Biology subjects

Obeid, M.

Publications and source records attributed to Obeid, M..

4 recordsLinked to original sources

bioRxiv2026

Modeling and targeting haploinsufficiency in SHINE syndrome

DLG4-related Synaptopathy, or SHINE syndrome, is a neurodevelopmental disorder caused by de novo heterozygous variants in DLG4 gene, encoding the postsynaptic scaffold PSD-95. Although clinical and genetic evidence support haploinsufficiency, the consequences of pathogenic DLG4 variants in human neurons remain poorly defined. Here, we model three mutations spanning distinct protein domains: a frameshift, nonsense and a missense mutation using iPSC-derived excitatory neurons. Molecular analysis of mature neurons reveals shared PSD-95 deficiency irrespective of transcript levels, together with reduced mature spine density. High-density microelectrode array recordings further reveal convergent and mutationspecific electrophysiological signatures at both single-neuron and network levels, as mutant cultures display genotype-dependent shifts in extracellular waveform states associated with altered firing dynamics. Importantly, restoration of PSD-95 levels using an adeno-associated viral vector (AAV9) harboring human DLG4 cDNA and driven by the human neuronal Synapsin I promoter (AAV9-hSynI-DLG4) rescues PSD95 abundance and associated cellular and electrophysiological deficits. Together, these findings establish DLG4 haploinsufficiency as a shared consequence of pathogenic DLG4 variants, while revealing additional variant-associated effects on neuronal structure and activity, rescued by AAV9-mediated neuronal restoration.

neuroscience↗

bioRxiv2026

Neuron-Specific WWOX Gene Therapy Produces Dose-Dependent, Durable Rescue in a Model of WWOX-Related Epileptic Encephalopathy

Biallelic loss-of-function mutations in WWOX cause a spectrum of neurodevelopmental disorders, including the severe, early-onset WOREE syndrome, frequently associated with intractable epilepsy and premature mortality, and the milder SCAR12, characterized by subtler neurological manifestations. While neuronal replacement of WWOX has emerged as a potential therapeutic strategy, the parameters required for safe, durable, and clinically translatable gene delivery remain undefined. Here, we systematically delineate the determinants of effective WWOX gene therapy by evaluating promoter selection, cellular targeting, vector configuration, dose, and developmental timing in a severe Wwox-null mouse model. Neuron-restricted expression driven by the human Synapsin I promoter uniquely enabled sustained phenotypic correction, whereas ubiquitous or oligodendrocyte-restricted expression failed to confer durable benefit. To better regulate transgene expression, we generated a vector lacking the WPRE element, enabling dose calibration within a clinically relevant range. Comparative dose-response analyses identified an optimal therapeutic dose of AAV9-hSynI-WWOX that produced robust, dose-dependent rescue of survival and growth. Moreover, the rescued mice displayed glucose, behavioral function and fertility indistinguishable from WT mice, accompanied by long-term restoration of WWOX DNA, transcript, and protein across central and peripheral neural tissues without detectable hepatic expression. Neuronal WWOX reconstitution promoted widespread myelination and attenuated neuroinflammatory responses, including astrogliosis and microglial activation to levels indistinguishable from WT. Continuous electrocorticographic monitoring uncovered early postnatal neuronal hyperexcitability in Wwox-null mice, which was effectively suppressed by therapeutic WWOX delivery. Finally, our data define an early postnatal therapeutic window in Wwox-null mice, showing that treatment initiated between postnatal days 1 and 5 supports durable rescue. Together, these findings define a rigorously optimized, neuron-targeted AAV9-WWOX gene therapy framework and establish critical design and timing principles for translational treatment of WWOX-associated developmental and epileptic encephalopathies.

neuroscience↗

bioRxiv2025

Rapid-Response, High-Gain Inkjet-Printed Organic Electrochemical Transistors with Geometry-Optimized Design for Neural Recording and Biosensing

Organic Electrochemical Transistors (OECTs) are witnessing rapid growth in biomedical applications and are increasingly becoming an integral part of bio-electronic interfaces. High-performing OECTs are typically fabricated using multistep photolithography and conventional spin-coating and lift-off processes, and while printing techniques have emerged as promising alternatives, they still face challenges in achieving comparable resolutions, reproducibility and performance metrics. Several groups have demonstrated printed OECTs using PEDOT:PSS as the channel material, highlighting the promise of additive manufacturing for scalable bioelectronics. In this work, we build upon these advances and develop an optimized inkjet-printed OECT platform that achieves transconductance values up to 15 mS and sub-millisecond response times as low as 0.31 ms. Our approach systematically optimizes OECT geometrical parameters--channel width, length, and thickness--through precise patterning and oxygen plasma surface modification to overcome longstanding limitations in inkjet printing resolution and reproducibility. The resulting devices exhibit outstanding electrical stability, high amplification, and fast dynamic response. Using a configuration optimized for biosensing, we demonstrate the detection of the heart failure biomarker NT-proBNP within a clinically relevant range of 10-400 pg/mL, with a sensitivity of 0.038% {Delta}IDS/pg/mL. In a separate configuration on a flexible substrate tailored for in vivo biopotential recording, we showcase the devices capabilities by effectively capturing epileptic seizure progression in a rat model with high signal fidelity. This work demonstrates how careful process and geometry optimization can close the performance gap between printed and conventionally fabricated OECTs, enabling scalable, reproducible, and substrate-flexible bioelectronic platforms.

bioengineering↗

bioRxiv2025

Ultraflexible, Biodegradable ECoG Arrays via Rapid Fabrication Enables High-Resolution Cortical Mapping and Seizure Network Classification In Vivo

Neural interfaces are essential tools for diagnosing and managing neurological disorders, yet conventional electrocorticography (ECoG) devices are limited by mechanical mismatch with brain tissue, chronic inflammation, and poor scalability. Here, we introduce a fully inkjet-printed, flexible, and biodegradable ECoG array fabricated on ultrathin polycaprolactone films with gold nanoparticle electrodes. The arrays achieve among the highest electrode densities reported for additive manufacturing (7.44 electrodes/mm{superscript 2}) while maintaining low impedance (10.6 k{Omega} at 1 kHz) and high-fidelity recordings (SNR 28 dB). A rapid, maskless prototyping process relying on photonic sintering enables scalable, cost-effective fabrication. In vivo, the devices conformally mapped cortical seizure propagation and resolved distinct ictal dynamics in a rat model. Histology at 30 days confirmed preserved neuronal density and astrocytic response comparable to controls, indicating minimal chronic inflammation. A convolutional neural network trained on recorded signals classified seizure stages with >95% accuracy, underscoring the translational potential for real-time monitoring and closed-loop neuromodulation. This platform unites rapid prototyping, biodegradability, and high performance, providing a scalable route toward next-generation, patient-specific, and disposable neural interfaces for epilepsy and other neuroengineering applications.

bioengineering↗