Disease Modification in Epilepsy

Asla Pitkänen, MD, PhDEpilepsy Research Laboratory

A.I.Virtanen Institute for Molecular SciencesUniversity of Eastern Finland (UEF),

Kuopio, FinlandE­mail: asla.pitkanen@uef.fi

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