RARE DISEASE
Phelan-McDermid syndrome
Phelan-McDermid syndrome
Phelan-McDermid syndrome
Drug discovery
5
drugs
With orphan designations
Overview
Phelan-McDermid syndrome (PMS) is a rare neurogenetic disorder caused by 22q13.3 deletions or pathogenic SHANK3 variants, disrupting synaptic function. Core features include global developmental delay, severe speech impairment, hypotonia, and autism spectrum disorder (ASD) in ~75% of cases. Associated manifestations encompass seizures, gastrointestinal dysfunction, sleep disturbances, and dysmorphic traits (e.g., dolichocephaly, large ears). Lifelong multidisciplinary care addresses developmental, behavioral, and systemic comorbidities [1][6][14][19].
Categories: rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare skin diseases
Research Papers
169 drug discovery papers about Phelan-McDermid syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
169 drug discovery papers about Phelan-McDermid syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Psychotropic Polypharmacy in a 5-Year-Old Boy with a SHANK3 Variant and Complex Mental Health Problems
Background: Dysfunction of the SHANK3 gene has been linked to several neuropsychiatric and neurodevelopmental disorders, such as attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder, and epilepsy. SHANK3 haploinsufficiency is the known etiology of Phelan–McDermid syndrome. Case presentation: This report presents a five-year-old boy in whom the c.2062G>C; p.Val688Leu variant was identified in a mosaic state in the SHANK3 gene (40% of heterozygous cells) and classified as a variant of uncertain significance (VUS). The patient was diagnosed with complex mental health problems, which, analogous to typical SHANK3 disruption, included ADHD, oppositional defiant disorder, developmental coordination disorder, Non-REM sleep arousal disorder, insomnia disorder, and avoidant/restrictive food intake disorder. Starting at the age of three years, his psychiatric treatment had included various medication trials over the course of two years. Ultimately, a substantial reduction in emotional outbursts, externalizing behaviors, and parental stress occurred following a multimodal treatment approach comprising psychotropic polypharmacy (PP), i.e., lisdexamfetamine, melatonin, and risperidone, along with behavioral therapy interventions, speech therapy, and occupational therapy. Under this PP, constipation was documented as the only adverse reaction. At the 15-month follow-up, improvements had been quite stable, despite risperidone medication being stopped about 19 weeks after initiation. Conclusions: As shown in this case report, even very young children with complex neuropsychiatric problems and SHANK3 variants might not be treated sufficiently by therapeutic interventions alone, but might require a combination of therapeutic and psychopharmacological interventions to achieve a substantial symptom reduction. However, PP must be approached with a high degree of caution and subjected to close monitoring in children with SHANK3 variants, who are susceptible to an elevated risk of adverse outcomes. Moreover, given the paucity of research in this population, it seems advisable to follow prevailing general guidelines in child and adolescent psychiatry.
2026-09-01 | 851. A mechanism for PHF21B recognition of H3K36me3
Abstract Background We have recently identified the epigenetic reader PHF21B as a regulator of synaptic plasticity and social memory in mice. The PHF21B gene is located on chromosome 22q13.3, a region that is deleted in Phelan-McDermid syndrome, a neurodevelopmental disorder characterized by intellectual disability, impaired social communication, and features overlapping with autism spectrum disorder. We have previously shown that PHF21B interacts with H3K36me3, an epigenetic mark associated with active gene expression and critical roles in transcription, splicing, and genomic stability. Deficiencies in H3K36me3 are associated with various cancers and developmental disorders. However, the structural domain that mediates the interaction between PHF21B and H3K36me3 has yet to be characterized. Aims & Objectives The identification of the specific protein domain in PHF21B that is required for H3K36me3 recognition could provide mechanistic insights relevant to understanding and treating PHF21B-associated neurodevelopmental features. Method Myc-tagged wild-type PHF21B and mutants PHF21BΔPHDZnf and PHF21B ΔCc, which respectively lack the PHD-zinc finger domain in residues 352–465 and the C-terminal region in residues 423–531, were generated and expressed in HEK293T cells. The interaction between PHF21B and H3K36me3 was assessed by bidirectional co-immunoprecipitation and anti-Myc and anti-H3K36me3 antibodies, followed by western blotting. GFP-transfected cells were used as negative controls. Results H3K36me3 was immunoprecipitated by wild-type PHF21B and PHF21B ΔCc, but not by PHF21B ΔPHDZnf (P < 0.001, one-way ANOVA with Tukey's post-hoc test). These findings were confirmed by reciprocal co-immunoprecipitation, where Anti-H3K36me3 antibodies pulled down wild-type PHF21B and PHF21B ΔCc, but not PHF21B ΔPHDZnf. Therefore, H3K36me3 binding was abolished in the ΔPHDZnf mutant. Discussion & Conclusions The PHD-zinc finger domain of PHF21B is necessary for its interaction with H3K36me3, and the C-terminal region is dispensable. Given that PHF21B reads active chromatin marks at synaptic plasticity genes, disruption of this PHD-zinc finger–H3K36me3 interface may underlie transcriptional dysregulation in neurodevelopmental conditions associated with 22q13.3 deletions. We have defined a specific protein domain that could serve as a therapeutic target for Phelan-McDermid syndrome. Future studies will need to examine whether the PHD-zinc finger domain is sufficient to rescue the neuronal functions of PHF21B.
2026-09-01 | 865. Metformin as a treatment of Fragile X and Phelan McDermid syndromes
Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms of persistent deficits in social communication and interaction, and repetitive behavior. Worldwide prevalence ranges between 1-2 %, with an incidence rate 4 times higher in males than females. Unfortunately, about 40% of children with ASD do not respond to standard behavioral and medical treatments. Aims & Objectives For the moment we are focusing on mouse models of Fragile X syndrome (FXS) and Phelan McDermid Syndrome (PMS), in both males and females. These 2 neurodevelopmental disorders have a very high incidence of ASD. Method We are studying the therapeutic effects of metformin, an FDA approved drug, for treating symptoms associated with ASD at a behavioral level. In addition, ERK/MAPK and mTOR pathways, involved in controlling mRNA translation, are overactivated in several brain areas of FXS and PMS mouse models. Results Metformin treatment, an inhibitor of these pathways, showed high efficacy in correcting pathway signaling and behavior in fragile X syndrome (FXS) fly and mouse models, and in male and female mouse models of PMS. Discussion & Conclusions Our work broadens the understanding of the effects of metformin on ASD and potentially supports the implementation of clinical strategies to alleviate symptoms associated with these neurological disorders in both sexes.
