Reply to G. R. Mohyuddin et al and A. Garfall et al

Richardson, Paul G.; Moreau, Philippe

doi:10.1200/jco.21.02081

Cited by 3 publications

(5 citation statements)

References 10 publications

(24 reference statements)

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“…Such ligand-induced CRL4-CRBN recruitment facilitates neosubstrate ubiquitination and subsequent proteasomal degradation, thereby dictating therapeutic efficacy (2). The CELMoD agent lenalidomide (Revlimid) has been used as a first-line therapy for multiple myeloma and other hematological malignancies for more than a decade, and next-generation CELMoD compounds markedly improve patient outcomes in clinical trials (3). Although crystal-lographic structural snapshots of CRBN-DDB1 bound to a variety of drugs and neosubstrates have facilitated a molecular description of the stable quaternary complex, the allostery associated with substrate targeting remains unknown, and the structural features of the unliganded complex have yet to be described.…”

mentioning

confidence: 99%

Molecular glue CELMoD compounds are regulators of cereblon conformation

Watson

Novick

Matyskiela

et al. 2022

Science

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Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN’s thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo–electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)–CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.

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mentioning

confidence: 99%

Molecular glue CELMoD compounds are regulators of cereblon conformation

Watson

Novick

Matyskiela

et al. 2022

Science

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“…Men with epilepsy may face a difficult decision when deciding on the best use of ASM for seizure prevention because valproate has consistently been shown to be the best-tolerated drug for generalized epilepsy, 4,5 and emerging human evidence of the potential adverse effects associated with valproate use in the context of reproduction stems mainly from observational studies.…”

Section: Jama Network Open | Neurologymentioning

confidence: 99%

“…Epilepsy is one of the most prevalent neurologic disorders among males of fertile age, [1][2][3] and the antiseizure medication (ASM) valproate is commonly used for epilepsy in males of fertile age. 4,5 The teratogenic potential of valproate is widely recognized, and use by mothers in pregnancy has been associated with an increased risk of congenital malformations 6,7 and neurodevelopmental disorders, including, and perhaps most notably, autism among the offspring. 8,9 Despite the well-known risks associated with maternal exposure to valproate in pregnancy, the risk of congenital malformations and neurodevelopmental disorders associated with paternal exposure in relation to conception is still uncertain.…”

Section: Introductionmentioning

confidence: 99%

Valproate Use During Spermatogenesis and Risk to Offspring

Christensen,

Trabjerg,

Dreier

2024

JAMA Netw Open

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ImportanceConcerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis.ObjectiveTo evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders.Design, Setting, and ParticipantsThis nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024.ExposuresPaternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception).Main Outcomes and MeasuresChildren with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders.ResultsAmong 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points.Conclusions and RelevanceIn all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.

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“…Valproate is one of the most efficacious antiseizure medications (ASMs) especially for generalized epilepsy, 1 but there is concern over the adverse-effect profile of the drug when used in pregnancy. 2 In animal models, prenatal exposure to valproate was associated with increased risk of various morphological and functional alterations in fetal brain development [3][4][5][6][7][8][9] and in human studies with poorer child neurodevelopmental outcomes such as developmental milestones, 10,11 intellectual functioning, [11][12][13][14] autism spectrum disorder (ASD), [13][14][15] and language and memory functioning.…”

Section: Introductionmentioning

confidence: 99%

“…Genetic risk of epilepsy varies according to the type of maternal epilepsy, which informs the selection of a specific ASM. Valproate is likely to be used for generalized epilepsies, 1,32 which have higher heritability than focal epilepsies, while sodium channel blockers, such as carbamazepine and oxcarbazepine, are used for focal epilepsies. 1,32 With these considerations in mind, we aimed to examine whether use of valproate and other ASMs among pregnant mothers with epilepsy was associated with epilepsy in their children.…”

Section: Introductionmentioning

confidence: 99%

Prenatal Exposure to Antiseizure Medications and Risk of Epilepsy in Children of Mothers With Epilepsy

Dreier,

Christensen,

Igland

et al. 2024

JAMA Netw Open

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ImportanceUse of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child.ObjectiveTo examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children.Design, Setting, and ParticipantsThis prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023.ExposureRedeemed prescription for an ASM from 30 days before pregnancy until birth.Main Outcomes and MeasuresThe main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses.ResultsThis cohort study included 38 663 children of mothers with epilepsy (19 854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22 207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05).Conclusions and RelevanceIn this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child’s risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.

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Reply to G. R. Mohyuddin et al and A. Garfall et al

Abstract: Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Cited by 3 publications

References 10 publications

Molecular glue CELMoD compounds are regulators of cereblon conformation

Molecular glue CELMoD compounds are regulators of cereblon conformation

Valproate Use During Spermatogenesis and Risk to Offspring

Prenatal Exposure to Antiseizure Medications and Risk of Epilepsy in Children of Mothers With Epilepsy

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