Paola Grandi, PhDAssistant Professor of Neurological Surgery/Molecular Genetics and Biochemistry
Paola Grandi, PhD, joined the Department of Neurological Surgery as an assistant professor in April of 2005. She has a joint appointment in the Department of Microbiology and Molecular Genetics.
Dr. Grandi received a bachelor degree in biology from University of Ferrara in 1996 and her master’s degree in genetics in 1997. She earned a PhD in biochemistry from the University of Ferrara in 2001. In 2001 Dr. Grandi received a fellowship for U.S. study from University of Ferrara and was a post-doctoral fellow from 2001-2005 in the Molecular Neurogenetics Department at the Massachusetts General Hospital.
She is a member of the American Society of Gene Therapy and American Association Cancer Research and is the assistant editor of the journal Gene Therapy.
Dr. Grandi’s research interests include studies to understand the development and progression of brain tumors emphasizing the role of miRNAs in cancer genetics. She has a long standing interest in the molecular biololgy of herpes simplex virus, mechanisms of virus replication and neuropathogenesis and virus host cells interactions that result in innate immune responses to infection.
Much of her recent work has centered on the creation of herpes viral vectors for treatment of glioblastoma. This research has recently been funded by both R01 and P01 NIH grant mechanisms.
Dr. Grandi's publications can be reviewed through the National Library of Medicine's publication database.
Professional Organization Membership
American Society of Gene and Cell Therapy
American Association of Cancer Research
Society for Neuroimmunology
International Society for Stem Cell Research
The research has gone really well with the establishment of new directions for vector retargeting and design of oncolytic vectors. Dr. Grandi has taken the view that targeting of HSV to infect glioblastoma cells through recognition of the EGFRvIII receptor that is present on the majority of these tumors and controlling replication of virus in neurons including neural stem cells by taking advantage of the natural expression of miRNAs. In this approach, several essential immediate early genes have been engineered to be down-regulated by miRs present in neurons but due to their absence in tumor cells, the viral IE gene products are expressed and the virus replicates very efficiently. Vector retargeting has been challenging since the normal HSV receptor usage must be blocked by mutagenesis of the viral attachment function gD while at the same time introducing single chain antibodies into gD that provide new receptor recognition specificities.
In addition, Dr. Grandi has used various selection systems to discover mutations in glycoproteins B and H that facilitate infection via these novel receptors. While the exact mechanism for enhanced infectivity is unknown, it appears that mutations in the fusion glycoproteins create a transition state that allow rapid virus entry. Because HSV has separate attachment and fusion functions that must talk to one another, the engineering of these retargeted vector has been tricky but fortunately, efforts have been successful. This work has been published, submitted and in preparation.
Dr. Grandi has applied for numerous grants last year as a PI (NIH: Stem Cell Neuralization, Glioblastoma and Susceptibility to oHSV (GRANT11049896); Enhanced GBM Therapy Using a New Class of HSV Oncolytic Vector (GRANT11144718) and as a co-PI (P01 grant with Ohio State School of Medicine: Circumventing Barriers to Effective Oncolytic Virotherapy of Neural Tumors; Telethon 2011: Development of retargeted Herpes Simplex vectors for efficient transcytosis of the blood-brain barrier and widespread transgene delivery to the brain. Application to Unverricht-Lundborg disease; ISS 2011: Role of TRIM8 in the pathogenesis of glioblastoma; AIRC grant: Dissecting TRIM8 functions in the pathogenesis of glioblastoma on Oncolytic Vectors to treat glioblastoma). Dr. Grandi will continue to push until funding is achieved.
She also is working on the creation of an Ataxia foundation focused on Sca1.