Neurodegenerative target discovery platform

Abstract

A microphysiological system (MPS) includes at least one first inlet for receiving a fluid medium. The MPS includes a brain module comprising brain tissue. The MPS includes a blood-brain-barrier (BBB) module comprising BBB tissue, the BBB module configured to receive the fluid medium. The MPS includes a crosstalk channel between the brain module and the BBB module, the crosstalk channel configured to promote a bidirectional crosstalk between the brain tissue and the BBB tissue in response to receiving the fluid medium at the BBB module. The MPS is configured for treating the brain tissue and the BBB tissue with a drug or a combination of drugs to determine a phenotypic effect and a transcriptomic effect of the drug. A drug perturbation is related to the phenotypic effect and the transcriptomic effect based on kinetic optimization.

1 - 13 . (canceled) 
     
     
         14 . A method, comprising:
 obtaining, from a microphysiological system (MPS) comprising a brain module and a blood brain barrier (BBB) module, transcriptomics data for gene expression for a healthy phenotype and for a disease phenotype;   training, based on the transcriptomics data, a machine learning model configured classify the healthy phenotype and the disease phenotype; and   determining one or more therapeutic targets for treatment of a neurodegenerative disease based on the machine learning model.   
     
     
         15 . The method of  claim 14 , further comprising rank-ordering the one or more therapeutic targets based on one or more of, for each therapeutic target, a druggability, therapeutic evidence from a third party data source, a tissue specificity, safety or toxicity information, and a novelty. 
     
     
         16 . The method of  claim 14 , further comprising:
 simulating target perturbations; and   evaluating one or more of the therapeutic targets using the machine learning model.   
     
     
         17 . A method comprising:
 obtaining a microphysiological system (MPS) comprising brain tissue and blood brain barrier (BBB) tissue, wherein at least one of the brain tissue and the BBB tissue comprises a disease;   treating the brain tissue and the BBB tissue with a drug or a combination of drugs to determine a phenotypic effect and a transcriptomic effect of the drug.   
     
     
         18 . The method of  claim 17 , further comprising:
 determining one or more phenotypic markers related to the disease;   perturbing the brain tissue and the BBB tissue using the drug;   optimizing at least one kinetic parameter representing the brain tissue or the BBB tissue; and   relating the perturbation to the phenotypic effect and the transcriptomic effect based on the optimization.   
     
     
         19 . The method of  claim 17 , further comprising:
 determining one or more therapeutic targets for treatment of a neurodegenerative disease based on context-specific genome-scale metabolic model (GEM).   
     
     
         20 . The method of  claim 19 , further comprising generating the GEM by:
 determining a tissue type represented in the MPS;   preserving a gene-protein-reaction association based on tissue-specificity data; and   performing a metabolic simulation including the gene-protein-reaction association to validate the GEM.   
     
     
         21 . The method of  claim 19 , wherein the one or more therapeutic targets comprise one or more of an mRNA, a protein, and a metabolite. 
     
     
         22 . The method of  claim 14 , wherein the MPS comprises crosstalk channel between the brain module and the BBB module, the crosstalk channel comprising neuron-glia and glia-BBB crosstalk. 
     
     
         23 . The method of  claim 14 , wherein the brain module comprises a plurality of compartments, the plurality of compartments comprising a neuron culture well and a glia culture chamber. 
     
     
         24 . The method of  claim 14 , wherein brain tissue in the brain module, BBB tissue in the BBB module, or both the brain tissue and the BBB tissue are diseased with a neurodegenerative disease. 
     
     
         25 . The method of  claim 24 , wherein the neurodegenerative disease is recreated from one of dopaminergic neurons or medium spiny neurons, astrocytes, pericytes, endothelial cells, microglia, oligodendrocytes, or a combination thereof. 
     
     
         26 . The method of  claim 24 , wherein the neurodegenerative disease is induced using one or more of a neurotoxin and a dopamine depletion treatment. 
     
     
         27 . The method of  claim 24 , wherein the neurodegenerative disease is introduced using tissue comprising one or more disease genotypes. 
     
     
         28 . The method of  claim 24 , wherein the brain tissue of the brain module comprises one or more of human iPSC-derived neurons, microglia, and astrocytes. 
     
     
         29 . The method of  claim 24 , wherein the BBB tissue of the BBB module comprises one or more of human brain microvascular endothelial cells (HBMECs), pericytes, and astrocytes. 
     
     
         30 . The method of  claim 14 , the MPS comprising a microelectrode array (MEA) comprising one or more electrodes, the MEA being configured to perform an electrophysiology measurement comprising one or more of a network bursting frequency, an interburst interval, a burst duration, one or more neuron spikes, a per burst Ca 21  signaling, and a disease-relevant ion channel activity. 
     
     
         31 . The method of  claim 14 , the MPS comprising a sensor configured to measure one or more biomarkers from a fluid medium of the brain module or the BBB module, the biomarkers including one or more of neuroinflammation biomarkers, antioxidant molecules, oxidative stress biomarkers, or reactive oxygen species biomarkers. 
     
     
         32 . The method of  claim 14 , wherein the BBB module comprises a first medium channel and a second medium channel for receiving a fluid medium, and wherein the BBB tissue is in a BBB culture channel between the first medium channel and the second medium channel. 
     
     
         33 . The method of  claim 14 , further comprising:
 sampling a first fluid medium from the BBB module, sampling a second fluid medium from the brain module, or sampling the first and second fluid media; and   determining the one or more therapeutic targets for the treatment of the neurodegenerative disease based on the machine learning model and the sampled first fluid medium, the sampled second fluid medium, or both the sampled first and second fluid media.