Shani Stern

WOREE and SCAR12 syndromes are rare neurodevelopmental disorders caused by WWOX mutations, severely impairing brain development. The pleiotropic nature of WWOX complicates identifying specific mechanisms, thus, the specific molecular pathways affected by WWOX deficiency and how they contribute to disease pathogenesis remain largely unknown. Using neural organoids derived from a broad iPSC cohort, including wildtype iPSCs, CRISPR-edited isogenic WWOX-knockout lines, and patient-derived lines, we applied molecular profiling and single-cell transcriptomics to map the early neurodevelopmental pathways disrupted upon loss of WWOX. We identified radial glial cells (RGs) as preferentially affected, with disrupted cell cycle dynamics leading to an accumulation of cells in the G2/M and S phases, overexpression of the proto-oncogene MYC, and concomitant reduction in neuronal generation. Patient-derived organoids exhibited milder phenotypes compared to knockout organoids, showing functional neuronal impairments like hyperexcitability and delayed differentiation rather than RG dysfunction. Remarkably, gene therapy restored neuronal function, normalizing hyperexcitability and promoting maturation, without disturbing RG populations. We propose a model in which WWOX mutations impair neurogenesis via RG through cell-type specific dysregulation of the MYC and Wnt signaling pathways. These insights highlight potential therapeutic strategies for WWOX-related disorders and open avenues for interventions targeting these key molecular pathways.

Parkinson's disease (PD) pathogenesis often involves progressive α-synuclein (α-Syn)-mediated neuronal dysfunction, yet the earliest cellular events that link α-Syn pathology to circuit failure remain poorly defined. Here, we used human induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons from patients carrying the familial A53T SNCA mutation to reconstruct a temporal course of dysfunction in vitro. We identified a biphasic trajectory with an early phase of hyperexcitability, characterized by elevated spontaneous firing, followed by a progressive transition into hypoexcitability as the neurons mature, accompanied by reduced network activity, synaptic dysfunction, and α-Syn accumulation. Transcriptomic profiling at the critical transition point revealed a dual transcriptional signature, with upregulation of stress-inflammatory pathways (p53, JAK-STAT, apoptosis) coupled with systematic downregulation of metabolic and synaptic maintenance genes. This molecular profile preceded functional collapse, linking early hyperactivity-driven metabolic stress to subsequent neuronal exhaustion. To counteract this pathology, we used extracellular vesicles (EVs), small membrane-bound particles carrying intercellular signals, as a cell-free treatment approach. Strikingly, treatment with EVs derived from healthy iPSCs completely rescued both electrophysiological deficits and pathological α-Syn accumulation, restoring normal firing patterns, synaptic function, and network activity. Consistent with these observations, EV treatment reduced α-Syn aggregation and improved motor responses in α-Syn fibril-injected mice, which are characterized by pathological α-Syn accumulation and motor deficits. Overall, these findings demonstrate that EVs derived from healthy iPSCs can reverse PD-related phenotypes in human and mouse models.

Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood–brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.

Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood–brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson’s, Huntington’s, and Alzheimer’s diseases is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.

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.

7q11.23 Duplication Syndrome (7Dup) is a type of syndromic autism spectrum disorder caused by duplication of a typically 1.5-1.8 Mb segment in section q11.23 of chromosome 7, including 25-27 genes. Previous work has highlighted the GTF2I gene as playing a major role in the phenotype of 7Dup patients. Accordingly, mice with Gtf2i duplication ( Gtf2i ^+/dup ) are commonly used as an animal model of 7Dup. We previously reported deficits in several behavioral and physiological modalities, which were associated with Gtf2i dosage in mice conducting a battery of social discrimination tests. Here, we report the effect of treating Gtf2i ^+/dup mice with Baicalin, a naturally occurring flavonoid added to the mice’s drinking water (0.15 mg/ml), on these deficits. We found that Baicalin treatment ameliorated the higher surface temperature observed in Gtf2i ^+/dup males and the lower tail temperature observed in Gtf2i ^+/dup females during the social behavior tests. It also prevented the increased defecation rate exhibited by Gtf2i ^+/dup mice during the social preference test. We further analyzed the effect of Baicalin treatment on cortical neurons differentiated from 7Dup patient-derived IPSCs. Using whole cell patch clamp and calcium imaging, we found an increased rate of excitatory postsynaptic currents in Baicalin-treated cells, without a change in their firing rate, indicating a stronger synaptic activity in the Baicalin-treated cells. Altogether, our results reveal that Baicalin administration alleviates some of the behavioral and physiological effects of Gtf2i duplication in mice, and affects neuronal activity in cultured 7Dup human neurons. Thus, Baicalin administration has the potential to serve as a treatment for 7Dup patients.

