Novel Viral Gene Therapy Vectors for Increased Genetic Payload and Long Term Chronic Expression of Therapeutic Transgene
Princeton Docket # 19-3539
Researchers in Princeton University’s Neuroscience Institute and Department of Molecular Biology have developed adeno-associated viral vectors (AAV) containing promoter sequences that are small in size yet able to provide strong, long-lasting transcription of any gene of interest. The size of such promoter sequences is less than that of commonly used promoters, allowing for larger size transgenes to be packaged into the AAV, for expression in most cell types and in most mammals. Since these novel promoter sequences are less prone to repression or inactivation than most common promoters, they are especially useful for gene therapies requiring stable and chronic expression of the therapeutic transgene.
Use in lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses
Increased genetic payload due to promoter size
Chronic expression of therapeutic transgene
Broad tissue, organ range
Use in viral and non-viral vectors
These novel viral vectors have been tested both in vitro and in vivo mainly in the context of the nervous system. However, their application should not be restricted to the nervous system, as these viral vectors could be used to express therapeutic transgenes in several organs or tissues of animal models and humans. They have the potential to be used in gene therapies to treat both acquired and inherited diseases of the nervous system or other organs. One immediate application is to use these novel gene promoters in AAV vectors, where the packaging capacity or payload is limited to a maximum size of ~5000 bases. Our smaller novel promoters can replace large conventional promoter sequences, releasing space in the AAV capsid to include additional or larger therapeutic genes.
Due to their origin we expect our novel promoters to achieve long-term, chronic transcription of therapeutic transgene(s) which is a critical aspect for gene therapy where the therapeutic transgene should be expressed for the lifespan of the patient/host. Other commonly used promoters for expression in brain tissue such as the synapsin promoter, has been shown to decay or get repressed only after 4-5 months. Our promoters can actively transcribe for a much longer time.
Intellectual Property & Development Status
Patent protection is pending. Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
Esteban Engel – Esteban A. Engel is the Director of the Viral Neuroengineering Laboratory at the Princeton Neuroscience Institute. He obtained his BSc and MSc in biochemistry from Universidad de Chile. He was part of the team that produced the first recombinant subunit vaccine fully produced in Chile, against the salmon pathogenic bacteria Piscirickettsia salmonis. The vaccine was licensed to Novartis Animal Health and it is commercialized globally. Next, he did his PhD in Biotechnology at Universidad Andres Bello with Pablo DT Valenzuela, studying plant viruses. Esteban developed a diagnostic oligonucleotide microarray for simultaneous detection of more than 50 grapevine viruses. He discovered new viral species infecting grapevines in Chile, some with high incidence and deleterious effects on the crop quality and yield. In 2010 Esteban moved to Princeton University in New Jersey, where he was a PEW postdoctoral fellow in the lab of Professor Lynn Enquist studying alpha herpesviruses infection in the nervous system. In 2015 Esteban started his own research lab at the Princeton Neuroscience Institute, where he also directs the Viral Core Facility.
Lynn Enquist- Lynn W. Enquist is Henry L. Hillman Professor in Molecular Biology and Professor in the Princeton Neuroscience Institute at Princeton University. He received his BS degree in Bacteriology at South Dakota State University in 1967. He received his Ph.D. in Microbiology from Medical College of Virginia, Virginia Commonwealth University in 1971 with S. Gaylen Bradley studying streptomyces biology. He did postdoctoral training at the Roche Institute of Molecular Biology from 1971 to 1973 studying bacteriophage lambda with Ann Skalka. He was a senior staff fellow at the National Institutes of Health in the laboratory of Dr. Philip Leder working with Robert Weisberg from 1974-1977 studying bacteriophage lambda site-specific recombination and development of recombinant DNA technology. He held a tenured staff position in the National Cancer Institute from 1977 to 1981 where he continued the development of recombinant DNA technology and also began his work on neurotropic herpes viruses. George Vande Woude was his lab chief. In 1981 he left the National Cancer Institute to be Executive Scientist at Molecular Genetics Incorporated in Minnetonka, Minnesota where he worked on recombinant DNA based viral vaccines. In 1984, he joined DuPont as a Research Leader where he ran a laboratory studying neurotropic viruses. In 1990, he joined DuPont Merck Pharmaceutical Company where he was a Senior Research Fellow working on developing neurotropic viruses as tools for gene therapy and studying the mammalian nervous system. In 1993, he accepted the position of tenured full professor of Molecular Biology at Princeton University. He was chair of the department of Molecular Biology from 2004 to 2013.
Andrew Esteves - Andrew is a graduate student in the Enquist Lab. He received his BS in Biochemistry from The New Jersey Institute of Technology in 2016 and a MS in Molecular Biology from Princeton University in 2018.
Carola Maturana – Carola is a post-doc in the Engel Lab. She completed her BSc in Biochemistry at Universidad Austral de Chile and MSc in Neuroscience from Universidad de Valparaiso in Chile, studying the effect of odorants on the expression of c-fos in zebrafish. She obtained her PhD in Physiological Sciences at Pontificia Universidad Católica de Chile studying connexin 43 and pannexin 1 hemichannels of gilal cells in the neuroinflammatory response. She was awarded a grant from the Universidad Católica Accelerator Program, to study the use of selective inhibitors of hemichannels formed by connexins to treat epilepsy that was patented in 2016. Carola then moved to Colorado State University, where she worked on the modulation of anestrus in sheep by hypothalamic estrogen receptors. In 2017 Carola started her Postdoc in the Engel lab at the Princeton Neuroscience Institute.
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