PHILADELPHIA—Two researchers from the Perelman School of Medicine at the University of Pennsylvania are among the recipients of the 2018 Clinical Research Achievement Award from the Clinical Research Forum, which recognizes the ten most outstanding clinical research accomplishments in the United States during the preceding twelve months.
Dr. Pablo Tebas
The Penn awardees are Pablo Tebas, MD, a professor of Infectious Diseases, for the first trial of a Zika vaccine in humans, which proved safe and effective in a test population; and Danish Saleheen, MBBS, PhD, an assistant professor of Epidemiology, for his research on the ramifications of genetic variation in humans on searching for new heart disease drugs.
In a study published in the New England Journal of Medicine this past October, Tebas and colleagues from The Wistar Institute, Inovio Pharmaceuticals, and GeneOne Life Science, Inc, reported that a first-of-its-kind vaccine to fight the Zika virus, which they developed, was both safe and effective. (While other potential vaccines are now in clinical trials, there are currently no approved versions.)
Zika infection, which is transmitted by mosquitoes, typically causes fever, rash, joint pain, conjunctivitis, and infrequently, serious neurologic conditions such as Guillain-Barré syndrome. Infection during pregnancy has resulted in thousands of cases of microcephaly — smallness of the head due to incomplete brain development and developmental disabilities.
The new vaccine is based on synthetic DNA and gives instructions to the body’s immune system to produce antibodies to attack Zika antigens. (Antigens are bacteria, viruses, and other foreign substances that trigger immune responses from the body.) In the study, a total of 40 participants (20 in each of two groups) received GLS-5700, the new vaccine, against two proteins of the Zika virus. The vaccine induced antibodies in 100 percent of the participants after a three-dose course of therapy and in 95 percent after two doses of vaccine. When blood from vaccinated subjects was then transferred to mice, more than 90 percent of the animals were protected from death and illness despite being exposed to a lethal dose of the Zika virus.
Dr. Danish Saleheen
GLS-5700, which was designed and tested in seven months, differs from conventional vaccines, which typically use inactivated or killed versions of a virus and can take years to develop and test. The synthetic vaccine features portions of Zika-virus genes made in a laboratory, which are added to a ring of genetic material called a plasmid. After the vaccine is injected under the skin, electrical impulses are generated, producing small holes in cells, allowing the DNA to enter and initiate the immune response.
Further studies will be needed to evaluate the efficacy of the vaccine and its long-term safety.
The biological function of the vast majority of the more-than 18,000 human genes remains unknown. One way of finding out is studying the effects of “knocking out” a gene. This refers to the practice of inactivating a gene in mice by replacing it or interfering with it. This helps scientists determine what the gene does in the body. It is ethically prohibited in humans, but some people are born without certain genes, achieving the same effect.
These people can be studied to determine the function of the missing gene or genes. In the cited study, Saleheen and his colleagues sequenced the DNA of 10,500 Pakistanis and found more than 1,300 missing genes. (This is an unusually large number and is due to the fact that first-cousin marriages are common in Pakistan, increasing the chances of offspring who have mutations in both copies of a given gene.) Many of these genes were observed to be completely missing for the first time in humans. The team then looked for abnormalities in about 200 blood biomarkers such as levels of cholesterol and insulin.
In an important finding, they determined that the APOC3 gene, which regulates the metabolism of triglyceride-rich lipoproteins in the blood, was missing in several dozen individuals (out of over 10,000 studied) who had very low triglyceride levels. (High levels of triglycerides raise the risk of heart disease.) The researchers gave the individuals a high-fat meal. Compared with family members who had the APOC3 gene, APOC3-knockout family members did not have the usual post-meal rise in plasma triglycerides. This finding may help validate APOC3 inhibition as a therapeutic target for cardiometabolic diseases – the leading cause of death globally.
To date, Saleheen and his colleagues have collected blood samples from more than 120,000 participants; the recruitment is being expanded to eventually include 200,000 people. This is projected to identify human knockouts for more than 8,000 unique genes, helping researchers understand the health consequences, and potential effect on medications, of the missing genes in a variety of medical conditions.
Researchers from all ten winning studies will be recognized at a dinner and reception at the National Press Club on April 18th in Washington, D.C.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.
The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.
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