I'm proud of my research because it focuses on developing therapies and tools that offer potential cures or, at the very least, long-term treatments that improve the quality of life for patients and families who currently have no options, both in humans and in animals. I’m personally committed to innovating beyond boundaries, and I understand that innovation is both an expensive and high-risk process. Yet, it remains essential for shaping our future, transforming disease outcomes, and creating pathways to make therapies more affordable, expand their reach, and enable broader patient access. I’ve been fortunate to be surrounded by an incredible team of scientists, mentors, and human beings who continuously nurture and support my vision and research, of which I am truly proud and grateful.
One of the most exciting and recent areas of research I am involved in is the rAAV Human-to-Human (H2H) project, which enables the evolution, selection, and characterization of rAAV capsids directly in human decedents (legally brain-dead individuals who are ineligible for organ donation). Despite the clinical success of rAAV-based therapies, naturally derived AAV capsids or engineered rAAVs evolved in non-human species remain a significant barrier to fully unlocking the therapeutic potential of rAAV in human gene therapy. These non-human–optimized capsids often fail to capture the complexity of human biology, limiting the precision, efficiency, safety, and overall therapeutic potential of rAAV gene delivery in clinical settings. Given the intricate biophysical nature of rAAV capsids and their dynamic interactions with host biology (e.g., serum proteins, the immune system, tissue architecture, cellular receptors, co-receptors, intracellular molecular environments, and other host factors that influence tissue tropism and cell transduction), capsid discovery performed exclusively in non-human species carries significant translational risks due to species-specific differences and host selection biases. By contrast, the H2H approach is designed to overcome these translational barriers, unlocking the full therapeutic and scalable potential of human-centered gene therapy. Through this approach, we aim to bridge the long-standing gap between rAAV discovery and its successful clinical translation.
I recognize the significant gaps that remain in our understanding of rAAV biology in humans and strongly advocate for a shift toward fundamental, human-centered research that transcends the limitations of traditional animal-based preclinical models. Through the H2H approach, my colleagues and I strive to redefine gene therapy development by minimizing and ultimately replacing unnecessary animal testing while accelerating and de-risking translational development, accelerating clinical readiness, and expanding our capacity to design safer and more effective rAAV gene therapy vectors. While this area of research may initially sound unsettling to some, the success of human-decedent preclinical models in fields such as xenotransplantation has already demonstrated their immense value in bridging the gap between experimental and clinical realities. Historically, in vivo screening of peptide libraries using phage display has been successfully performed in human patients, setting a strong precedent for this type of translational research. We believe that the use of human decedents through the H2H project offers an unprecedented opportunity to study the critical determinants of vector performance in a physiological environment that closely resembles “real-time patient testing,” while mimicking Mother Nature’s evolutionary principles through directed evolution within a human host. Ultimately, this approach will benefit patients and their families and make a meaningful contribution to the advancement of human health and the future of medicine.
Gene therapy is often perceived as an expensive approach; however, China is already demonstrating that high-quality gene therapies can be developed and manufactured at a fraction of the current cost. This shift offers a new perspective that challenges the outdated standards and production models that continue to limit progress in the United States and Europe. Equally important is the need for continuous innovation within the rAAV field, rather than remaining constrained by legacy systems that no longer reflect the pace or potential of modern biotechnology. One example of recent innovation in the rAAV gene therapy field is the development of second-generation self-complementary AAV (scAAV) vector technology, known as covalently closed-end double-stranded AAV (cceAAV). This novel platform enables the design of more potent therapeutic cassettes that achieve higher efficacy at significantly lower doses while supporting a more homogeneous and efficient manufacturing process. Importantly, cceAAV addresses key limitations of conventional scAAV systems by minimizing the production of undesired single-stranded AAV byproducts, thereby improving both product quality and translational consistency. On the other hand, advances in molecular biology, bioinformatics, and the expanding global network of CROs, CMOs, and CDMOs now make it possible to bring gene therapy concepts to life with unprecedented speed, efficiency, and precision. However, significant work remains to develop more potent therapeutic strategies that achieve efficacy at lower doses while further enhancing safety, an essential goal for the field. Our laboratory is actively working to make this vision a reality, focusing on generating gene therapies that are not only more efficient and effective but also more accessible and affordable.
Today, gene therapy is transforming nearly every aspect of modern medicine as both society and scientific understanding advance, from RNA vaccines to in situ CAR-T cell therapies. In gene therapy, true innovation will come not from adding complexity, but from mastering the elegant simplicity of nature’s own design and evolution.
One of the areas of research with unprecedented potential for innovation and translational application through gene therapy is cellular transdifferentiation and reprogramming. When we look deeply into the biological systems that define us, everything we are as multicellular organisms originates from a single cell. Essentially, almost every cell in our body holds the genetic information needed to become any other type of cell.
In our lab, we are exploring the possibility of generating new neurons in vivo and in situ through transdifferentiation combined with gene therapy. At the same time, other research groups are reprogramming in vivo tumor cells into antigen-presenting type 1 conventional dendritic cell (cDC1)-like cells, and in vivo in situ CAR-T cell generation has already become a reality.
When you observe Mother Nature in action, you do not see organ transplantation; you see tissue regeneration occurring without tumor formation. It happens when a lizard regrows its tail, when certain species recover from heart attacks, or when hibernating animals endure long periods of extreme physiological stress, as well as in species that often live far longer than humans. The ability to control tissue regeneration through cellular transdifferentiation and reprogramming will undoubtedly redefine the future of many diseases, extend healthy lifespan, and even influence humanity’s progress toward space exploration and interplanetary travel. Biological enhancement is already taking place in the real world, although for now it remains primarily focused on treating disease. Gene transfer was, and will continue to be, an essential part of life’s evolution, whether guided by Mother Nature and her own vectors, or by ours.