Neurological Disease Models for Efficacy Evaluation

Rett Syndrome

Identifying effective therapeutics with human neural models

CNS-3D technology models disease-relevant neural activity using patient-derived iPSCs and matched isogenic controls to identify therapeutic candidates for Rett Syndrome. Organoids exhibit distinct electrophysiological signatures, with Rett samples showing irregular firing compared to the coordinated bursting in controls.

Proprietary analytics extract 67 functional metrics, synthesized into a Global Recovery score to rank treatment responses. Because functional activity clusters by mechanism of action, the technology also reveals how different therapies affect neural networks, offering clinically relevant insights with predictive power.

Functional signatures of CNS-3D Rett Syndrome organoids treated with Donepezil, showing dose-dependent rescue.

Disease-specific neural activity patterns are readily observed, with RTT organoids showing irregular firing compared to the coordinated bursting of controls

Proprietary analytics extract 67 distinct functional metrics to quantify treatment response and rank therapeutic candidates using a simplified Global Recovery score

Functional signatures cluster by mechanism of action, offering mechanistic insight into how compounds affect neural networks

Strong clinical relevance, accurately predicting outcomes and informing the design of clinical trials

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CDKL5 Deficiency Disorder

High-throughput phenotypic screening for disease-modifying therapies

To identify novel therapeutics for CDKL5 Deficiency Disorder (CDD), a parallel screen is conducted using human neural organoids from both CDD patients and familial controls. An initial single-dose screen of 5,200 compounds yields 288 hits, which are rescreened to assess selectivity.

A follow-up 7-point dose-response assay refines the list to 22 top candidates across 15 biological targets. Comparing IC50 values between CDD and control organoids highlights compounds with selective potency in the disease model, linking their mechanisms to CDD-specific pathway disruptions.

CNS-3D Control and CKDL5 KO organoids share similar cellular ratios neurons (MAP2/green) and astrocytes (GFAP/magenta) but exhibit distinct functional signatures. CNS-3D CDKL5 KO organoids display network hyperexcitability.

An initial 5,200-compound screen in CDD organoids at a single-point dose narrowed 288 hits, which were subsequently screened in both CDD and CTL organoids at the same dose

Follow up studies in 7-point, half-log dose in both CDD and CTL organoids revealed 22 top therapeutic hits that encompass 15 distinct biological targets

By screening in both healthy and disease-state organoids, the IC50s from each cell line identified compounds selectively more potent in CDD than CTL, confirming the mechanism of these hits is based in perturbation of CDD pathways

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Chemotherapy-induced Peripheral Neuropathy

Differentiating effective from ineffective neuroprotective strategies

PNS-3D technology integrates human iPSC-derived sensory neurons and primary Schwann cells to model functional deficits associated with chemotherapy-induced peripheral neuropathy (CIPN).

The technology replicates neurotoxic responses, such as those induced by vincristine, and supports evaluation of neuroprotective strategies, including SARM1 inhibition. It enables detection of dose-dependent effects on axonal integrity and the onset of neurotoxicity, providing a powerful tool for assessing therapeutic efficacy and optimizing dosing strategies.

SARM1 inhibitor treatment effects over time across electrophysiology (left), neurite-growth metrics (middle), and the combination of both (right). While vincristine alone causes swift declines in function and morphology, NB-7 and WX-02-37 confer prolonged protection across endpoints compared to DSRM-3716, which mirrors the positive-control decline.

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