4-Aminopyridine is a promising treatment option for patients with gain-of-function
            <i>KCNA2</i>
            -encephalopathy

Hedrich, Ulrike B. S.; Lauxmann, Stephan; Wolff, Markus; Synofzik, Matthis; Bast, Thomas; Binelli, Adrian; Serratosa, José M.; Martínez-Ulloa, Pedro; Allen, Nicholas M.; King, Mary D.; Gorman, Kathleen; Zeev, Bruria Ben; Tzadok, Michal; Wong‐Kisiel, Lily C.; Marjanović, Dragan; Rubboli, Guido; Sisodiya, Sanjay M.; Lutz, Florian; Ashraf, Harshad Pannikkaveettil; Torge, Kirsten; Yan, Peijing; Boßelmann, Christian; Schwarz, Niklas; Fudali, Monika; Lerche, Holger

doi:10.1126/scitranslmed.aaz4957

Cited by 49 publications

(48 citation statements)

References 66 publications

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“…Studies on diagnosis and recovery from peripheral nerve injury have already led to two clinical trials on 4-AP treatment of acute injuries [ 28 , 29 ]. A recent report of 4-AP treatment in patients with KCNA2-encephalopathy has interesting mechanistic implications; 4-AP reduced seizures in patients with gain-of-function variants of the Kv1.2 subunit and antagonized the electrophysiological defects in vitro in transfected neurons that expressed variant Kv1.2 channels [ 37 ]. In addition, methods to evaluate 4-AP target engagement and potential mechanism(s) of action in the brain may be facilitated by development of a 4-AP radioligand for neuroimaging, which has detected cortical pathology from brain injury in nonhuman primate testing and has advanced to a clinical trial [ 9 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

Radomski

Lischka

et al. 2022

acta neuropathol commun

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Damage to long axons in white matter tracts is a major pathology in closed head traumatic brain injury (TBI). Acute TBI treatments are needed that protect against axon damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our prior characterization of axon damage and demyelination after TBI led us to examine repurposing of 4-aminopyridine (4-AP), an FDA-approved inhibitor of voltage-gated potassium (Kv) channels. 4-AP is currently indicated to provide symptomatic relief for patients with chronic stage multiple sclerosis, which involves axon damage and demyelination. We tested clinically relevant dosage of 4-AP as an acute treatment for experimental TBI and found multiple benefits in corpus callosum axons. This randomized, controlled pre-clinical study focused on the first week after TBI, when axons are particularly vulnerable. 4-AP treatment initiated one day post-injury dramatically reduced axon damage detected by intra-axonal fluorescence accumulations in Thy1-YFP mice of both sexes. Detailed electron microscopy in C57BL/6 mice showed that 4-AP reduced pathological features of mitochondrial swelling, cytoskeletal disruption, and demyelination at 7 days post-injury. Furthermore, 4-AP improved the molecular organization of axon nodal regions by restoring disrupted paranode domains and reducing Kv1.2 channel dispersion. 4-AP treatment did not resolve deficits in action potential conduction across the corpus callosum, based on ex vivo electrophysiological recordings at 7 days post-TBI. Thus, this first study of 4-AP effects on axon damage in the acute period demonstrates a significant decrease in multiple pathological hallmarks of axon damage after experimental TBI.

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Section: Discussionmentioning

confidence: 99%

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

Radomski

Lischka

et al. 2022

acta neuropathol commun

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“…In a second step, emerging aimed therapeutic considerations are starting to be delineated for a number of DEE entities, relating to the optimization of indications of known anti-seizure drugs, and repurposing of drugs without epilepsy-related indications. Examples of these strategies are the possible favorable response to specific antiseizure medications (KCNQ2 DEE and sodium channel blockers), other families of drugs (KCNA2 DEE with gain of function and aminopyridine) or dietary treatments (SLC2A1 and ketogenic diet), the avoidance of specifically harmful drugs in some entities (POLG encephalopathies and valproic acid) (6,(81)(82)(83), or the possible tendency to relapse manifested by patients with other DEEs when discontinuing anti-seizure medication after a long seizure-free period (PCDH19 DEE), among many other examples (84,85).…”

Section: Clinical Implications Of Diagnosis: Optimization Of Therapy ...mentioning

confidence: 99%

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Beltrán‐Corbellini

Aledo‐Serrano

Møller³

et al. 2022

Front. Neurol.

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This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

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“…4-aminopyridine is a potassium channel blocker that can antagonize GOF defects in the KCNA2 gene that cause a DEE. In a study of n-of-1 trials in nine different centers, nine of 11 patients showed improvement in seizure burden, gait, ataxia, alertness, and cognition after starting 4-aminopyridine ( 43 ). Because of these findings, it seems a promising tailored treatment for KCNA2-encephalopathy caused by GOF variants.…”

Section: Therapies For Genetic Epilepsiesmentioning

confidence: 99%

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

2022

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Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.

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4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2 -encephalopathy

Abstract: 4-Aminopyridine is a potential therapeutic option for a subgroup of patients with KCNA2 -encephalopathy and gain-of-function variants.

Cited by 49 publications

References 66 publications

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes

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