2026-08-20 | Phelan-McDermid Syndrome Clinical Trials: Approved Therapies, Pivotal Trial Endpoints, Clinical Failures, and Drug Development Insights
A comprehensive overview of Phelan-McDermid Syndrome (PMS), including disease background, current treatment landscape, failed clinical trials, key efficacy endpoints, emerging SHANK3-targeted therapies, and strategies for designing successful FDA-ready clinical trials.
2026-08-14 | Severe Expressive Language Impairment and Infection-Associated Dystonic Deterioration with Multidomain Improvement After Levodopa Initiation in SHANK3-Related Disorder: A Case Report and Focused Literature Review
SHANK3-related disorder within the Phelan-McDermid syndrome spectrum is clinically heterogeneous and commonly includes severe expressive language impairment, hypotonia, motor coordination difficulties, sensory features, sleep disturbance, reduced pain expression, and regression in a subset of affected individuals. However, a potential dystonic contribution to expressive language impairment, orofacial dysfunction, other motor abnormalities, and illness-associated functional deterioration has not been systematically examined. Case Presentation: We report a 7-year-old girl whose early presentation was dominated by severe expressive language delay. Receptive communication, social reciprocity and practical problem-solving appeared substantially stronger than expressive output suggested. Longitudinal features included fine-motor incoordination, toe walking, intermittent atypical hand movements, sensory reactivity, overload-associated dysregulation and prolonged mouthing/oral exploration of objects. During febrile illness in March 2025, she developed painful gait deterioration, continuous toe walking, dystonic hand posturing and worsening orofacial motor function. Low-dose levodopa was initiated because dopa-responsive dystonia or a related dopaminergic disorder was clinically considered. Following initiation of levodopa, improvements were observed across several functional domains that had shown only slow progress or prolonged plateau phases during the preceding years. Short-read whole-genome sequencing identified a heterozygous pathogenic SHANK3 frameshift variant, NM_001372044.2:c.3904dup, with the predicted protein consequence NP_001358973.1:p.(Ala1302fs). With continued levodopa and later trihexyphenidyl, further gains were observed across gait stability, orofacial control, spoken language output, sensory tolerance and functional participation; the previously persistent mouthing/oral exploration was no longer observed after dopaminergic treatment had been established. Conclusion: Across neurodevelopmental disorders of diverse genetic aetiology and across age groups, the co-occurrence of marked expressive language impairment, orofacial dysfunction, and fine- or gross-motor abnormalities should prompt targeted assessment for dystonia or another movement disorder. Such motor manifestations may represent a convergent and potentially modifiable component of the clinical phenotype, including previously unrecognized impairment of speech-motor control. The multidomain improvement observed following initiation of levodopa in this case of SHANK3-related disorder was clinically meaningful and hypothesis-generating and warrants prospective investigation.
cell therapies
2026-02-22 | Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models.
Extracellular vesicles (EVs) are lipid bilayer-enclosed structures that mediate intercellular communication by transferring diverse cargoes, including RNA and proteins. SHANK3, a synaptic scaffolding protein critical for synapse structure and function, is implicated in autism spectrum disorder (ASD) and Phelan-McDermid Syndrome (PMS). Early hyperexcitability in cortical neurons is a characterized endophenotype in ASD. Here, we investigated EV-mediated effects in the context of SHANK3 deficiency using human iPSC-derived cortical neurons and Shank3B-/- mice. Switching EVs between SHANK3 mutant and control neurons revealed that SHANK3 mutant-derived EVs transferred the hyperexcitability and accelerated maturation phenotypes to control neurons. Proteomic analysis revealed enrichment of synaptic structural regulators (e.g., ACTB, CFL1, AGRN, and CLSTN1) in SHANK3 mutant neuron-derived EVs. This is consistent with known actin cytoskeletal dysregulation driven by SHANK3 deficiency. However, control neuron-derived EVs failed to rescue mutant phenotypes, likely due to their decreased enrichment of synaptic proteins and related pathways. Further, EVs from mesenchymal stem cells (MSCs) and healthy donor iPSCs, containing synaptic modulators such as complement proteins (C1R, C1S), plasticity-associated proteins (MDK, IGFBP3), and homeostatic regulators (FGF2, SFRP1), rescued the hyperexcitability and normalized the maturation in SHANK3 mutant neurons. In addition, intranasal administration of iPSC-derived EVs in Shank3B-/- mice significantly rescued ASD-like behavioral deficits, emphasizing their therapeutic potential. Together, these findings reveal a novel EV-mediated mechanism for modulating dysregulated excitability and synaptic maturation, addressing a critical unmet need in ASD and associated neurodevelopmental disorders.
2024-08-27 | Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associated Shank3 mutation.
