Key Points
- Dr. Szablowski’s biomedical engineering laboratory at Rice University has been steadily growing over the past five years.
- His work using focused ultrasound–mediated and targeted gene delivery to the brain may help patients with neurodegenerative disorders and psychiatric diseases.
Jerzy Szablowski, PhD, is an assistant professor of bioengineering and a core member of the Rice Neuroengineering Initiative. After the 2024 publication of an innovative paper on engineering viral vectors for acoustically targeted drug delivery, the Focused Ultrasound Foundation began funding the optimization phase of his research to deliver the vectors across the blood-brain barrier (BBB). If translation to human trials becomes possible, targeted gene delivery to the brain could significantly change the way that many diseases are treated.
Read the Q&A with Dr. Szablowski to learn more about this promising research.
Where did you do your academic training?
I completed my undergraduate degree at the Massachusetts Institute of Technology (MIT) in biological engineering. I was fortunate to join several different laboratories during my undergraduate years, including the Langer, Jasanoff, and Boyden labs. Robert Langer is a chemical engineer and Institute Professor at MIT who is working on drug and gene delivery. Alan Jasanoff is an MRI imaging expert at MIT who develops contrast agents. Ed Boyden is one of the co-inventors of optogenetics who develops neuroscience tools and analysis methods. My experiences in these laboratories allowed me to combine knowledge from each area to develop a multidisciplinary skillset.
Also during my undergraduate studies, I participated in a collaboration with Frances Arnold, a Nobel Laureate and expert in the directed evolution of enzymes and protein engineering, at the California Institute of Technology (Caltech). I then completed my PhD in bioengineering at Caltech as a member of Peter Dervan’s biological chemistry lab. Dr. Dervan is an expert in developing small molecule drugs that bind to DNA. In his lab I learned how a single kind of molecule can treat multiple disorders by binding to different DNA sequences – it is an incredibly versatile technology.
How did you decide to attend MIT?
I was born in Poland but moved to the United States for college. When I was in middle school, I became enamored with MIT because of the number of inventions developed there. MIT education is very practical, with a goal of developing life-changing technologies and deploying them into the real world. Going there matched my expectations. I still follow that same approach, focusing on practical applications of my research.
How did you begin doing cellular therapy research?
I stayed at Caltech for my postdoctoral fellowship. Then Mikhail Shapiro, PhD, whom I knew from my time at MIT, joined the faculty at Caltech. Mikhail and I realized that we both planned to deliver cells into the brain using a very similar approach. Even though we both had the same initial idea – it quickly failed. We simplified our approach and used focused ultrasound BBB opening to deliver viral vectors, which gave rise to Acoustically Targeted Chemogenetics, or ATAC (see “Acoustically targeted chemogenetics for the non-invasive control of neural circuits” by Jerzy O. Szablowski et al., published in Nature Biomedical Engineering, in 2018). This research created the basis for some of the future discoveries that we are now translating for the treatment of psychiatric and neurological disorders.
Tell us about your laboratory at Rice University. How many people now work with you there?
I opened my Laboratory for Noninvasive Neuroengineering in January 2020. I chose Rice University because it is well-connected to one of the world’s largest medical centers and attracts excellent students. These features help us conduct translational studies, and I have a strong interest in making translatable technologies. Our team has grown to more than 20 people. Our group has one postdoctoral scholar, 10 PhD students, three master’s students, six undergraduate students, and one lab technician. The entire team is featured on my lab website, and the website also lists all of the alumni from my lab.
Are you expanding your lab?
We are currently recruiting research scientists, graduate students, postdocs, and technicians. In particular, we are looking for people with experience in protein engineering, neuroscience, in vivo work, and ultrasound device development, but willingness to learn new things is the most important. Our work is highly interdisciplinary, so everyone learns more upon joining. Possible research projects and contact information can be found on my website.
What is the overall goal of your work?
It takes a lot of effort, expertise, time, and money to develop new medical therapies but, despite all the resources invested, they are only accessible about 8% of the time. Overall, I am interested in finding ways to make therapies faster, easier, and cheaper. Toward that end, I am working to develop and deliver a type of gene therapy that can be applied to specific regions of the brain for various diseases and disorders.
Our projects are divided into the following five areas of research:
- Noninvasive control of brain circuits with acoustically targeted chemogenetics
- Gene therapy and gene delivery for the central nervous system
- Site-specific therapeutics
- Protein engineering for neuroscience
- Noninvasive monitoring of deep tissue physiology
What are your areas of interest in focused ultrasound? What mechanisms and clinical indications do you study?
