Rational Small Molecule Treatment for Genetic Epilepsies

Abstract

Genetic testing has yielded major advances in our understanding of the causes of epilepsy. Seizures remain resistant to treatment in a significant proportion of cases, particularly in severe, childhood-onset epilepsy, the patient population in which an underlying causative genetic variant is most likely to be identified. A genetic diagnosis can be explanatory as to etiology, and, in some cases, might suggest a therapeutic approach; yet, a clear path from genetic diagnosis to treatment remains unclear in most cases. Here, we discuss theoretical considerations behind the attempted use of small molecules for the treatment of genetic epilepsies, which is but one among various approaches currently under development. We explore a few salient examples and consider the future of the small molecule approach for genetic epilepsies. We conclude that significant additional work is required to understand how genetic variation leads to dysfunction of epilepsy-associated protein targets, and how this impacts the function of diverse subtypes of neurons embedded within distributed brain circuits to yield epilepsy and epilepsyassociated comorbidities. A syndrome-or even variant-specific approach may be required to achieve progress. Advances in the field will require improved methods for large-scale target validation, compound identification and optimization, and the development of accurate model systems that reflect the core features of human epilepsy syndromes, as well as novel approaches towards clinical trials of such compounds in small rare disease cohorts.

KCNT2‐Related Disorders: Phenotypes, Functional, and Pharmacological Properties

“…For patients carrying GoF KCNT1 variants, sensitivity 9,39 or insensitivity 40 to treatment with the potassium channel blocker quinidine parallels drug responses in vitro. Moreover, heterogeneous functional changes (LoF or GoF) triggered by pathogenic KCNT2 variants in vitro may require distinct pharmacological approaches to restore channel function in vivo 41 . Our in vitro results revealed that each KCNT2 variant exhibits a distinct pattern of pharmacological sensitivity.…”

“…Moreover, heterogeneous functional changes (LoF or GoF) triggered by pathogenic KCNT2 variants in vitro may require distinct pharmacological approaches to restore channel function in vivo. 41 Our in vitro results revealed that each KCNT2 variant exhibits a distinct pattern of pharmacological sensitivity. Indeed, while GoF KCNT2 variants are all blocked by quinidine and fluoxetine, KCNT2 channels carrying W156L or N182I LoF variants, similarly to wildtype KCNT2 channels, were potentiated by loxapine or riluzole, 2 openers of wild-type KCNT1 channels, 31 showing for the first time their capability to activate also KCNT2 channels.…”

In vitro effects of eslicarbazepine (S‐licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders

“…Precision medicine approaches based on the development of treatment regimens enabling selective targeting of causative channel subtypes are a promising strategy toward optimized therapy (Goldberg, 2021).…”

“…Precision medicine approaches based on the development of treatment regimens enabling selective targeting of causative channel subtypes are a promising strategy toward optimized therapy (Goldberg, 2021). Toward this aim, we investigated the functional effects of eslicarbazepine (S‐licarbazepine; S‐lic), a derivative of carbamazepine with a strong preference for Na V 1.2 and Na V 1.6 over Na V 1.1 and Na V 1.3 channels (Holtkamp et al, 2018) in the context of genetic channel variants previously described in patients with Na V 1.6 ( SCN8A ) related developmental encephalopathy (see Introduction).…”

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“…Various metabolic and structural disorders are primarily associated as the main epilepsy-causing factors occur due to genetic alterations or physical injury to the brain. Advancements in genetic testing revealed the genetic basics of epilepsy in more than half of neonatal and childhood epilepsy cases [4]. Genetic-caused epilepsy, also known as the idiopathic epilepsy type, accounts for >40% of all epilepsy types [5].…”