We use chemical engineering, nanotechnology, genomics, and molecular biology to treat disease.
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High throughput in vivo screens for targeted nanoparticles
We can make thousands of chemically distinct lipid nanoparticles (LNPs). Historically, we have tested if nanoparticles work in cell culture, even though systemic drug delivery is extremely difficult to model in a dish. Now, using high throughput microfluidics and DNA barcoding, we can study how hundreds of LNPs work in a single mouse. How do we do this? By 'barcoding' LNPs, and using DNA deep sequencing to measure where they all go at once. For example, the 'heat map' above shows how dozens of LNPs deliver drugs to different cell in vivo - we measured this at all once. We now regularly generate 2,000 in vivo drug delivery data points per experiment; this is hundreds of times more in vivo data than a typical experiment. Why is this important? We can study thousands of nanoparticles in vivo, to find candidates for gene therapies.
We can make thousands of chemically distinct lipid nanoparticles (LNPs). Historically, we have tested if nanoparticles work in cell culture, even though systemic drug delivery is extremely difficult to model in a dish. Now, using high throughput microfluidics and DNA barcoding, we can study how hundreds of LNPs work in a single mouse. How do we do this? By 'barcoding' LNPs, and using DNA deep sequencing to measure where they all go at once. For example, the 'heat map' above shows how dozens of LNPs deliver drugs to different cell in vivo - we measured this at all once. We now regularly generate 2,000 in vivo drug delivery data points per experiment; this is hundreds of times more in vivo data than a typical experiment. Why is this important? We can study thousands of nanoparticles in vivo, to find candidates for gene therapies.
The biology of drug delivery
When nanoparticles carrying genetic drugs are injected, the body dictates where they go. We know physical barriers (e.g., blood brain barrier) can alter nanoparticle targeting. There is a lot of evidence that specific genes also affect nanoparticle targeting (and safety). Unfortunately, the genes that affect how well nanoparticles work in vivo are difficult to study, so we don't know what the genes are. What are we doing? We develop tools to study nanoparticle biology directly in vivo. This involves combining molecular biology, chemistry, and in vivo experiments. Why is this important? First, this is super interesting. There may be master regulatory genes that dictate nanoparticle safety. Understanding how to manipulate genes that to improve nanoparticle safety would help siRNA and Cas9 therapies.
When nanoparticles carrying genetic drugs are injected, the body dictates where they go. We know physical barriers (e.g., blood brain barrier) can alter nanoparticle targeting. There is a lot of evidence that specific genes also affect nanoparticle targeting (and safety). Unfortunately, the genes that affect how well nanoparticles work in vivo are difficult to study, so we don't know what the genes are. What are we doing? We develop tools to study nanoparticle biology directly in vivo. This involves combining molecular biology, chemistry, and in vivo experiments. Why is this important? First, this is super interesting. There may be master regulatory genes that dictate nanoparticle safety. Understanding how to manipulate genes that to improve nanoparticle safety would help siRNA and Cas9 therapies.
In vivo multigene editing
Using nanoparticles, Cas9, siRNAs, and miRNAs, we can study how many genes work together to promote disease. How do we do this? By delivering multiple siRNAs, miRNAs, or sgRNAs concurrently in vivo. Why is this important? Many diseases are caused by combinations of genes, not a single gene. For example, we co-delivered two RNAs, each targeting a different cancer pathway, to create a 'targeted combination gene therapy' for cancer. We also designed a five gene therapy for heart disease, and reduced inflammation with Cas9 in vivo.
Using nanoparticles, Cas9, siRNAs, and miRNAs, we can study how many genes work together to promote disease. How do we do this? By delivering multiple siRNAs, miRNAs, or sgRNAs concurrently in vivo. Why is this important? Many diseases are caused by combinations of genes, not a single gene. For example, we co-delivered two RNAs, each targeting a different cancer pathway, to create a 'targeted combination gene therapy' for cancer. We also designed a five gene therapy for heart disease, and reduced inflammation with Cas9 in vivo.
Designing RNAs and proteins for gene editing
Using molecular biology, we rationally design the genetic drugs we want to deliver. How do we do this? For example, using 'dead' guide RNAs, we can simultaneously turn off gene A and turn on gene B in the same cell using CRISPR-Cas9. Why is this important? Precisely turning certain genes on, and others off, will allow us to study how gene combinations promote disease.
Using molecular biology, we rationally design the genetic drugs we want to deliver. How do we do this? For example, using 'dead' guide RNAs, we can simultaneously turn off gene A and turn on gene B in the same cell using CRISPR-Cas9. Why is this important? Precisely turning certain genes on, and others off, will allow us to study how gene combinations promote disease.