Kelli L. Kuhen, PhD
Kelli Kuhen, PhD, is a Senior Research Investigator in the Infectious Disease / Lead Discovery group at the Genomics Institute of the Novartis Research Foundation (GNF). Dr. Kuhen obtained her M.A. in 1994 in Biology and Ph.D. in 1997 in Biochemistry - Molecular Biology from the University of California, Santa Barbara. Kuhen's doctoral dissertation was based on cloning of the human interferon-inducible RNA-dependent protein kinase (PKR) gene and promoter, and characterizing the molecular mechanisms involved in interferon-inducible expression of the PKR gene. PKR is a pivotal mediator of the interferon-induced antiviral response in host cells upon viral infection. In 1998, Kuhen started a postdoctoral appointment with Flossie Wong-Staal at the University of California, San Diego, focused on development of lentiviral vectors (HIV-1, HIV-2, FIV) for gene therapy of HIV infection using ribozyme technology. In 2000, Kuhen began a second postdoctoral appointment at GNF focused on identification of critical host cell factors required for HIV-1 infection by small molecule screening and molecular interaction screening. With a background in antiviral mechanisms (PKR function), HIV-1 vector development, small molecule screening, and host-pathogen interaction studies, this training provided the tools to embark on the next stage of her career as Principal Investigator in the Lead Discovery group leading the HIV-1 effort at GNF.
Kuhen led the HIV biology effort as part of a multi-disciplinary team to identify new chemical scaffolds with the potential to be effective in the highly active antiretroviral therapy (HAART) regimen. Using a cell-based HIV-reporter virus infection approach an ultra high-throughput screen (uHTS) in 1536-well format was developed and optimized and a compound library collection of 1.2 million compounds was screened. GNF has state-of-the-art screening facilities with cutting-edge robotics and automation that streamline lead discovery and lead optimization processes of drug discovery. Numerous chemically attractive scaffolds with drug-like properties were identified and prioritized based on potency, lack of cytotoxicity, in vitro safety profiles, and in vivo pharmacokinetic properties suitable for once-a-day dosing. Together with medicinal chemistry and pharmacology teams, three series were advanced into late stage lead optimization and one selected as a pre-clinical candidate for HIV infection (pre-IND candidate). This series was transferred to Novartis, and all three chemical series led to publications in peer-reviewed journals as well as several patents. In addition to her HIV drug discovery efforts, Kuhen and her group also engaged in screening of genomics libraries (siRNA, cDNA) to identify factors in human cells that are critical for HIV replication. In fact, Dr. Kuhen's group was the first to run an siRNA genomics screen to identify host-derived effectors of HIV-1 replication. All work has been published in peer reviewed journals, presented at conferences, and has led to several patents.
With a continued interest in drug discovery and virology, Kuhen accepted a position with the Novartis Institute of Biomedical Research (NIBR) in Cambridge, MA, in the newly expanded Virology group in the Infectious Disease unit as a Research Investigator in 2006. At NIBR Kuhen set up the respiratory syncytial virus (RSV) and influenza drug discovery programs, and led the Biology effort as part of a multi-disciplinary team for RSV pre-clinical drug discovery.
In 2007 Kuhen returned to GNF with an interest in pursuing drug discovery for neglected diseases including both malaria and tuberculosis. These two programs are a joint collaboration with the Novartis Institute of Tropical Diseases in Singapore. The malaria program is funded by Wellcome Trust and the Medicines for Malaria Venture (MMV) while the tuberculosis program is funded in part by the Grand Challenges in Global Health (Gates Foundation). Plasmodium falciparum is the most deadly form of the malaria parasite and Dr. Kuhen's group uses this parasite in a red blood cell based infection system to identify small molecule inhibitors and assess their activity against P. falciparum parasite proliferation. A 2.6 million compound library was initially screened for antimalarial activity in P. falciparum infected red blood cells in 1536-well microtiter plates. This has led to a successful new drug discovery effort at GNF with two compound scaffolds currently approaching pre-clinical candidate status. Several additional scaffolds are ready for medicinal chemistry optimization and this has been well-received and funded further by the MMV. Similarly, for tuberculosis, screening efforts are underway to identify antimycobacterial compounds that work against drug-resistant Mycobacterium tuberculosis (Mtb) strains and / or shorten the length of therapy that is currently six months for drug-susceptible Mtb and two years for multi-drug resistant Mtb.
Lastly, Kuhen is a member of the Novartis Global Program Team (GPT) for Coartem. Coartem is an antimalarial drug developed by Novartis, approved in over 80 countries, and delivered in a not-for-profit manner. Coartem is a combination tablet of artemether and lumefantrine and is extremely effective in achieving cure in patients infected with Plasmodium falciparum. As a member of the GPT, one of DKuhen's responsibilities was to write the pre-clinical pharmacology section of the NDA that was subsequently submitted by Novartis to the FDA in Oct, 2007, and in turn granted Priority Review in June, 2008. The NDA was well-received by the Anti-Infectives Advisory Committee to the FDA in December, 2008, and Coartem is anticipated to gain FDA approval in early 2009 thereby allowing US travelers, US citizens living / working abroad, and those in the Armed Services to be prescribed Coartem tablets for treatment of Plasmodium falciparum infections.