ABSTRACT Shank3 , a scaffolding protein, is critical for synaptic structure and function, particularly for the formation and maintenance of dendritic spines. Shank3 mutations are strongly implicated in autism spectrum disorder (ASD) and related neuropsychiatric conditions such as Phelan-McDermid Syndrome (PMS) also known as the 22q13.3 deletion syndrome. Previous work has recognized early hyperexcitability in cortical neurons derived from ASD patients with various gene mutations as a potential common endophenotype. In this study, we examined the effects of exosomes extracted from several cell types on the neurophysiological properties of cortical neurons derived from Shank3 (c.3679insG mutation) induced pluripotent stem cells (iPSCs). First, we sought to understand the implications of exosome-based intercellular communication on the neurophysiology of Shank3 mutant and control neurons by switching their respective exosomes. We found that while control neuron-derived exosomes do not change the neurophysiology of Shank3 neurons, the Shank3 neuron-derived exosomes transfer the early hyperexcitability and other ASD-related phenotypes to control neurons. Next, we also explored the therapeutic potential of mesenchymal stem cells (MSC) and iPSC-derived exosomes from healthy donors in the Shank3 cortical neurons. We demonstrate that both MSC and iPSC-derived exosomes rescue the early hyperexcitability and accelerated maturation of Shank3 neurons. Proteomic analysis of exosomes derived from Shank3 mutant and control neurons, as well as from exosomes derived from MSCs and iPSCs, revealed distinct protein cargoes that may cause changes in the neurophysiological properties of the recipient neurons. Our results hence provide novel insights into the pathophysiology of ASD emphasizing the importance of exosomes in intercellular communication and their potential to influence intrinsic and network properties of neurons. Moreover, our findings support the need for further exploration of exosome-based interventions as potential therapeutics for treating neurodevelopmental disorders.
2022-10-03 | Translational pediatrics: clinical perspective for Phelan-McDermid syndrome and autism research.
Phelan-McDermid syndrome (PMS) is a rare genetic disorder presenting with developmental delay, epilepsy, and autism spectrum disorder (ASD). The segmental deletion of chromosome 22q13.3 affects the copy number of SHANK3, the gene encoding a scaffolding protein at the postsynaptic density. Biological studies indicate that SHANK3 plays crucial roles in the development of synaptic functions in the postnatal brain. Notably, induced pluripotent stem (iPS) cells have enabled researchers to develop brain organoids and microglia from patients and to explore the pathophysiology of neurodevelopmental disorders in human cells. Single-cell RNA sequencing of these cells revealed that human-specific genes are uniquely expressed during cortical development. Thus, patient-derived disease models are expected to identify as-yet-unidentified functions of SHANK3 in the development of human brain. These efforts may help establish a new style of translational research in pediatrics, which is expected to provide therapeutic insight for children with PMS and broader categories of disease. IMPACT: Phelan-McDermid syndrome is a prototypic model for molecular studies of autism spectrum disorder. Brain organoids are expected to provide therapeutic insight. Single-cell RNA sequencing of microglia may uncover the functional roles of human-specific genes.
2020-08-17 | Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B
Abstract Background Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan–McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. Methods Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 10 7 particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. Results Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. Conclusions Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.
2020-06-23 | Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B
Abstract Background: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular-vesicle that contain important molecular information of the cell and are used for cell-to cell communication. Within the fraction of the extracellular-vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. Methods: Exosomes derived from MSC (MSC-exo) were purified, characterized and given via intranasal administration to Shank3B KO mice (in concentration of 10 7 particals/ml). Three weeks post treatment the mice were tested for behavioral scoring and their results were compared to control saline treated and to their wild type littermates. Results: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. Conclusions: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mice model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation. Limitations: Although the behavioral scoring of the MSC-exo treated group was significantly improved compared to their saline treated littermates, there is much more to learn regarding the mechanism of action of the MSC-exo.
proteins
2025-12-26 | NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results.
Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder with no currently approved treatments. NNZ-2591, a synthetic analog of the insulin-like growth factor 1 metabolite cyclic glycine-proline, was evaluated in children and adolescents with PMS in a phase 2, multisite, open-label clinical trial. Participants aged 3-12 years at screening received twice-daily oral NNZ-2591 for 13 weeks; doses were uptitrated from 4 mg/kg to 12 mg/kg over 6 weeks (NCT05025241). Safety and pharmacokinetic profiles were primary end points; 14 efficacy assessments were secondary end points, which included global and symptom-specific PMS assessments, quality of life, communication, behavior, adaptive behavior/self-care, gastrointestinal health, and sleep assessments. Wilcoxon signed-rank tests evaluated change from or observed change relative to baseline vs the null median, with p < 0.05 indicating significance. Eighteen participants received NNZ-2591 (mean [SD] age 8.6 years, mean [SD] weight: 30.4 [10.8] kg). NNZ-2591 was well tolerated; most treatment-emergent adverse events were mild to moderate. Significant improvements from baseline were observed in 10 of 14 efficacy assessments at week 13, including global and symptom-specific PMS assessments, quality of life, behavior, gastrointestinal symptoms, and sleep. At week 13, the PMS-specific Clinical Global Impression (CGI) of Improvement mean (SD) score was 2.4 (0.9) and the median (range) score was 2.0 (1.0, 4.0) (p < 0.0001), with 16 of 18 participants showing improvement; the PMS-specific Caregiver Impression of Change mean (SD) score was 2.7 (1.0) and the median (range) score was 3.0 (1.0, 5.0) (p = 0.0003), with 15 of 18 participants showing improvement. PMS-specific assessment subdomains of communication, cognition/learning, and socialization showed consistent improvements. A 24-hour steady-state area under the curve (AUC24,ss) was estimated for each participant using a one-compartment, linear, population pharmacokinetic model where clearance and volume of distribution parameters were scaled by body weight. Participants with an NNZ-2591 AUC24,ss > 300 μg ⋅ h/mL experienced improvements in the PMS-specific CGI of Improvement scores. For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefit-risk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS. ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022.
2025-03-17 | P166: Safety, efficacy, and exposure-response of NNZ-2591, a synthetic analog of an IGF-1 metabolite, for Phelan-McDermid syndrome in children and adolescents*
Phelan-McDermid syndrome (PMS), a rare genetic condition associated with delayed neurodevelopment, currently has no approved treatments. The treatment effects and pharmacokinetics (PK) of NNZ-2591, a synthetic analog of cyclic glycine-proline (cGP), a metabolite of IGF-1, were evaluated in a phase 2, multisite, open-label clinical trial of children and adolescents with PMS.
2024-05-06 | Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report
Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.
