Christos Suriano, a postdoctoral researcher in the Princeton Neuroscience Institute (PNI), was awarded a prestigious TL1 fellowship from the New Jersey Alliance for Clinical and Translational Science (NJ ACTS).
Suriano, who works in the lab of Lisa Boulanger, associate professor of neuroscience, will explore ways to make gene therapy safer and more effective. He joins PNI postdoc Camden MacDowell and five other Princeton Fellows who, through the TL1 program, are enhancing their knowledge, skills and abilities to conduct translational team research across disciplines.
NJ ACTS is a multi-institutional endeavor between New Jersey Institute of Technology, Rutgers University and Princeton University. The collaboration began in 2019 and is supported by a $29 million grant from the National Institute of Health (NIH) that helps investigators translate basic research into innovations that can benefit patients and have a positive impact on public health.
Suriano did his PhD at Wesleyan University working on the molecular evolution of neural circuit development. One of the synaptogenic proteins that he studied was also considered an immune protein, so he became deeply interested in neuroimmunology, a subfield of neuroscience that studies ways in which the immune and nervous systems interact. In his postdoctoral work, Suriano is focusing on the role of a class of membrane immune-system proteins called MHC-I proteins.
MHC-I proteins are part of the immune system as they are involved in presenting antigens to surveilling immune cells. Recently, these proteins were found to have dual roles, meaning that they are not only involved in the immune response but also have neuronal functions. The brain has long been thought to be immune-privileged — in other words, tolerating antigens without provoking an immune response — but recent evidence is challenging this long-standing assumption. In the nervous system, MHC-I activation can limit dendritic density and synaptic density and thus affect neuronal morphology. The activation of those MHC-I proteins also leads to a decrease in the miniature excitatory postsynaptic potential (EPSP) thus decreasing neuronal excitability.
Adeno-associated viruses (AAV) are one of the most widely used gene delivery tools in basic neuroscience and in gene therapy. As viral proteins can elicit an immune response, Suriano wondered if gene therapy to the brain involving AAV could induce both an immune and neuronal response.
Suriano’s work indicates that AAV, in high doses used for gene delivery, has mildly toxic effects on neuronal morphology and excitability. Suriano was able to block this effect by limiting immunodetection of AAV by injecting a TLR9 (an immune protein) antagonist, thus reducing the immune response. This approach to block the effects of AAV can work in basic neuroscience experiments but is not appropriate for human gene therapy, as TLR inhibitors can induce generalized immunosuppression in patients.
As an NJ ACTS sponsored Fellow, Suriano will engineer AAV viruses that carry the TLR antagonist within its genome, aiming to specifically target the cells that are infected by AAV. This could thus make AAV-mediated therapy safer and more effective by lowering the amount of virus injected.
There are already gene therapies on the market using AAV viral vectors to treat genetic diseases. Examples of diseases with available FDA-approved gene therapies include spinal muscular atrophy, a genetic neuromuscular disorder that mostly affects children, and Leber's Congenital Amaurosis 2, a form of congenital retinal dystrophy leading to childhood blindness. AAV is used in high doses to deliver these gene therapies in children and, given Suriano’s finding, there is a risk of developing sub-toxic effects on neurons, hence the urgency of developing ways to reduce those effects. Moreover, there is pipeline of gene therapies that are currently in the pre-clinical phase and will emerge in the future.
Moving to translational applications requires a certain set of skills as well as connections with clinicians that are usually not available to investigators conducting basic research. The TL1 fellowship program fills this gap.
Through NJ ACTS, Princeton researchers can gain access to resources needed to advance their translational research, such as tissue samples, blood cells, core facilities and patients for studies. The consortium of partners and affiliates, funding, and resources available through NJ ACTS can facilitate translation of research for Princeton faculty and trainees. Through the alliance with Rutgers Biomedical and Health Sciences, the lead academic partner in the collaboration, Princeton researchers are more easily able to interact with clinical partners, hospitals, community health centers, industry, and policymakers.
“I am very excited to meet the patients and interact with clinicians who are involved in delivering these gene therapies,” Suriano said. He also mentioned that the program provides training and networking opportunities to guide him through the process. Through a customized training program and a valuable network of health professionals, the fellowship aims to position Suriano to be a leader in translational neuroscience research.
NJ ACTS is organized into a number of core areas that provide research grants, training, informatics support and resources, collaborations with community groups and industry, expertise studying underserved populations, and improved access to clinical trials.
NJ ACTS also provides educational and training opportunities to Princeton students and postdoctoral researchers through established programs and its network of medical professionals, clinical experts, and the Academy of Mentors.
Learn more about funding opportunities, training and resources available through NJ ACTS. To apply for the Fellowship program or other grants, contact NJ ACTS Manager, Research and Administration, Bianca Freda.
The collaboration is supported by the National Institutes of Health Clinical and Translational Science Awards (CTSA) Program grants UL1TR003017, KL2TR003018 (career development) and TL1TR003019 (training).
by Ahmed El Hady