Ramya Kumar wins NSF CAREER Award for research on genome editor delivery

Ramya Kumar, assistant professor of chemical and biological engineering at Colorado School of Mines, has received a National Science Foundation CAREER Award for her work to develop polymeric biomaterials that could make genetic therapies cheaper and more accessible.

Genome editors treat people with rare inherited genetic disorders (like sickle cell anemia) or more prevalent diseases with an underlying genetic basis (like cancer) by providing new DNA to specific cells or by changing their DNA. Currently, viral vectors–viruses modified to no longer be infectious—deliver genome editors into cells, but their high manufacturing costs can make these therapies unattainable for many. Synthetic materials like polymers, though, have shown promise and could help lower the cost.

“We understand the genetic basis of disease more thoroughly than we have in the past – and every day we hear about newer more powerful genome editing platforms. But methods for delivering these powerful genome editors into cells remain underdeveloped.” Kumar said. “We have made a lot of progress in synthetic polymer chemistry, particularly experimental and computational methods to design and test polymers faster. It’s the perfect time to put this all together and solve the delivery challenge for genetic therapies.”

The $803,495 award from NSF covers five years of research, during which time Kumar and her team will apply machine learning and advanced polymer science methods to understand why some polymers work well in delivering genome editor proteins to cells while others do not. 

Here, Kumar answers some questions about her research and how using advanced polymer chemistry techniques could lower the cost of genetic therapies.

Q: What is your latest research focused on?

Ramya Kumar: For extremely rare diseases that might affect a small handful of people, researchers engineer viral particles to deliver genetic cargoes. These are just viruses that are modified so that they’re no longer infectious, but you’re still exploiting their ability to get into cells and introduce DNA into cells. But the problem is these engineered viral particles are incredibly expensive and won’t be feasible for larger patient cohorts. My lab engineers materials that lower economic and manufacturing barriers facing gene therapies, especially for diseases that affect millions of patients. 

I’m from India and this research can make a big difference in my country. For example, Novartis has a treatment for a rare pediatric disease, spinal muscular atrophy (SMA), that costs between $1 to $2 million for every patient. This treatment depends on engineered viruses, which contribute significantly to the costs. In the United States, Medicaid pays for cell and gene therapies but in India, SMA patients are left to their own devices. Converted to Indian currency, the Novartis treatment is well beyond the reach of most people. I go home to India often, and each time, I hear stories about children with SMA dying because their crowdfunding campaigns couldn’t make it in time. There is an urgent need to bring down the cost of these therapeutics. 

My CAREER award will help us design polymers that will deliver genome editor proteins based on CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology. Polymers are long-chained molecules with highly tunable material properties. Polymers will wrap around fragile genome editor proteins and protect them from damage en route to target cells. These polymers will also make it easier for genome editor proteins to enter cells and navigate delivery barriers inside cells. Our approach is to synthesize chemically diverse polymer libraries and characterize their binding interactions with CRISPR proteins. Can polymers bind and protect these proteins from degradation? Can polymers carry these proteins into the nuclei of target cells so that we can actually edit the disease-causing DNA sequence? Does the same polymer work across all types of genome editor proteins, for instance base editors and not just CRISPR proteins? If not, how do we tailor polymer chemical features to maximize delivery of a given genome editor protein? Does the same polymer work across all types of cells and how do we change polymer properties to ensure selective delivery to each cellular target? These genome editors are extremely fragile proteins, and they can lose their shape and activity if you don’t supply them with the right chemical environment. So, we’re really interested in finding out what kind of polymer design motifs conserve the native structure and make sure proteins don’t lose their therapeutic editing activity during delivery. Subtle alterations to polymer properties can dramatically alter outcomes. However, it is difficult to predict which polymer will stabilize and deliver genome editor proteins, and which ones won’t because of gaps in our fundamental knowledge of polymer-protein binding interactions. Because of this, polymer chemists employ trial-and-error methods to design polymers for genome editor delivery, which is inefficient and time consuming. In this CAREER project, we will develop tools to guide our experiments so that we can efficiently explore the vast polymer design space to understand and predict even counterintuitive results in polymer-mediated genome editor delivery. Our work will fill many gaps in our mechanistic understanding of polymer – protein complexation and protein delivery.

Q: What do you find most exciting about your research?

Kumar: I love working at the interface of polymers and biology and it satisfying to use my polymer chemistry skills in healthcare. We are living in an exciting period where polymer chemistry, data science, and next-gen cell and gene therapies are all evolving rapidly. I am grateful for the opportunity to combine polymer synthesis, biointerfacial characterization, and data science to make these treatments affordable. I hope to someday apply precision medicine tools in polymer design and create bespoke polymers that adapt to individual patients’ immune systems. It would be really cool to integrate omics data and engineer personalized patient-specific polymers.

I’m also excited about training students in polymer chemistry and data science. For me, research is teaching, and I don’t think of research and teaching as separate aspects of my work. I tend to think of research as teaching students over a longer time scale than a typical class. So instead of teaching a class that may end in a semester, it will take four or five years to train students in research. But students are learning skills that will stay with them for life. Even if we don’t solve polymer-mediated delivery of genome editors over the span of a project, or even in my lifetime, it’s nice to pass on skills to future generations who may end up cracking this later on. 

Q: What is the potential impact of this work?

Kumar: Polymers are highly versatile and well placed to address many of the shortcomings of lipid nanoparticles, gold nanoparticles, viral vectors, etc. But polymers are also far more chemically complex than other materials which is why we are proposing a fresh conceptual framework to analyze and predict interactions between polymers, genome editors, and cells. If this work succeeds, the biopharma industry will have an entirely new toolbox and can look beyond lipids and viruses to solve delivery challenges.  If you think about genetic diseases like sickle cell anemia, they are more prevalent in South Asia and Africa than in North America. The current treatment that’s approved for using genome editor proteins to treat sickle cell anemia is really expensive. This is because electroporation, the delivery method, consumes large amounts of genome editor reagents. We hope to engineer materials that can bring down these costs and make sure that you have these lifesaving cures available to everyone, no matter where they are born.

Q: How does this research agenda inform your teaching?

Kumar: In “Intro to Biomedical Engineering,” I get the chance to teach sophomores, juniors and seniors all about my research. My CAREER educational plan involves a lot of high school outreach. My first PhD students, Adam Humpal and Jessica Lawson, have developed some fantastic lab modules for high school chemistry classrooms. We visit a local high school in Arvada regularly and take over their chemistry class. We spend the entire day running experiments related to polymer chemistry so that we can get these kids interested in biomaterials at an early age. We also host high school students in our lab over the summer. Hopefully, this motivates them to apply to Mines and hopefully major in chemical and biological engineering or quantitative biosciences and engineering. My PhD students and I share a passion for undergraduate research mentorship, and we are always thrilled when undergraduate students from our research group pursue PhD programs at top universities after their studies at Mines. Two undergraduates from our group have been admitted to top materials science and chemical engineering PhD programs so far and the CAREER award will help us continue to nurture talented undergraduate researchers at Mines.