2024-01-01 | P163: Functional assessment of IGF-1 and hGH as candidate treatments for Phelan-McDermid syndrome*
Phelan-McDermid syndrome (PMS) is characterized by variable clinical presentations such as intellectual disability, autistic features, developmental delays, sleep disturbances, as well as different genetic causes, which range from point mutations in the SHANK3 gene to 22q13 deletions of over 9 Megabases. This extensive clinical and genetic variability in PMS has hindered the development of viable treatment options. Several clinical trials have employed insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) to alleviate neurological symptoms in PMS with inconsistent and differing results across the PMS population.
2023-03-14 | An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome.
We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.
gene therapies
2023-10-26 | Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia
Phelan–McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.
2022-03-21 | Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.
Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.
2020-03-30 | Apparent Genetic Rescue of Adult Shank3 Exon 21 Insertion Mutation Mice Tempered by Appropriate Control Experiments.
SHANK3 (ProSAP2) is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan-McDermid syndrome (PMS). We performed genetic rescue of Shank3 mutant phenotypes in adult mice expressing a Shank3 exon 21 insertion mutation (Shank3G ). We used a tamoxifen-inducible Cre/loxP system (CreTam ) to revert Shank3G to wild-type (WT) Shank3+/+ We found that tamoxifen treatment in adult Shank3GCreTam+ mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared to Shank3+/+CreTam+ controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice (Shank3+/+CreTam- and Shank3+/+CreTam+) demonstrated clear effects of CreTam on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the CreTam tamoxifen-inducible system is a powerful tool that successfully rescues Shank3 expression in our Shank3G/G reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.
2018-04-27 | Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32-q13.33 and mosaic monosomy 22
Ring chromosome instability may influence a patient's phenotype and challenge its interpretation. Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient's lymphocytes and skin fibroblasts, respectively, had monosomy 22. We believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the in vivo presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols.
other
2026-01-01 | P377: Response to intravenous immunoglobulin in a patient with Phelan McDermid syndrome and subacute regression
IVIG was initiated at 2 g/kg divided over 2 days (1g/kg per day over 2 days) for presumed autoimmune encephalitis. A gastric tube was also placed during admission to optimize nutrition. The patient was discharged with outpatient follow up to evaluate response to IVIG.
2025-11-24 | Case Report: Co-occurring de novo SHANK3 and SRCAP variants in a patient with autoimmune encephalitis and exhibiting Phelan-McDermid syndrome features.
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by a deletion or variant of SHANK3. Patients with PMS typically present with global developmental delay, delayed or absent speech, intellectual disability, hypotonia, autism spectrum disorder, behavioral abnormalities, and minor specific dysmorphic features. The SRCAP variation is rare and may be associated with chromatin remodeling and neural development. The SRCAP and SHANK3 phenotypes display certain overlapping features, including impaired intellectual and delayed speech development as well as behavioral and psychiatric problems. We report the case of a young male with significant recurrent neuropsychiatric symptoms, developmental regression, and cerebrospinal fluid white blood cell 72/mm3. The diagnosis was consistent with antibody-negative autoimmune encephalitis; the patient improved after immunomodulatory treatment. Whole-exome sequencing identified two de novo pathogenic frameshift variants, one in SHANK3 and the other in SRCAP, with SRCAP being a chimeric variant. Both variants were novel and pathogenic according to the pathogenicity rating provided by the American College of Medical Genetics and Genomics.
2023-02-01 | Elevation of SHANK3 Levels by Antisense Oligonucleotides Directed Against the 3'-UTR of the Human SHANK3 mRNA.
SHANK3 is a member of the SHANK family of scaffolding proteins that localize to the postsynaptic density of excitatory synapses. Mutations within the SHANK3 gene or SHANK3 haploinsufficiency is thought to be one of the major causes for Phelan-McDermid Syndrome (PMDS) that is characterized by a broad spectrum of autism-related behavioral alterations. Several approaches have already been proposed to elevate SHANK3 protein levels in PMDS patients like transcriptional activation or inhibition of SHANK3 degradation. We undertook a systematic screening approach and tested whether defined antisense oligonucleotides (ASOs) directed against the 3′ untranslated region (3′-UTR) of the human SHANK3 mRNA are suitable to elevate SHANK3 protein levels. Using human induced pluripotent stem cells (hiPSCs) and hiPSCs-derived motoneurons from controls and PMDS patients we eventually identified two 18 nucleotide ASOs (ASO 4-5.2-4 and 4-5.2-6) that were able to increase SHANK3 protein levels in vitro by about 1.3- to 1.6-fold. These findings were confirmed by co-transfection of the identified ASOs with a GFP-SHANK3-3′-UTR construct in HEK293T cells using GFP protein expression as read-out. Based on these results we propose a novel approach to elevate SHANK3 protein concentrations by 3′-UTR specific ASOs. Further research is needed to test the suitability of SHANK3-specific ASOs as pharmacological compounds also in vivo.
2019-01-31 | Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism
Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abΔC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC+/− heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abΔC+/− mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abΔC+/− mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abΔC+/− and shank3abΔC−/− mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abΔC+/− larvae. Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD.
2017-02-14 | Proteomic Analysis of Post-synaptic Density Fractions from Shank3 Mutant Mice Reveals Brain Region Specific Changes Relevant to Autism Spectrum Disorder
Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome (PMS), autism spectrum disorder (ASD) and intellectual disability (ID). Although a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the postsynaptic protein scaffold, the molecular processes at synapses of individuals harboring SHANK3 mutations are still far from being understood. In this study, we biochemically isolated the postsynaptic density (PSD) fraction from striatum and hippocampus of adult Shank3Δ11-/- mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes (Data are available via ProteomeXchange with identifier PXD005192). This unbiased approach to identify molecular disturbances at Shank3 mutant PSDs revealed hitherto unknown brain region specific alterations including a striatal decrease of several molecules encoded by ASD susceptibility genes such as the serine/threonine kinase Cdkl5 and the potassium channel KCa1.1. Being the first comprehensive analysis of brain region specific PSD proteomes from a Shank3 mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for SHANK3 mutation-associated synaptopathies and possibly also ASD in general.
