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Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome / A. KOLEVZON in Molecular Autism, 13 (2022)
[article]
Titre : Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : A. KOLEVZON, Auteur ; M. S. BREEN, Auteur ; P. M. SIPER, Auteur ; Danielle B. HALPERN, Auteur ; Y. FRANK, Auteur ; H. RIEGER, Auteur ; J. WEISMANN, Auteur ; M. P. TRELLES, Auteur ; B. LERMAN, Auteur ; R. RAPAPORT, Auteur ; J. D. BUXBAUM, Auteur Article en page(s) : 17 p. Langues : Anglais (eng) Mots-clés : Child Chromosome Deletion Chromosome Disorders/drug therapy/genetics Chromosomes, Human, Pair 22 Humans Insulin-Like Growth Factor I/therapeutic use Pilot Projects Asd Autism spectrum disorder Igf-1 Insulin-like growth factor-1 Pms Phelan-McDermid syndrome shank3 Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene and is characterized by global developmental delays and autism spectrum disorder (ASD). Based on several converging lines of preclinical and clinical evidence supporting the use of insulin-like growth factor-1 (IGF-1) in PMS, this study aims to follow-up a previous pilot study with IGF-1 to further evaluate this novel therapeutic for core symptoms of ASD in children with PMS. METHODS: Ten children aged 5-9 with PMS were enrolled. Participants were randomized to receive IGF-1 or placebo (saline) using a 12-week, double-blind, crossover design. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as secondary outcome measures reflecting core symptoms of ASD. To increase power and sample size, we jointly analyzed the effect of IGF-1 reported here together with results from our previous controlled trail of IGF-1 in children with PMS (combined N=19). RESULTS: Results on the ABC-SW did not reach statistical significance, however significant improvements in sensory reactivity symptoms were observed. In our pooled analyses, IGF-1 treatment also led to significant improvements in repetitive behaviors and hyperactivity. There were no other statistically significant effects seen across other clinical outcome measures. IGF-1 was well tolerated and there were no serious adverse events. LIMITATIONS: The small sample size and expectancy bias due to relying on parent reported outcome measures may contribute to limitations in interpreting results. CONCLUSION: IGF-1 is efficacious in improving sensory reactivity symptoms, repetitive behaviors, and hyperactivity in children with PMS. Trial registration NCT01525901. En ligne : http://dx.doi.org/10.1186/s13229-022-00493-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477
in Molecular Autism > 13 (2022) . - 17 p.[article] Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / A. KOLEVZON, Auteur ; M. S. BREEN, Auteur ; P. M. SIPER, Auteur ; Danielle B. HALPERN, Auteur ; Y. FRANK, Auteur ; H. RIEGER, Auteur ; J. WEISMANN, Auteur ; M. P. TRELLES, Auteur ; B. LERMAN, Auteur ; R. RAPAPORT, Auteur ; J. D. BUXBAUM, Auteur . - 17 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 17 p.
Mots-clés : Child Chromosome Deletion Chromosome Disorders/drug therapy/genetics Chromosomes, Human, Pair 22 Humans Insulin-Like Growth Factor I/therapeutic use Pilot Projects Asd Autism spectrum disorder Igf-1 Insulin-like growth factor-1 Pms Phelan-McDermid syndrome shank3 Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene and is characterized by global developmental delays and autism spectrum disorder (ASD). Based on several converging lines of preclinical and clinical evidence supporting the use of insulin-like growth factor-1 (IGF-1) in PMS, this study aims to follow-up a previous pilot study with IGF-1 to further evaluate this novel therapeutic for core symptoms of ASD in children with PMS. METHODS: Ten children aged 5-9 with PMS were enrolled. Participants were randomized to receive IGF-1 or placebo (saline) using a 12-week, double-blind, crossover design. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as secondary outcome measures reflecting core symptoms of ASD. To increase power and sample size, we jointly analyzed the effect of IGF-1 reported here together with results from our previous controlled trail of IGF-1 in children with PMS (combined N=19). RESULTS: Results on the ABC-SW did not reach statistical significance, however significant improvements in sensory reactivity symptoms were observed. In our pooled analyses, IGF-1 treatment also led to significant improvements in repetitive behaviors and hyperactivity. There were no other statistically significant effects seen across other clinical outcome measures. IGF-1 was well tolerated and there were no serious adverse events. LIMITATIONS: The small sample size and expectancy bias due to relying on parent reported outcome measures may contribute to limitations in interpreting results. CONCLUSION: IGF-1 is efficacious in improving sensory reactivity symptoms, repetitive behaviors, and hyperactivity in children with PMS. Trial registration NCT01525901. En ligne : http://dx.doi.org/10.1186/s13229-022-00493-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome / S. SETHURAM in Molecular Autism, 13 (2022)
[article]
Titre : A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : S. SETHURAM, Auteur ; T. LEVY, Auteur ; J. FOSS-FEIG, Auteur ; Danielle B. HALPERN, Auteur ; S. SANDIN, Auteur ; P. M. SIPER, Auteur ; H. WALKER, Auteur ; Joseph D. BUXBAUM, Auteur ; R. RAPAPORT, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 6p. Langues : Anglais (eng) Mots-clés : Asd Autism spectrum disorder Growth hormone Igf-1 Insulin-like growth factor-1 Pms Phelan–McDermid syndrome Shank3 Jaguar, Neuren, GW Pharma, and Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in Phelan–McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 . En ligne : http://dx.doi.org/10.1186/s13229-022-00485-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 13 (2022) . - 6p.[article] A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / S. SETHURAM, Auteur ; T. LEVY, Auteur ; J. FOSS-FEIG, Auteur ; Danielle B. HALPERN, Auteur ; S. SANDIN, Auteur ; P. M. SIPER, Auteur ; H. WALKER, Auteur ; Joseph D. BUXBAUM, Auteur ; R. RAPAPORT, Auteur ; A. KOLEVZON, Auteur . - 6p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 6p.
Mots-clés : Asd Autism spectrum disorder Growth hormone Igf-1 Insulin-like growth factor-1 Pms Phelan–McDermid syndrome Shank3 Jaguar, Neuren, GW Pharma, and Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in Phelan–McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 . En ligne : http://dx.doi.org/10.1186/s13229-022-00485-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome / J. FASTMAN in Molecular Autism, 12 (2021)
[article]
Titre : A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : J. FASTMAN, Auteur ; J. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; Danielle B. HALPERN, Auteur ; Hala HARONY-NICOLAS, Auteur ; C. LAYTON, Auteur ; S. SANDIN, Auteur ; P. SIPER, Auteur ; L. TANG, Auteur ; P. TRELLES, Auteur ; J. ZWEIFACH, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 62 p. Langues : Anglais (eng) Mots-clés : Asd Autism spectrum disorder Oxytocin Pms Phelan-McDermid syndrome Shank3 Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in Phelan-McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U?=?50, p?=?0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084. En ligne : http://dx.doi.org/10.1186/s13229-021-00459-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 62 p.[article] A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / J. FASTMAN, Auteur ; J. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; Danielle B. HALPERN, Auteur ; Hala HARONY-NICOLAS, Auteur ; C. LAYTON, Auteur ; S. SANDIN, Auteur ; P. SIPER, Auteur ; L. TANG, Auteur ; P. TRELLES, Auteur ; J. ZWEIFACH, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur . - 62 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 62 p.
Mots-clés : Asd Autism spectrum disorder Oxytocin Pms Phelan-McDermid syndrome Shank3 Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in Phelan-McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U?=?50, p?=?0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084. En ligne : http://dx.doi.org/10.1186/s13229-021-00459-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459