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Improving the efficacy of immunomodulatory therapies on individual patient…
Improving the efficacy of immunomodulatory therapies on individual patient immune systems
Modeling Pathophysiology
In vivo
Human
Type of sample
Blood
Saliva
Sputum
Sputum
Urine
Physiological parameters
Circulating cytokine level
Non-human
Model Animals
Generate model animals that can be used to simulate inflammation and cytokine storm inside of human
Generate model animals that can be individualized to test the therapy for individual patient
In silico
Whole immune system simulations
simulate each cell type individually
simulate the interactions between individual cell-types
Build system-level simulation for individual patients upon receiving their baseline data. Patients can have routine tests with their PCP and the data will be used to build individualized models that can be used if the patient has inflammatory symptoms.
Cell-level simulation
simulate numbers of specific cell type
simulate activation status of specific cell-type
simulate gene expression patterns within cell type
Simulate immune cell response to immunomodulatory therapies
Patient level simulation
Model the physiological parameters to enable prediction of inflammation disease disease using those parameters
Model the changes of physiological parameters upon inflammation
In vitro
Model of immune system
Model pathological state
The mechanism a cytokine storm
The interaction of different cytokines with immune cells before and during a cytokine storm
Model the individual differences of immunological state between different patients
Model baseline
Normal immune cell population and gene expression in healthy population
Normal cytokine level in healthy patient
Model response to immunomodulatory therapies
Model immunomodulatory therapies effect on the immune cell population and gene expression
Model how immunomodulatory therapies affect the cytokine level of immune cells
Model the differences of response toward the same therapy between immune cells from different patients
Model the response of immune cells to cell therapies
Model the dynamics of cytokine levels upon perturbation
Model of single cell populations
Easier immune cell culture
Diagnostics
in vivo
biology
Overall disease state
physiological marker analysis
visual readout of cell functional state
engineered cells that alert physician to sepsis/that provide read put of overall immune state
Gene therapy
CRISPR knock-in of fluorescent tags for cytokine genes
CRISPR knock-in of cytokine sensitive protein
CRISPR knock-in of chimeric cytokine receptor
Engineering embryonic cells
Engineering cells to produce phenotype in response to pre-sepsis physiology
Engineered immune cells to change color based on activity
Engineered immune cells to be excreted based on phenotype
Engineered immune cells to produce reporter protein based on activity
Engineer immune cells to change color in response to cytokine levels/when releasing cytokines
Spleen metabolism and spleen function
Cytokine detection
Engineered small molecules that bind cytokines
Fluorescent antibodies for cytokines
Cell populations
Mechanical
overall disease state
Wearable physiological signs monitor
Blood conductivity over time
Tracking hormone level overtime
gene expression
Wearable gene sequencer
Wearable RT-PCR
Wearable RNA sequencer
Cytokines detection
Bedside cytokine sensor
Method of measurement
Particle mobility (bait-prey) :<3:
Cytokine subtypes
Pro-inflammatory cytokines
IL-6
TNF-alpha
Anti-inflammatory cytokines
Pro&Anti-inflammatory cytokines
Innate immune response over time
Type of measurement
Fold changes
Relative concentration
Baseline vs. present
Exact concentration
High or low
Body fluid type
lymph
Blood
Estimating cell populations
wearable cell counter
Stain-based counting
Image analysis based counting
FACS/size based sorting
Measuring immune cell in the blood stream by capturing their membrane protein
Cell function measurement over time
Cell types
NK cell
Dendritic cells
leukocytes
in silico
Data analysis
Computer-based assessment of patient history/health records to determine which treatment would be most effective.
in vitro
new diagnostics
Assessment of functional state of key immune cells
Biological precursors to cytokine storm
Characterization of population counts downstream immune cell populations
Paper that changes color when it detects pre sepsis
Existing diagnostics
Cell free
Better ELISA
cell based
FACS
Improving clinical practice
Patient is in sepsis
Therapeutic
Collecting medical records of patients' response to different therapies
Machine learning to develop a predictive model for which patients are response to which drugs
Encouraging drug companies to include diverse demographics in clinical trials
Legislation and Advocacy
Financial incentiives
localized antibody infusion/treatments
dCas9
Highly specific small molecule cell inhibitors
Lentivirus to sparsely infect lung tissue and KO cytokine receptors. Potentially via epigenetic change.