small molecules
2026-09-24 | Psychotropic Polypharmacy in a 5-Year-Old Boy with a SHANK3 Variant and Complex Mental Health Problems
Background: Dysfunction of the SHANK3 gene has been linked to several neuropsychiatric and neurodevelopmental disorders, such as attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder, and epilepsy. SHANK3 haploinsufficiency is the known etiology of Phelan–McDermid syndrome. Case presentation: This report presents a five-year-old boy in whom the c.2062G>C; p.Val688Leu variant was identified in a mosaic state in the SHANK3 gene (40% of heterozygous cells) and classified as a variant of uncertain significance (VUS). The patient was diagnosed with complex mental health problems, which, analogous to typical SHANK3 disruption, included ADHD, oppositional defiant disorder, developmental coordination disorder, Non-REM sleep arousal disorder, insomnia disorder, and avoidant/restrictive food intake disorder. Starting at the age of three years, his psychiatric treatment had included various medication trials over the course of two years. Ultimately, a substantial reduction in emotional outbursts, externalizing behaviors, and parental stress occurred following a multimodal treatment approach comprising psychotropic polypharmacy (PP), i.e., lisdexamfetamine, melatonin, and risperidone, along with behavioral therapy interventions, speech therapy, and occupational therapy. Under this PP, constipation was documented as the only adverse reaction. At the 15-month follow-up, improvements had been quite stable, despite risperidone medication being stopped about 19 weeks after initiation. Conclusions: As shown in this case report, even very young children with complex neuropsychiatric problems and SHANK3 variants might not be treated sufficiently by therapeutic interventions alone, but might require a combination of therapeutic and psychopharmacological interventions to achieve a substantial symptom reduction. However, PP must be approached with a high degree of caution and subjected to close monitoring in children with SHANK3 variants, who are susceptible to an elevated risk of adverse outcomes. Moreover, given the paucity of research in this population, it seems advisable to follow prevailing general guidelines in child and adolescent psychiatry.
2026-09-01 | 851. A mechanism for PHF21B recognition of H3K36me3
Abstract Background We have recently identified the epigenetic reader PHF21B as a regulator of synaptic plasticity and social memory in mice. The PHF21B gene is located on chromosome 22q13.3, a region that is deleted in Phelan-McDermid syndrome, a neurodevelopmental disorder characterized by intellectual disability, impaired social communication, and features overlapping with autism spectrum disorder. We have previously shown that PHF21B interacts with H3K36me3, an epigenetic mark associated with active gene expression and critical roles in transcription, splicing, and genomic stability. Deficiencies in H3K36me3 are associated with various cancers and developmental disorders. However, the structural domain that mediates the interaction between PHF21B and H3K36me3 has yet to be characterized. Aims & Objectives The identification of the specific protein domain in PHF21B that is required for H3K36me3 recognition could provide mechanistic insights relevant to understanding and treating PHF21B-associated neurodevelopmental features. Method Myc-tagged wild-type PHF21B and mutants PHF21BΔPHDZnf and PHF21B ΔCc, which respectively lack the PHD-zinc finger domain in residues 352–465 and the C-terminal region in residues 423–531, were generated and expressed in HEK293T cells. The interaction between PHF21B and H3K36me3 was assessed by bidirectional co-immunoprecipitation and anti-Myc and anti-H3K36me3 antibodies, followed by western blotting. GFP-transfected cells were used as negative controls. Results H3K36me3 was immunoprecipitated by wild-type PHF21B and PHF21B ΔCc, but not by PHF21B ΔPHDZnf (P < 0.001, one-way ANOVA with Tukey's post-hoc test). These findings were confirmed by reciprocal co-immunoprecipitation, where Anti-H3K36me3 antibodies pulled down wild-type PHF21B and PHF21B ΔCc, but not PHF21B ΔPHDZnf. Therefore, H3K36me3 binding was abolished in the ΔPHDZnf mutant. Discussion & Conclusions The PHD-zinc finger domain of PHF21B is necessary for its interaction with H3K36me3, and the C-terminal region is dispensable. Given that PHF21B reads active chromatin marks at synaptic plasticity genes, disruption of this PHD-zinc finger–H3K36me3 interface may underlie transcriptional dysregulation in neurodevelopmental conditions associated with 22q13.3 deletions. We have defined a specific protein domain that could serve as a therapeutic target for Phelan-McDermid syndrome. Future studies will need to examine whether the PHD-zinc finger domain is sufficient to rescue the neuronal functions of PHF21B.
2026-09-01 | 865. Metformin as a treatment of Fragile X and Phelan McDermid syndromes
Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms of persistent deficits in social communication and interaction, and repetitive behavior. Worldwide prevalence ranges between 1-2 %, with an incidence rate 4 times higher in males than females. Unfortunately, about 40% of children with ASD do not respond to standard behavioral and medical treatments. Aims & Objectives For the moment we are focusing on mouse models of Fragile X syndrome (FXS) and Phelan McDermid Syndrome (PMS), in both males and females. These 2 neurodevelopmental disorders have a very high incidence of ASD. Method We are studying the therapeutic effects of metformin, an FDA approved drug, for treating symptoms associated with ASD at a behavioral level. In addition, ERK/MAPK and mTOR pathways, involved in controlling mRNA translation, are overactivated in several brain areas of FXS and PMS mouse models. Results Metformin treatment, an inhibitor of these pathways, showed high efficacy in correcting pathway signaling and behavior in fragile X syndrome (FXS) fly and mouse models, and in male and female mouse models of PMS. Discussion & Conclusions Our work broadens the understanding of the effects of metformin on ASD and potentially supports the implementation of clinical strategies to alleviate symptoms associated with these neurological disorders in both sexes.
2026-08-20 | Phelan-McDermid Syndrome Clinical Trials: Approved Therapies, Pivotal Trial Endpoints, Clinical Failures, and Drug Development Insights
A comprehensive overview of Phelan-McDermid Syndrome (PMS), including disease background, current treatment landscape, failed clinical trials, key efficacy endpoints, emerging SHANK3-targeted therapies, and strategies for designing successful FDA-ready clinical trials.