We are interested in focused ultrasound BBB opening, both for molecule delivery to and recovery from the brain. We develop research tools to accelerate discovery, but a lot of our work is focused on Parkinson’s disease and epilepsy.
How could one type of gene therapy help multiple diseases?
ATAC can be used to treat different diseases and conditions. The technologies that we are developing will allow us to monitor gene expression (in human or mouse brains) and learn how diseases develop and progress (e.g., what genetic changes precede the development of disease? What is the cause and effect?). Our vectors can be customized and delivered to the regions of the brain where they are needed. For example, targeting the feeding center of the brain can control obesity. However, targeting the seizure onset zone can control epilepsy. Similarly, targeting the central pain circuitry could control chronic pain. In summary, with ATAC, one drug controlling neuronal activity, targeted to specific brain regions, could be used to control many different diseases.
Tell us about your current preclinical grant from the Foundation.
For this project, “Development of Viral Vectors Optimized for Noninvasive, Site-Specific Gene Delivery to the Brain,” we are developing systemically administered adeno-associated virus (AAV) vectors that are engineered to increase efficiency and specificity of gene delivery to the brain when used in conjunction with focused ultrasound BBB opening. These next-generation vectors should help achieve therapeutically relevant transduction efficiencies at lower doses. The eventual goal for this type of gene therapy is to treat disorders such as Parkinson’s disease, epilepsy, or psychiatric disorders. This project continues the work that we published last year where we found that our newly created gene vectors provided more than a ten-fold improvement in delivering genes to specific regions of the brain.
When will you begin to conduct clinical trials using your technology?
In 2021, we received a grant from The Michael J. Fox Foundation for Parkinson’s Research to use focused ultrasound to open the BBB for liquid biopsy. The goal is to release proteins from the part of the brain affected by Parkinson’s disease, collect the proteins, and analyze how they change or evolve as the disease progresses. These analyses will help us develop gene therapy for human use. This is an innovative way to study human disease (as opposed to using an animal model). There is a substantial logistical effort underway to get this trial started.
Has the Foundation played a role in your work?
Yes, the Foundation is doing a great job. I have attended Foundation workshops, including the fall 2023 Focused Ultrasound for Gene and Cell Therapy workshop in Washington, DC. I also received the Foundation grant mentioned earlier for a preclinical project. I complete site reports for the State of the Field Report. I like those reports and often share them with people who are surprised by how the field has advanced so quickly. There is still a lot of education that needs to be done about focused ultrasound and how it can improve patient care.
I hear you have an innovative idea to fund research.
I was surprised to see how much money is spent on life-saving research on a per-person basis. It can cost almost a billion dollars to make a new drug, but science budgets are simply not high enough to resolve thousands of diseases. For example, even with a budget of $8 billion per year for the National Cancer Institute, if you divide that by the number of Americans, it ends up being about $2 per month per person. People spend 5–10 times more on a video streaming subscription, and on average, each of us has 40% chance of getting cancer in our lifetimes. I think, if we had monthly subscription to research, we could dramatically increase science funding, and that would result in real-world treatments. Right now, I am afraid we will have the treatments we pay for. I am worried a $2/month treatment for cancer will not cure anyone. It is a lot harder to cure cancer than to make movies, or coffee, but we spend a lot less money on the former.
Key Publications
Seo JP, Trippett JS, Huang Z, et al. Acoustically targeted measurement of transgene expression in the brain. Sci Adv 2024 Aug 9;10(32):eadj7686.
Li HR, Harb M, Heath JE, et al. Engineering viral vectors for acoustically targeted gene delivery. Nat Commun 2024 Jun 10;15(1):4924.
Lee, S., Nouraein, S., Kwon, J.J. et al. Engineered serum markers for non-invasive monitoring of gene expression in the brain. Nat Biotechnol 2024;42:1717–1725.
Nouraein S, Lee S, Saenz VA, et al. Acoustically targeted noninvasive gene therapy in large brain volumes. Gene Ther 2024 Mar;31(3-4):85-94.
Szablowski JO, Lee-Gosselin A, Lue B et al. Acoustically targeted chemogenetics for the non-invasive control of neural circuits. Nat Biomed Eng 2018;2:475–484.