Patient is ill and at risk of sepsis
Informing treatment decision
On-call sepsis treatment experts
Quicker notification/turnaround w/ regards to whether first line therapies (e.g., antibiotics) are working, so doctors can know sooner whether to start other more risky treatment
Rapid diagnostics and decision tree for PCP
Improved patient data collection and interpretation
more regular testing protocol for frequent immune system checks (i.e., check daily during hospital stay)
ML to interpret immunoprofiling data
molecular imaging like a PET scan but small molecule that is not radiolabeled
Tool for rapid transcriptomics in a cell population specific manner
tagging cells to lung population blood population etc. to see where cells are in the patient
Pre-illness
More information for doctors regarding treatment options
Neonatal diagnostic/screening
Point of care screening offered pre disease for sepsis risk and for personalized immunomodulatory drug recommendations
GWAS studies
Identify populations where IL-6 isn't predictive of sepsis risk/severity and look to see what other markers may be predictive in these patients
Information on who is most vulnerable
Inflammation profile as part of yearly physical to establish baseline and catch problems early
Collating empirical data from physicians
Conception/Nature of sepsis/sepsis as a medical construct
Defining Sepsis
Defining immune dysregulation
Improve Tools for Researchers
Ways to help with data analysis
Data collection
Ways to collect physiological data in real-time
nanotechnology based circulating biosensors
Wearable sensors for all ICU patients
Ways to collect cellular/molecular data in real time
Take piece of tonsillar tissue
Needle prick to collect specimen
Improved culturing of immune cells
Microneedle biopsy at various time points from lymph nodes in neck
Patient data
A baseline immunological model to compare to
Ways to do GWAS or large meta-analysis from existing data
GWAS for cytokine storm patients
Patient outcome versus drug GWAS or existing data analysis
Collecting hospital-wide data on immune status of all patients for whom blood samples were taken to relate patient outcomes to immune state, identify patterns, and generate hypotheses
Ways to manipulate biological system
Gene knock-out to screen for gene/molecule important for a pathway
Studying the control circuits of the immune system based on the methodologies that were used to elucidate control mechanisms in the endocrine system
Control of cellular activity/state
Targeted activation of different parts of the immune system
Specific bidirectional control of activation state of a genetically/functionally defined population of immune cells
Manipulation of patient samples
iPSC reprogramming to immune/cytokine producing cells
Test function of specific immune cell populations from a single sample w/o component separation
Collabs and data sharing
Website to ask for data or opinions from experts and other labs
Centralized database of patient immune response
data
More collabs between researchers and doctors ask about getting tissue samples for research
Standardized recording of patient data to inform research
Online platform for collaboration
multi-institutional database of immunological data from patients
A website with all of the latest findings in the field in one place
Therapeutic
Treating cytokine storm
Cell therapies
Apoptotic cell therapies to repress cytokine storms
https://www.nature.com/articles/s41419-020-02748-8
Cells therapies to modulate the number of immune cells in the body to repress the cytokine storm
Whole immune replacement
Irradiate the individual and replace their immune cells with donor cells
Molecular therapies
Drugs to repress the cytokine storm without significant affect the immune system
Mechanical
Physically filtering out particular cytokines
Mitigate the damage of cytokine storm
Molecular therapies
Targeted T-cell destruction using small molecules
Cytokine receptor blocker
Competitive inhibitor for cytokines
Cell therapies
Increase lung tissue restoration
Preventing cytokine storm
Molecular therapies
Drugs to control the circulating cytokine level
Drug to control immune cell activity to lower the cytokine secretion from cells
Drug to block cytokine receptors on immune cells to lower the effect of high cytokine level
Synthetic biology therapies
A self-regulatory gene circuit to prevent cytokine storm
New enzyme or cell to better destroy cytokines
Add CRISPR to human cells to combat viral infections in a new way, thus avoiding cytokines
Lentiviral treatment