2026-08-14 | Severe Expressive Language Impairment and Infection-Associated Dystonic Deterioration with Multidomain Improvement After Levodopa Initiation in SHANK3-Related Disorder: A Case Report and Focused Literature Review
SHANK3-related disorder within the Phelan-McDermid syndrome spectrum is clinically heterogeneous and commonly includes severe expressive language impairment, hypotonia, motor coordination difficulties, sensory features, sleep disturbance, reduced pain expression, and regression in a subset of affected individuals. However, a potential dystonic contribution to expressive language impairment, orofacial dysfunction, other motor abnormalities, and illness-associated functional deterioration has not been systematically examined. Case Presentation: We report a 7-year-old girl whose early presentation was dominated by severe expressive language delay. Receptive communication, social reciprocity and practical problem-solving appeared substantially stronger than expressive output suggested. Longitudinal features included fine-motor incoordination, toe walking, intermittent atypical hand movements, sensory reactivity, overload-associated dysregulation and prolonged mouthing/oral exploration of objects. During febrile illness in March 2025, she developed painful gait deterioration, continuous toe walking, dystonic hand posturing and worsening orofacial motor function. Low-dose levodopa was initiated because dopa-responsive dystonia or a related dopaminergic disorder was clinically considered. Following initiation of levodopa, improvements were observed across several functional domains that had shown only slow progress or prolonged plateau phases during the preceding years. Short-read whole-genome sequencing identified a heterozygous pathogenic SHANK3 frameshift variant, NM_001372044.2:c.3904dup, with the predicted protein consequence NP_001358973.1:p.(Ala1302fs). With continued levodopa and later trihexyphenidyl, further gains were observed across gait stability, orofacial control, spoken language output, sensory tolerance and functional participation; the previously persistent mouthing/oral exploration was no longer observed after dopaminergic treatment had been established. Conclusion: Across neurodevelopmental disorders of diverse genetic aetiology and across age groups, the co-occurrence of marked expressive language impairment, orofacial dysfunction, and fine- or gross-motor abnormalities should prompt targeted assessment for dystonia or another movement disorder. Such motor manifestations may represent a convergent and potentially modifiable component of the clinical phenotype, including previously unrecognized impairment of speech-motor control. The multidomain improvement observed following initiation of levodopa in this case of SHANK3-related disorder was clinically meaningful and hypothesis-generating and warrants prospective investigation.
cell therapies
2026-02-22 | Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models.
Extracellular vesicles (EVs) are lipid bilayer-enclosed structures that mediate intercellular communication by transferring diverse cargoes, including RNA and proteins. SHANK3, a synaptic scaffolding protein critical for synapse structure and function, is implicated in autism spectrum disorder (ASD) and Phelan-McDermid Syndrome (PMS). Early hyperexcitability in cortical neurons is a characterized endophenotype in ASD. Here, we investigated EV-mediated effects in the context of SHANK3 deficiency using human iPSC-derived cortical neurons and Shank3B-/- mice. Switching EVs between SHANK3 mutant and control neurons revealed that SHANK3 mutant-derived EVs transferred the hyperexcitability and accelerated maturation phenotypes to control neurons. Proteomic analysis revealed enrichment of synaptic structural regulators (e.g., ACTB, CFL1, AGRN, and CLSTN1) in SHANK3 mutant neuron-derived EVs. This is consistent with known actin cytoskeletal dysregulation driven by SHANK3 deficiency. However, control neuron-derived EVs failed to rescue mutant phenotypes, likely due to their decreased enrichment of synaptic proteins and related pathways. Further, EVs from mesenchymal stem cells (MSCs) and healthy donor iPSCs, containing synaptic modulators such as complement proteins (C1R, C1S), plasticity-associated proteins (MDK, IGFBP3), and homeostatic regulators (FGF2, SFRP1), rescued the hyperexcitability and normalized the maturation in SHANK3 mutant neurons. In addition, intranasal administration of iPSC-derived EVs in Shank3B-/- mice significantly rescued ASD-like behavioral deficits, emphasizing their therapeutic potential. Together, these findings reveal a novel EV-mediated mechanism for modulating dysregulated excitability and synaptic maturation, addressing a critical unmet need in ASD and associated neurodevelopmental disorders.
2024-08-27 | Exosomes can modulate the early hyperexcitability in cortical neurons with ASD-associated Shank3 mutation.
ABSTRACT Shank3 , a scaffolding protein, is critical for synaptic structure and function, particularly for the formation and maintenance of dendritic spines. Shank3 mutations are strongly implicated in autism spectrum disorder (ASD) and related neuropsychiatric conditions such as Phelan-McDermid Syndrome (PMS) also known as the 22q13.3 deletion syndrome. Previous work has recognized early hyperexcitability in cortical neurons derived from ASD patients with various gene mutations as a potential common endophenotype. In this study, we examined the effects of exosomes extracted from several cell types on the neurophysiological properties of cortical neurons derived from Shank3 (c.3679insG mutation) induced pluripotent stem cells (iPSCs). First, we sought to understand the implications of exosome-based intercellular communication on the neurophysiology of Shank3 mutant and control neurons by switching their respective exosomes. We found that while control neuron-derived exosomes do not change the neurophysiology of Shank3 neurons, the Shank3 neuron-derived exosomes transfer the early hyperexcitability and other ASD-related phenotypes to control neurons. Next, we also explored the therapeutic potential of mesenchymal stem cells (MSC) and iPSC-derived exosomes from healthy donors in the Shank3 cortical neurons. We demonstrate that both MSC and iPSC-derived exosomes rescue the early hyperexcitability and accelerated maturation of Shank3 neurons. Proteomic analysis of exosomes derived from Shank3 mutant and control neurons, as well as from exosomes derived from MSCs and iPSCs, revealed distinct protein cargoes that may cause changes in the neurophysiological properties of the recipient neurons. Our results hence provide novel insights into the pathophysiology of ASD emphasizing the importance of exosomes in intercellular communication and their potential to influence intrinsic and network properties of neurons. Moreover, our findings support the need for further exploration of exosome-based interventions as potential therapeutics for treating neurodevelopmental disorders.