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), arises from complex genetic and environmental interactions. Here, we integrate genome-wide association study (GWAS) meta-analyses with tissue-specific expression data from GTEx to map the polygenic architecture of IBD and its systemic implications. We identified 69 genome-wide significant single-nucleotide polymorphisms (SNPs) across 26 genes shared by CD and UC, revealing an almost equal partition of subtype-specific (50.7%) and shared (49.3%) risk variants. IL23R exhibited the highest allelic heterogeneity—three UC-specific, one CD-specific, and three shared SNPs—while ATG16L1′s four CD-specific variants underscored autophagy’s pivotal role in CD. Chromosomal mapping revealed distinct regulatory hotspots: UC-only loci on chromosomes 1 and 6, CD-only loci on chromosomes 10 and 16, and shared loci on chromosomes 7 and 19. Pathway enrichment emphasized IL-23/IL-17, Th17 differentiation, NF-κB, and JAK–STAT signaling as central to IBD pathogenesis. GTEx analyses showed uniformly high expression of IBD genes in gastrointestinal tissues, but pronounced heterogeneity across brain regions, including the cerebellum, frontal cortex, and hippocampus. This neuro-expression, together with enrichment of neurotrophin and neurodegeneration pathways and a nearly two-fold gene overlap with autism spectrum disorder, schizophrenia, and depression (FDR < 0.05), provides integrative evidence for gut–brain axis involvement in IBD. These findings consolidate prior work while extending perspectives on systemic disease implications. This study consolidates and systematizes dispersed genetic and transcriptomic findings into a unified reference framework. Our results highlight recurrent immune-regulatory and neuro-inflammatory pathways shared between gut and brain, offering a resource to guide future mechanistic, clinical, and translational investigations in IBD and related disorders.

Schizophrenia is a highly polygenic and clinically heterogeneous disorder. In this paper, we first review layer-specific evidence across genetics, epigenetics, transcriptomics, proteomics, and patient-derived induced pluripotent stem cell (iPSC) models, then integrate cross-layer findings. Genetics research identifies widespread risk architecture. Hundreds of loci from common, rare, and CNV analyses. Epigenetics reveals disease-associated DNA methylation and histone-mark changes. These occur at neuronally active enhancers and promoters, together with chromatin contacts that link non-coding risk to target genes. Transcriptomics show broad differential expression, isoform-level dysregulation, and disrupted co-expression modules. These alterations span synaptic signaling, mitochondrial bioenergetics, and immune programs. Proteomics demonstrates coordinated decreases in postsynaptic scaffold and mitochondrial respiratory-chain proteins in cortex, with complementary inflammatory signatures in serum/plasma. iPSC models recapitulate disease-relevant phenotypes: including fewer synaptic puncta and excitatory postsynaptic currents, electrophysiological immaturity, oxidative stress, and progenitor vulnerability. These same models show partial rescue under targeted perturbations. Integration across layers highlights convergent pathways repeatedly supported by ≥3 independent data types: synaptic signaling, immune/complement regulation, mitochondrial/energetic function, neurodevelopmental programs and cell-adhesion complexes. Within these axes, several cross-layer convergence genes/proteins (e.g., DLG4/PSD-95, C4A, RELN, NRXN1/NLGN1, OXPHOS subunits, POU3F2/BRN2, PTN) recur across cohorts and modalities. Framing results through cross-layer and shared-pathway convergence organizes heterogeneous evidence and prioritizes targets for mechanistic dissection, biomarker development, and translational follow-up.

Induced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. Furthermore, these abnormalities are normalised after the application of lithium in neurons derived from clinical lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus. We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into dentate gyrus networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using a linear mixed-effects model. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results mirror previous research demonstrating that mnemonic discrimination improves after lithium therapy in lithium responders only, supporting a hypothesised link between behavioural mnemonic discrimination and dentate gyrus PS. Our work can be expanded to also consider the effects of lithium-induced neurogenesis on PS.