Sodium Channel Modulators & Precision Medicine for Infant

Epilepsy

29th March 2017

Robin Sherrington, PhD

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Sodium Channels Gene Family

•  Family of 9 highly homologues proteins (Nav1.1 to Nav1.9) •  Major role in electrical signaling e.g. nervous system action

potentials & neurotransmission •  Distinct roles & tissue expression for many •  To much & to little sodium current cause inherited

channelopathies

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α-subunit β-subunit 1-4

Ahuja et al., 2015

9 Sodium channels with very different roles

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NaV Role

1.1 1.2

CNS e.g. convulsions, dizziness, somnolence

1.4 Muscle e.g. periodic paralysis, muscle weakness

1.5 Heart e.g. sinus rhythm & arrhythmia

1.6 CNS e.g. ataxia, dizziness, cognition

1.7 Peripheral e.g. pain

1.8/1.9 Peripheral e.g. pain

CNS Navs

Heart Navs

Sensory Navs (pain)

SCN8A Mutations & Epilepsy

•  Infantile Epileptic Encephalopathy (IEE) •  Multiple heterozygous de novo missense mutations

in Nav1.6 causing too much sodium current •  Presents 1 day to 18 months after birth •  High seizure frequency

•  Multiple seizure types, focal, spasms, tonic clonic, myoclonic & absence

•  Moderate to severe intellectual disability & autistic features •  Prominent motor deficits, hyptonia, dystonia, ataxia hypereflexia •  >10% risk of SUDEP before 5yrs

•  Generally treatment resistant

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Selective Nav1.6 inhibition why it makes good sense

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Nav1.6 Nav1.1

Excitatory Pyramidal

Inhibitory Interneuron

Nav1.6 GOF Epilepsy (IEE)

•  Nav1.6 GOF in excitatory neurons •  Increased Nav1.6 mediated

excitation & seizures •  Non-selective inhibitors may limit

efficacy due to concomitant Nav1.1 inhibition

NaV1.6 selective inhibitors are now possible

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In Vitro In Vivo SCN8A GOF

Orphan Drug Act of 1983

•  “A drug or biologic used to treat a rare disease or condition” •  Affects <200,000 persons in the US •  Grant program to help certain companies with

cost •  Provides tax incentives •  Market exclusivity for 7 years •  Priority FDA reviews & protocol assistance •  FDA fees waived

•  Orphan drugs are NOT the cause of increasing healthcare costs

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Precision Medicine & Channelopathies

•  Genetics provides molecular insight

•  Drug discovery can target the right mechanism

•  Gene testing to target the right drug

•  Drug development needs support & collaboration •  Patient advocacy •  Patient registries (International Ion

Channel Patient Registry “IICPR”) •  KOL & clinical collaborators •  Regulators •  Industry

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SCN8A

“The whole is greater than the sum of the parts” Aristotle 384-322 BC