Induced pluripotent stem cells derived from patient cells have emerged as complementary tools to study human neurological disorders. Neurxstem Inc has generated human iPSC-derived synthetic neural organoids (Neural Organoid PlatformTM) which exhibit a remarkable level of development that morphologically resembles a nearly complete human central nervous system at ~5 weeks in development in utero, but after ~12 weeks in culture in vitro. These synthetic organoids express a complex milieu of markers characteristic of nearly all types of neurons in the human embryonic central nervous system, as well as cells that are astrocytic, oligodendritic, microglial, and vascular in lineage. Our analysis supports the formation of all the major regions of the central nervous system including the retina, cortex, midbrain, brain stem and the spinal cord in a single complete neural organoid and is the first time this milestone in human brain organogenesis has been achieved. Using Neurxstem’s proprietary process, we have now engineered synthetic neural organoids from Alzheimer’s disease and tuberous sclerosis patient skin cells. Whole genome transcriptomic shows close genotype-clinical phenotype correlations.
This success strongly suggests that Neurxstem’s Neural Organoid PlatformTM has a multitude of future applications to study neurodegenerative diseases (Alzheimer’s and Parkinsons’s disease, ALS, and MS), neurodevelopmental disorders (autism), and neuropsychiatric disorders (Post Traumatic Stress Disorder (PTSD), bipolar and schizophrenia).
The Neural Organoid PlatformTM is also useful to study the effect of nutrition and environmental toxins on prenatal brain development.
Future exciting applications include assessing effects of changes in gravity and geomagnetic fields on prenatal development of the human brain for space explorations and colonization of new planets.
Methods: We characterize neural organoid responses to genetic or environmental perturbations at the molecular, cellular and structural level using transcriptomics, immunohisto-chemistry, and 3D whole brain imaging.
Results: Neurxstem has generated human iPSC-derived synthetic Neural Organoid Platforms which exhibit a remarkable level of development that morphologically resembles a nearly complete human embryonic central nervous system at ~5 week in utero development, but after ~12 weeks in culture in vitro. Using our proprietary process, we have engineered neural organoids from Alzheimer’s disease and tuberous sclerosis patient skin cells with identified genetic mutations in susceptibility genes. Our transcriptomics results remarkably show comprehensive and accurate correlation of the dysregulated expression of hundreds of genes previously correlated with the clinical symptoms and/or pathologies of both of these diseases. For Alzheimer’s disease these include genes for lipid homeostasis, inflammation, metal ion homeostasis, and water homeostasis and amyloid peptide beta and tau metabolism. For tuberous sclerosis these include genes for tumor formation, autism, blood pressure regulation, Zn++ ion homeostasis, Pb++ ion toxicity, round worm infections, and cholesterol metabolism among others.
Conclusions: Neurxstem’s “NexGen” synthetic Neural Organoid PlatformTM allows the use of whole genome transcriptomic “digitization” of the gene expression response of the models to genetic or environmental perturbations of human brain physiology and thus accurately predict susceptibility to brain disease.