Efficacy of antiseizure medication in a mouse model of <i>HCN1</i> developmental and epileptic encephalopathy

Bleakley, Lauren E; McKenzie, Chaseley E; Reid, Christopher A.

doi:10.1111/epi.17447

Cited by 7 publications

(7 citation statements)

References 25 publications

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“…4 Treatment is limited to ASMs, with emerging evidence that sodium valproate is the most effective in HCN1 -DEE. 2,3,5,8,10,20 However, HCN1 -DEE patients remain mostly refractory to standard ASMs. 2,7 Comorbid states need to be treated independently, with parent reports suggesting that these are also poorly controlled with standard of care therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…‘Spikes’ had distinctive morphology and were defined as biphasic events lasting < 200 ms with at least thrice the amplitude of baseline ECoG activity. 8,10 Baseline spikes were counted from a 1 hour recording epoch prior to drug administration. Spikes post-Org 34167 were counted from an epoch 10 to 70 minutes following drug administration.…”

Section: Methodsmentioning

confidence: 99%

“…9 We predict that the majority of HCN1 -DEE cases involve variants that result in cation leak. 10 Therapeutic strategies that target HCN1 channel cation leak are therefore expected to improve outcomes for a high proportion of HCN1 -DEEs.…”

Section: Introductionmentioning

confidence: 99%

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A precision medicine approach forHCN1Developmental and Epileptic Encephalopathy

Bleakley,

McKenzie,

Zhao

et al. 2024

Preprint

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Pathogenic variants inHCN1causing cation leak result in a severe developmental and epileptic encephalopathy (DEE). Current treatment options for patients withHCN1-DEE are limited and are insufficient to fully address both the seizures and clinical comorbidities of this disorder.Org 34167 is a brain penetrant broad-spectrum HCN channel inhibitor that has completed phase I clinical trials. We used a range of assays at molecular, cellular, network and behavioural levels to explore the potential of Org 34167 as a precision medicine forHCN1-DEE.Org 34167 restored the voltage sensitivity of the DEE HCN1M305Lmutated channel, significantly reducing cation leak. It also restored Ih-mediated ‘sag’, hyperpolarised the resting membrane potential and reduced firing of layer V neurons from the Hcn1M294Lmouse model ofHCN1-DEE, which was engineered based on the HCN1M305Lpathogenic variant. Additionally, Org 34167 reduced neuronal epileptiform activity and restored retinal light sensitivity in these mice, suggesting it may improve both seizures and other clinical comorbidities. However, Org 34167-mediated tremors were noted at therapeutic doses. Org 34167 was also effective at reducing cation leak caused by five additionalHCN1pathogenic variants, suggesting broader utility.Overall, these data demonstrate that a small molecule HCN inhibitor can restore channel and consequent physiological functions, positioning it as a promising precision therapeutic approach forHCN1-DEE.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A precision medicine approach forHCN1Developmental and Epileptic Encephalopathy

Bleakley,

McKenzie,

Zhao

et al. 2024

Preprint

Self Cite

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“…Importantly, both the Hcn1 M294L and Hcn1 G380D HCN1 -DEE mouse models respond to standard anti-seizure medications (ASMs) in a similar manner. 14 , 22 , 23 This includes seizure exacerbation induced by lamotrigine and phenytoin, both sodium channel blocking ASMs. 14 , 22 In contrast, valproate reduced excitability on EEG (reduced spiking) in the Hcn1 M294L mouse and did not exacerbate seizures in the Hcn1 G380D mouse model.…”

Section: Discussionmentioning

confidence: 99%

Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy

McKenzie

Forster

Soh

et al. 2023

Brain Communications

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Pathogenic variants in HCN1 are an established cause of developmental and epileptic encephalopathy (DEE). To date, the stratification of patients with HCN1-DEE based on the biophysical consequence on channel function of a given variant has not been possible. Here, we analysed data from eleven patients carrying seven different de novo HCN1 pathogenic variants located in the transmembrane domains of the protein. All patients were diagnosed with severe disease including epilepsy and intellectual disability. The functional properties of the seven HCN1 pathogenic variants were assessed using two-electrode voltage-clamp recordings in Xenopus oocytes. All seven variants showed a significantly larger instantaneous current consistent with cation leak. The impact of each variant on other biophysical properties was variable, including changes in the half activation voltage and activation and deactivation kinetics. These data suggest that cation leak is an important pathogenic mechanism in HCN1-DEE. Furthermore, published mouse model and clinical case reports suggest that seizures are exacerbated by sodium channel blockers in patients with HCN1 variants that cause cation leak. Stratification of patients based on their ‘cation leak’ biophysical phenotype may therefore provide key information to guide clinical management of individuals with HCN1-DEE.

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“…In murine models of p.G391D and p.M153I, administration of the sodium channel antagonists lamotrigine and phenytoin resulted in paradoxical induction of seizures; however, administration of sodium valproate did not lead to convulsive seizures 13 . In Hcn1 M294L mice carrying a homolog of the HCN1 p.M305L variant; phenytoin, lamotrigine, retigabine, and carbamazepine increased spike frequency, whereas levetiracetam, diazepam, sodium valproate, and ethosuximide significantly reduced spike frequency 14 . Sodium channel blockers such as carbamazepine or phenytoin may aggravate seizures in Dravet syndrome with SCN1A variants 15 .…”

mentioning

confidence: 93%

The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus

et al. 2023

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HCN1 is one of four genes encoding hyperpolarization-activated cyclic nucleotide-gated channels. The phenotypic spectrum associated with HCN1 variants ranges from neonatal developmental and epileptic encephalopathy to idiopathic generalized epilepsy. We report a Japanese patient with repetitive focal seizures and super-refractory status epilepticus since early infancy caused by a de novo HCN1 variant, NM_021072.4, c.1195T>C, p.(Ser399Pro). This variant might have a dominant-negative effect on channel function, leading to severe epileptic encephalopathy.

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Efficacy of antiseizure medication in a mouse model of HCN1 developmental and epileptic encephalopathy

Cited by 7 publications

References 25 publications

A precision medicine approach forHCN1Developmental and Epileptic Encephalopathy

A precision medicine approach forHCN1Developmental and Epileptic Encephalopathy

Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy

The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus

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