2022-10-03 | Translational pediatrics: clinical perspective for Phelan-McDermid syndrome and autism research.
Phelan-McDermid syndrome (PMS) is a rare genetic disorder presenting with developmental delay, epilepsy, and autism spectrum disorder (ASD). The segmental deletion of chromosome 22q13.3 affects the copy number of SHANK3, the gene encoding a scaffolding protein at the postsynaptic density. Biological studies indicate that SHANK3 plays crucial roles in the development of synaptic functions in the postnatal brain. Notably, induced pluripotent stem (iPS) cells have enabled researchers to develop brain organoids and microglia from patients and to explore the pathophysiology of neurodevelopmental disorders in human cells. Single-cell RNA sequencing of these cells revealed that human-specific genes are uniquely expressed during cortical development. Thus, patient-derived disease models are expected to identify as-yet-unidentified functions of SHANK3 in the development of human brain. These efforts may help establish a new style of translational research in pediatrics, which is expected to provide therapeutic insight for children with PMS and broader categories of disease. IMPACT: Phelan-McDermid syndrome is a prototypic model for molecular studies of autism spectrum disorder. Brain organoids are expected to provide therapeutic insight. Single-cell RNA sequencing of microglia may uncover the functional roles of human-specific genes.
2020-08-17 | Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B
Abstract Background Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan–McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. Methods Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 10 7 particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. Results Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. Conclusions Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.
2020-06-23 | Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B
Abstract Background: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular-vesicle that contain important molecular information of the cell and are used for cell-to cell communication. Within the fraction of the extracellular-vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. Methods: Exosomes derived from MSC (MSC-exo) were purified, characterized and given via intranasal administration to Shank3B KO mice (in concentration of 10 7 particals/ml). Three weeks post treatment the mice were tested for behavioral scoring and their results were compared to control saline treated and to their wild type littermates. Results: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. Conclusions: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mice model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation. Limitations: Although the behavioral scoring of the MSC-exo treated group was significantly improved compared to their saline treated littermates, there is much more to learn regarding the mechanism of action of the MSC-exo.
proteins
2025-12-26 | NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results.
Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder with no currently approved treatments. NNZ-2591, a synthetic analog of the insulin-like growth factor 1 metabolite cyclic glycine-proline, was evaluated in children and adolescents with PMS in a phase 2, multisite, open-label clinical trial. Participants aged 3-12 years at screening received twice-daily oral NNZ-2591 for 13 weeks; doses were uptitrated from 4 mg/kg to 12 mg/kg over 6 weeks (NCT05025241). Safety and pharmacokinetic profiles were primary end points; 14 efficacy assessments were secondary end points, which included global and symptom-specific PMS assessments, quality of life, communication, behavior, adaptive behavior/self-care, gastrointestinal health, and sleep assessments. Wilcoxon signed-rank tests evaluated change from or observed change relative to baseline vs the null median, with p < 0.05 indicating significance. Eighteen participants received NNZ-2591 (mean [SD] age 8.6 years, mean [SD] weight: 30.4 [10.8] kg). NNZ-2591 was well tolerated; most treatment-emergent adverse events were mild to moderate. Significant improvements from baseline were observed in 10 of 14 efficacy assessments at week 13, including global and symptom-specific PMS assessments, quality of life, behavior, gastrointestinal symptoms, and sleep. At week 13, the PMS-specific Clinical Global Impression (CGI) of Improvement mean (SD) score was 2.4 (0.9) and the median (range) score was 2.0 (1.0, 4.0) (p < 0.0001), with 16 of 18 participants showing improvement; the PMS-specific Caregiver Impression of Change mean (SD) score was 2.7 (1.0) and the median (range) score was 3.0 (1.0, 5.0) (p = 0.0003), with 15 of 18 participants showing improvement. PMS-specific assessment subdomains of communication, cognition/learning, and socialization showed consistent improvements. A 24-hour steady-state area under the curve (AUC24,ss) was estimated for each participant using a one-compartment, linear, population pharmacokinetic model where clearance and volume of distribution parameters were scaled by body weight. Participants with an NNZ-2591 AUC24,ss > 300 μg ⋅ h/mL experienced improvements in the PMS-specific CGI of Improvement scores. For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefit-risk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS. ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022.
2025-03-17 | P166: Safety, efficacy, and exposure-response of NNZ-2591, a synthetic analog of an IGF-1 metabolite, for Phelan-McDermid syndrome in children and adolescents*
Phelan-McDermid syndrome (PMS), a rare genetic condition associated with delayed neurodevelopment, currently has no approved treatments. The treatment effects and pharmacokinetics (PK) of NNZ-2591, a synthetic analog of cyclic glycine-proline (cGP), a metabolite of IGF-1, were evaluated in a phase 2, multisite, open-label clinical trial of children and adolescents with PMS.
2024-05-06 | Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report
Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.
2024-01-01 | P163: Functional assessment of IGF-1 and hGH as candidate treatments for Phelan-McDermid syndrome*
Phelan-McDermid syndrome (PMS) is characterized by variable clinical presentations such as intellectual disability, autistic features, developmental delays, sleep disturbances, as well as different genetic causes, which range from point mutations in the SHANK3 gene to 22q13 deletions of over 9 Megabases. This extensive clinical and genetic variability in PMS has hindered the development of viable treatment options. Several clinical trials have employed insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) to alleviate neurological symptoms in PMS with inconsistent and differing results across the PMS population.
2023-03-14 | An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome.
We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.
gene therapies
2023-10-26 | Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia
Phelan–McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.
2022-03-21 | Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.
Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.
2020-03-30 | Apparent Genetic Rescue of Adult Shank3 Exon 21 Insertion Mutation Mice Tempered by Appropriate Control Experiments.
