Dr. Lanford is Director of the Southwest National Primate Research Center. SNPRC is one of the seven NIH-funded National Primate Research Centers. The Center focuses on the development and use of nonhuman primate models of human diseases. Dr. Lanford and Dr. John Bernal are also the Principal Investigators of the U42 grant “Establishment of a SPF Rhesus Macaque Colony” that provides animals for AIDS research.
His scientific focus is on hepatitis viruses, especially how viral-host interactions and innate immune response influence disease progression.
- Primate models of liver disease
- Hepatitis B virus (HBV)
- Hepatitis C virus (HCV)
- GB virus-B (GBV-B), a surrogate model for HCV
- Liver cancer
Dr. Lanford has more than 40 years expertise as virologist.
In The Lab
In a multi-team effort, we studied the mechanism of viral clearance and persistence by comparing infections with two viruses: HCV (a virus that frequently causes chronic infections) and HAV (a virus that is always cleared by the immune system). These studies highlighted the differences in innate immune response and the CD4+ T cell response in these two models.
Our lab pioneered the use of total genome microarrays to examine the innate immune response in the liver to HCV infection. In our chimpanzee studies, we demonstrated that specific liver gene expression patterns during chronic infection correlate with a lack of efficacy to interferon therapy, later recognized in humans as the Null Responder Phenotype. These studies initiated the use of microarrays in the field of hepatitis, defined the interferon stimulated gene response (ISG), and provided insight into the basis for the Null Responder Phenotype to interferon in chimpanzees and humans.
We have been involved in the testing of new antiviral therapies for the treatment of chronic hepatitis infections. My group collaborated with more than 20 biotech and pharmaceutical companies to examine the safety and efficacy of HCV antivirals in the chimpanzee model as the last preclinical step prior to human trials. Today, two antiviral cocktails are FDA approved and others are near approval that can cure HCV with 12 weeks of daily oral medications. SNPRC helped develop one of the FDA- approved cocktails with safety and efficacy studies that spanned a 10-year period.
One of the novel inhibitors of HCV that we examined involved inhibition of a molecule in the liver required by the virus for replication.
This inhibitor sequestered a liver-specific microRNA called miR122. The drug Miravirsen is a Locked Nucleic Acid (LNA) antisense oligonucleotide. This was the first example of a DNA-based therapy that is highly efficacious when administered systemically. Our proof-of- concept study demonstrated the feasibility of treating other diseases using LNA technology, including cancer and inflammatory diseases.
In collaboration with Gilead, we examined a toll-like receptor 7 (TLR7) agonist in HBV therapy; it induced the innate immune response and triggered activation of the adaptive immune response during chronic infection, to eliminate infected cells. This compound is currently in human clinical trials for HBV. Our recently completed studies with Arrowhead use a novel siRNA that targets HBV in the liver and presents a very promising therapy that has also progressed to human clinical trials.
We are currently working on the development of several new primate models for liver disease. One area of interest is the development of a small primate model for HBV chronic infection to replace the chimpanzee model. A second project involves the development of a baboon model for liver cancer. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, and HCC has become the most rapidly increasing cause of death due to cancer in the U.S., primarily attributable to the HCV epidemic. We have created a model of liver cancer in the baboon by genetic engineering of liver cells, hepatocytes, in vitro and implantation of the cells back into the liver of the donor baboon. Tumor development occurs in 1-3 months, rather than after decades of chronic hepatitis. We are currently using this model to explore novel therapeutics in collaboration with the biotech industry.
Main Technologies And Methods Used
- Nonhuman primate model development
- Gene expression using microarrays and qRT-PCR
- Primary hepatocyte technology
- Lentivirus expression vectors with oncogenes