André Lieber, MD, PhD

I am an academic researcher with training in molecular and applied medicine. I studied Medicine and Biochemistry at the Moscow Pirogov Institute and received a PhD at the Humboldt University Berlin. After post-graduate training at the Max Planck Institute for Biochemistry, Berlin, I joined Mark Kay’s lab at the University of Washington as a post-doc in 1994 and became an independent investigator in 1998. In 2015, I was promoted to the rank of Professor of Medicine with Tenure. I have published 127 papers as first or senior author and >50 papers as a co-author. As of 2020, I have supervised 25 post-docs, 7 graduate students, 35 undergraduate students, and 11 visiting scientists.

I have been working on basic and translational aspects of adenoviruses for more than 25 years. I believe that I have made seminal contributions that have advanced the field of basic adenovirus research. Among them is the discovery of two of the known three receptors that are commonly used by human adenoviruses. Two years before the death of Jesse Gelsinger, I have demonstrated that intravenously injected adenovirus vectors triggered critical innate toxicity. My lab was the first to show that adenoviruses interact with blood coagulation factors and that this influences in vivo tropism. My lab has also made contributions to a better understanding of how adenoviruses spread in epithelial tissues.

Examples of translational adenovirus research include new approaches for the treatment of cancer involving recombinant adenovirus proteins. Two of these approaches are currently at the IND stage. The first approach is based on a a small recombinant Ad3 fiber knob derivative (JO) that binds to desmoglein 2 (DSG2), a junction protein that is overexpressed in epithelial cancers. Binding of JO to DSG2 triggers signaling pathways and results in transient opening of tight junctions between tumor cells. This, in turn, increased the intratumoral penetration and efficacy of monoclonal antibodies and chemotherapeutic drugs. JO in combination with PEGylated liposomal doxorubicin will be tested in patients with recurrent ovarian/fallopian tube cancer. The second approach involves a modified recombinant Ad35 fiber knob (Ad35K++). This protein is capable of downregulating CD46, a complement inhibitor, thereby sensitizing leukemia and lymphoma cells to CDC therapy with monocolonal anitbodies. The first clinical trial will be a combination of Ad35K++ and rituximab in patients with CD20+ B-cell maligancies.

In 2016, we published a paper demonstrating the feasibility of a new approach to transduce hematopoietic stem cells (HSCs) in vivo after mobilization. Central to this approach was the idea that mobilized HSCs, transduced with an intravenously injected helper-dependent adenovirus vector (HDAd5/35++) in the peripheral blood circulation, return to the bone marrow and persist there. In the original setting, we used a hyperactive Sleeping Beauty transposase for HDAd5/35++ vector integration and an in vivo selection system to expand transduced HSPCs. Over the last 5 years, we have demonstrated the safety and efficacy of the in vivo gene addition approach in mouse disease models for hemoglobinopathies, hemophilia A, cancer, and infectious diseases. Furthermore, we used non-integrating HDAd5/35++ vectors for genome editing by designer nucleases and, recently, by base and prime editors. We have optimized HSC mobilization as well as prophylactic regiments to prevent innate responses associated with the intravenous injection of HDAd5/35++ vectors. Recent achievements include the cure of Sickle Cell Disease in a mouse model by a single intravenous injection of a therapeutic HDAd5/35++ vector and the demonstration of safety and efficacy of the in vivo approach in five rhesus macaques.

I am a scientific co-founder of a start-up company (www.ensoma.com) to support the clinical translation of the in vivo HSC gene therapy approach. Our vision is to make HSC gene therapy more cost-efficient and accessible to patients in resource-poor countries.