SHANK3 (ProSAP2) is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan-McDermid syndrome (PMS). We performed genetic rescue of Shank3 mutant phenotypes in adult mice expressing a Shank3 exon 21 insertion mutation (Shank3G ). We used a tamoxifen-inducible Cre/loxP system (CreTam ) to revert Shank3G to wild-type (WT) Shank3+/+ We found that tamoxifen treatment in adult Shank3GCreTam+ mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared to Shank3+/+CreTam+ controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice (Shank3+/+CreTam- and Shank3+/+CreTam+) demonstrated clear effects of CreTam on baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while the CreTam tamoxifen-inducible system is a powerful tool that successfully rescues Shank3 expression in our Shank3G/G reversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.
2018-04-27 | Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32-q13.33 and mosaic monosomy 22
Ring chromosome instability may influence a patient's phenotype and challenge its interpretation. Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient's lymphocytes and skin fibroblasts, respectively, had monosomy 22. We believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the in vivo presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols.
other
2026-01-01 | P377: Response to intravenous immunoglobulin in a patient with Phelan McDermid syndrome and subacute regression
IVIG was initiated at 2 g/kg divided over 2 days (1g/kg per day over 2 days) for presumed autoimmune encephalitis. A gastric tube was also placed during admission to optimize nutrition. The patient was discharged with outpatient follow up to evaluate response to IVIG.
2025-11-24 | Case Report: Co-occurring de novo SHANK3 and SRCAP variants in a patient with autoimmune encephalitis and exhibiting Phelan-McDermid syndrome features.
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by a deletion or variant of SHANK3. Patients with PMS typically present with global developmental delay, delayed or absent speech, intellectual disability, hypotonia, autism spectrum disorder, behavioral abnormalities, and minor specific dysmorphic features. The SRCAP variation is rare and may be associated with chromatin remodeling and neural development. The SRCAP and SHANK3 phenotypes display certain overlapping features, including impaired intellectual and delayed speech development as well as behavioral and psychiatric problems. We report the case of a young male with significant recurrent neuropsychiatric symptoms, developmental regression, and cerebrospinal fluid white blood cell 72/mm3. The diagnosis was consistent with antibody-negative autoimmune encephalitis; the patient improved after immunomodulatory treatment. Whole-exome sequencing identified two de novo pathogenic frameshift variants, one in SHANK3 and the other in SRCAP, with SRCAP being a chimeric variant. Both variants were novel and pathogenic according to the pathogenicity rating provided by the American College of Medical Genetics and Genomics.
2023-02-01 | Elevation of SHANK3 Levels by Antisense Oligonucleotides Directed Against the 3'-UTR of the Human SHANK3 mRNA.
SHANK3 is a member of the SHANK family of scaffolding proteins that localize to the postsynaptic density of excitatory synapses. Mutations within the SHANK3 gene or SHANK3 haploinsufficiency is thought to be one of the major causes for Phelan-McDermid Syndrome (PMDS) that is characterized by a broad spectrum of autism-related behavioral alterations. Several approaches have already been proposed to elevate SHANK3 protein levels in PMDS patients like transcriptional activation or inhibition of SHANK3 degradation. We undertook a systematic screening approach and tested whether defined antisense oligonucleotides (ASOs) directed against the 3′ untranslated region (3′-UTR) of the human SHANK3 mRNA are suitable to elevate SHANK3 protein levels. Using human induced pluripotent stem cells (hiPSCs) and hiPSCs-derived motoneurons from controls and PMDS patients we eventually identified two 18 nucleotide ASOs (ASO 4-5.2-4 and 4-5.2-6) that were able to increase SHANK3 protein levels in vitro by about 1.3- to 1.6-fold. These findings were confirmed by co-transfection of the identified ASOs with a GFP-SHANK3-3′-UTR construct in HEK293T cells using GFP protein expression as read-out. Based on these results we propose a novel approach to elevate SHANK3 protein concentrations by 3′-UTR specific ASOs. Further research is needed to test the suitability of SHANK3-specific ASOs as pharmacological compounds also in vivo.
2019-01-31 | Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism
Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abΔC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC+/− heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abΔC+/− mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abΔC+/− mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abΔC+/− and shank3abΔC−/− mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abΔC+/− larvae. Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD.
2017-02-14 | Proteomic Analysis of Post-synaptic Density Fractions from Shank3 Mutant Mice Reveals Brain Region Specific Changes Relevant to Autism Spectrum Disorder
Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome (PMS), autism spectrum disorder (ASD) and intellectual disability (ID). Although a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the postsynaptic protein scaffold, the molecular processes at synapses of individuals harboring SHANK3 mutations are still far from being understood. In this study, we biochemically isolated the postsynaptic density (PSD) fraction from striatum and hippocampus of adult Shank3Δ11-/- mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes (Data are available via ProteomeXchange with identifier PXD005192). This unbiased approach to identify molecular disturbances at Shank3 mutant PSDs revealed hitherto unknown brain region specific alterations including a striatal decrease of several molecules encoded by ASD susceptibility genes such as the serine/threonine kinase Cdkl5 and the potassium channel KCa1.1. Being the first comprehensive analysis of brain region specific PSD proteomes from a Shank3 mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for SHANK3 mutation-associated synaptopathies and possibly also ASD in general.
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Drug Discovery Landscape
5 orphan drug designations for Phelan-McDermid syndrome.
5 orphan drug designations for Phelan-McDermid syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
N-omega-propyl-l-arginine phosphate salt | small molecules | FDA | — | nNOS U.S., Inc. |
insulin-like growth factor-1(IGF-1) | proteins | FDA | Sarcomed AB | |
adeno-associated virus 2/9 expressing a miniature version of the human SHANK3 gene (AAV2/9-miniSHANK3) | gene therapies | FDA | Jaguar Gene Therapy, LLC | |
Cyclo-L-glycyl-L-2-allylproline | small molecules | EMA | Orphix Consulting GmbH | |
Cyclo(-L-Glycyl-L-2-Allylproline) | small molecules | FDA | Neuren Pharmaceuticals, Ltd. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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