings et al. Alzheimer’s and Dementia 2009:5:406418
Elements Required to Establish Disease Modification
Modified from Cummings et al. Alzheimer’s and Dementia 2009:5:406418
DiseaseModification
Sz ReductionCircuitry
Normalization
Clinical TrialOutcome
BiomarkerOutcome
Correlation Between Clinicaland Biomarker Outcome
Symptomatictreatment (AED)
Diseasemodifyingtreatment (DMT)
Baseline
Ictogenicnetwork
Suppressedictogenicnetwork
Repairedictogenicnetwork
Symptomatic vs. DiseaseModifying
Disease Modifying Treatment (DMT) in Epilepsy
Study Design Scenario
•Disease modifying treatment (DMT) is NOT antiepileptic
•Administration of treatment•before epilepsy onset
•genetic•acquired
•after epilepsy onset•animals with frequent spontaneous seizures•patients with frequent seizures
DMT Outcome Measures
Experimental Studies Clinical Studies
Clinical OutcomePrevention of epilepsy (yes/no) Yes
Time to 1st seizure Yes
Seizure frequency Yes
Progression in seizure frequency Yes
Seizure duration Yes
Behavioral severity of seizures Yes
Therapy resistance Yes
Seizure threshold (?) No
BiomarkerBiochemistry, imaging, cognitive testing,behavior, motor function
Yes
DMT notantiepileptic
If AEDcotreatmentunchanged
Seizuremodification
DMT
Placebo
Study Design DMT Before Epilepsy Onset
Ictogenicnetwork to
be developed
Comorbiditynetwork to
be developed
TBIIctogenicnetwork
neverdevelops
Ictogenicnetwork
Paradiso et al. PNAS 2009:106(17):71917196; Bovolenta et al., Neuroinflammation 2010:7:8186; Paradiso et al., Epilepsia 2011: 52(3):5728
PilocarpineSE in rat vEEG for 20d
•neuroprotection
DMT Before Epilepsy OnsetReversal of Circuitry Alterations BDNF + FGF2 Gene Therapy
Unilateral HCvirus injection
Network Outcome 28 d postSEClinical outcome –Sz Frequency
Co Empty Vector
•normalization of neurogenesis•inflammation ò•mossy fiber sproutingò
Recent "12 ProofofPrinciple Success Stories“DMT Before Epilepsy Onset
Pitkänen, Epilepsia 2010:51(suppl. 3):217 Pitkänen and Lukasiuk Lancet Neurology 2011:10(2):17386; Pitkänen et al., Neurosci Lett, in press
1. Atipamezole α2adrenergic receptor (Pitkänen et al., 2004)2. Levetiracetam SVA2 (Yan et al., 2005)3. Celecoxib COX2 inhibition (Jung et al., 2006)4. Rapamycin mTOR inhibition (Zeng et al., 2008)5. 4 integrinspecific mAb integrin alpha4 (Fabene et al., 2008)6. Erythropoietin erythropoietin receptor (Chu et al., 2008)7. Ethosuximide Ttype Cachannels (Blumenfeld et al., 2008)8. BDNF+FGF2 FGF and NTRAK2 (Paradiso et al., 2009)9. Rimonabant CB1 receptor (Echegoyen et al., 2009)10. Parecoxib COX2 inhibition (Polascheck et al., 2010)11. Minozac cytokine productionò (Chrzaszcz et al., 2010)12. Hypothermia (Atkins et al., 2010)
No anticonvulsant effect
Study Design DMT After Epilepsy Onset
DMT
Placebo
Ictogenicnetworkrepaired
Ictogenicnetwork
Ictogenicnetwork(w/AEDs)
AEDs reduced
DMT After Epilepsy OnsetHumans
Patients withfrequentseizures
(on AEDs)
OUTCOMEDMT discontinued
Szò
Szò onlyif DMT
continued
Reintroduction of DMT
Nonresponders
Responders
DMT
Placebo
DMT
No antiepilepticeffect in
preclinicaltesting
Biomarkeranalysis(MRI)
Clinicalresponse
100%Baseline
Responders
Cure
AEDsòDMTò
TemporaryResponders
DMT After Epilepsy OnsetHumans
Seizurefrequency
AEDs reduced
OUTCOMEDMT discontinued
Szò
Szò onlyif DMT
continued
Reintroduction of DMT
Nonresponders
Responders
DMT
Placebo
DMT
DMT After Epilepsy OnsetSpontaneously Seizing Animals
Patients withfrequentseizures
(on AEDs)
DMT After Epilepsy OnsetReversal of Circuitry Alterations mTOR Inhibition
Everolimus Rapamycin
Krueger et al., N Engl J Med 2010::363(19):180111
No evidence in acquiredmodels
Zeng et al. Ann Neurol 2008:63:444453
Zeng et al. Ann Neurol 2008:63:444453
KO+Veh KO+Rap
Next Step
Understanding the Network Change and ItsMolecular Basis In “Each Epilepsy Type”
SETBI
TBIsham SE
… they all look the same, but…
TSC1
TBI
SE
stroke
SAHencephalitis
corticaldysplasia
unknown
ICH
How To Get Further?
•Identification of a realistic target population with an ictogenicnetwork/molecular change that can be monitored
•Availability of biomarkers monitoring of circuitry
•Duration of evolution and repair of ictogenic circuitry•duration of DMT treatment
•Spontaneous remission
•Elimination of the trigger maintaining circuitry reorganization
•AEDs with multiple mechanisms of action•diseasemodification? (e.g. via epigenetic modulation)•how to test?•solution: ”multiple pills with 1 mechanism of action”
Epilepsy Research GroupA.I.Virtanen Institute, Kuopio, Finland
NMR Research Groupat A.I.Virtanen InstituteProf. Olli Gröhn
PhDstudentsXavier Ekolle NdodeEkaneNoora HuuskoSofya ZiyatdinovaOlena ShatilloDiana MiszczukTeemu Laitinen*Antti Airaksinen*
PostdocsHeli MyöhänenJari NissinenTamuna BolkvadzeNino Kutchiashvili
TechniciansMerja LukkariJarmo Hartikainen
Alzheimer Research GroupProf. Heikki Tanila
Funding• Academy of Finland• Sigrid Juselius Foundation• The Finnish Technology Fund• NIH/NINDS (R21 NS049525)• EU (EpiCURE) (LSHCT2006037315)• CURE (USA)• ESF• COST Action ECMNET