CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment

Hong, William; Haviland, Isabel; Pestana-Knight, Elia M.; Weisenberg, Judith; Demarest, Scott; Marsh, Eric D.; Olson, Heather E.

doi:10.1007/s40263-022-00921-5

Cited by 18 publications

(15 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6 Despite the high rate of ES in CDD, the literature on treatment of seizures in CDD thus far is not specific to ES. 7 Retrospective clinical studies and a family survey suggest limited or short-lived benefit from firstline treatments (adrenocorticotropic hormone [ACTH], prednisolone, vigabatrin) in infantile epileptic spasms syndrome (IESS). [8][9][10][11] Disease-specific information on treatment response in IESS is limited.…”

Section: Introductionmentioning

confidence: 99%

“…Clinical experience and initial data from three CDKL5 Centers of Excellence have suggested that response to first‐line treatments for ES in individuals with CDD is poor 6 . Despite the high rate of ES in CDD, the literature on treatment of seizures in CDD thus far is not specific to ES 7 . Retrospective clinical studies and a family survey suggest limited or short‐lived benefit from first‐line treatments (adrenocorticotropic hormone [ACTH], prednisolone, vigabatrin) in infantile epileptic spasms syndrome (IESS) 8–11 …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first‐line therapies

et al. 2023

Self Cite

View full text Add to dashboard Cite

Objective: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. Methods:We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. Results:We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%),

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first‐line therapies

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…[6][7][8] Multiple seizures per day are common, with seizure types varying over time. 5,9 Achieving durable seizure control is problematic, with up to 84% of patients developing refractoriness to antiseizure medications (ASMs) within weeks to months of treatment initiation. [10][11][12] This high seizure burden substantially impairs quality of life, and there is an unmet need for targeted therapeutic interventions with meaningful impact.…”

Section: Introductionmentioning

confidence: 99%

Long‐term treatment with ganaxolone for seizures associated with cyclin‐dependent kinase‐like 5 deficiency disorder: Two‐year open‐label extension follow‐up

Olson,

Amin,

Bahi‐Buisson

et al. 2023

Epilepsia

Self Cite

View full text Add to dashboard Cite

ObjectiveIn the placebo‐controlled, double‐blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD). We report 2‐year safety and clinical outcomes data from the open‐label extension (OLE) phase of Marigold.MethodsPatients with CDD who completed the double‐blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from pre‐randomization baseline, responder rates, and Clinical Global Impression of Improvement scale (CGI‐I) scores, including assessment of seizure intensity and duration (CGI‐CSID). Safety assessments included treatment‐emergent adverse events (TEAEs) and TEAEs leading to discontinuation.ResultsOf 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age 5 years; 79.5% female). Median 28‐day MMSF at baseline was 50.6. At 2 years in the OLE (Months 22‐24), MMSF was reduced by a median of 48.2% (n=50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During Months 22‐24, 23/50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12/50 (24.0%) patients experienced MMSF reductions of ≥75%. During Months 22‐24, 40/49 (81.6%) patients were rated by caregivers as having improvement in seizure‐related outcomes based on CGI‐CSID scores. Thirty‐seven patients discontinued ganaxolone due to: lack of efficacy (n=13), withdrawal by caregiver (n=12), adverse event (n=10), physician decision (n=1), or death (n=1; unrelated to study drug). The most common treatment‐related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n=28, 31.8%); those reported in ≥3% of patients were: seizure (n=6), pneumonia (n=5), acute respiratory failure (n=3), aspiration pneumonia (n=3), and dehydration (n=3).SignificanceSustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double‐blind phase.

show abstract

“… 23 The CDD is characterised by poor cognition, epilepsy of infancy or newborn, and suboptimal locomotive efficiency. 24 Most therapeutic interventions fail to effectively manage the seizure or developmental outcome. The molecular pathomechanism of action of CDD involves aberrant synaptic plasticity and neuron morphogenesis, resulting in erratic network currents and hyperexcitability in neurons.…”

Section: Resultsmentioning

confidence: 99%

Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders

Ademuwagun

Oduselu

Rotimi

et al. 2023

Bioinform Biol Insights

View full text Add to dashboard Cite

Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.

show abstract

CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment

Cited by 18 publications

References 78 publications

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first‐line therapies

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first‐line therapies

Long‐term treatment with ganaxolone for seizures associated with cyclin‐dependent kinase‐like 5 deficiency disorder: Two‐year open‐label extension follow‐up

Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders

Contact Info

Product

Resources

About