University of Maryland School of Medicine (UMSOM) Professor of Diagnostic Radiology and Nuclear Medicine, Linda Chang, MD, MS, received the National Institute on Drug Abuse (NIDA) Avant-Garde Prize 2021 (DP1) for research on HIV / AIDS and substance use disorders – a pioneering award from the director of the National Institutes of Health (NIH). This prestigious award supports researchers with exceptional creativity, who deliver high-impact research with the potential to transform the field. His proposed project will involve a team of experts in brain imaging, infectious diseases, drug addiction, animal research and gene editing technology with the goal of essentially removing all traces of HIV from the body and treating substance use disorders. coexisting. The Avant Garde 2021 winners are expected to receive more than $ 5 million over five years.
âI am extremely happy and feel very fortunate to have received this award,â said Dr Chang, who has a secondary position in the Department of Neurology at UMSOM. “This project takes my work in a new direction. I believe that my ability to work in multiple disciplines with various researchers to initiate new areas of research and achieve good results, as well as the outstanding collaborators and resources of UMB, gave the proposal reviewers are confident that my team and I can significantly advance this new project. “
About 38 million people worldwide are living with HIV, according to the Centers for Disaster Control and Prevention. Although antiretroviral therapy can treat HIV to undetectable viral levels and lead to long, healthy lifetimes, these drugs need to be taken for life to avoid a resurgence, as HIV can hide from these drugs by integrating copies of itself into a person’s genome. Once the drugs are stopped, the virus may come back.
From start to finish, Dr. Chang’s plan is to eliminate HIV from the genome, even in hard-to-reach places like the brain, introduce more antiretroviral therapy to the brain, and stimulate the reward system in the brain. brain to reduce drug cravings. Work will begin in mice before it can be tested in humans.
Dr Chang plans to use the gene-editing technology known as CRISPR to cut copies of hidden HIV genes from the genomes of mice, so that they can be eradicated by antiretroviral drugs.
However, introducing CRISPR therapy into the brain can be difficult due to the blood brain barrier, which protects the brain from infectious bacteria and foreign substances. The blood-brain barrier also prevents antiretroviral drugs from reaching high enough concentrations in the brain and central nervous system to effectively destroy HIV.
To test the brain for HIV, Dr. Chang and his team will temporarily disrupt the blood-brain barrier to allow more antiretroviral drugs or CRISPR compounds to cross the blood-brain barrier using a unique resource at the University of Maryland. –the MRI guided focused ultrasound system. This technique uses MRI to help guide 2,000 localized beams of high-energy sound waves, as well as microscopic bubbles, to non-invasively and temporarily open up an area of ââthe brain in an effort to eliminate hidden reservoirs of viruses in immune cells of the brain. .
About half of people living with HIV use substances, such as drugs or alcohol, or have a substance use disorder. Even the consumption of tobacco or cannabis among people living with HIV is 2-3 times that of the general population. Together with Victor Frenkel, PhD, Associate Professor in the Department of Radiology and Director of Translational Focused Ultrasound, and Donna Calu, PhD., an assistant professor in the Department of Anatomy and Neurobiology, Dr Chang will use low-energy magnetic resonance-guided focused ultrasound to suppress brain activity in the brain’s reward center, the nucleus accumbens. They hope this approach will suppress drug cravings in people living with HIV who suffer from substance use disorders.
The various components of this project will first be tested on mouse or rat models before moving on to clinical studies. Since HIV does not normally infect mice, researchers are using “humanized” mice with weakened immune systems, which are replaced by human blood stem cells which become human immune cells that can be infected with HIV. Although these humanized mice make many T cells – a main cell for HIV infection – they do not make the immune cells that HIV uses to hide in the brain, called microglia. Recently, Dr. Chang’s collaborator Howard E. Gendelman, MD, Margaret R. Larson, professor of internal medicine and chair of infectious diseases at the University of Nebraska Medical Center, and her lab have created a modified humanized mouse that has an additional human gene that allows human blood stem cells to make now microglia.
“These new mice mean that these experiments can be performed in a fraction of the time and cost and without the other hurdles that come with using non-human primates, which are the only other animal that a special strain of HIV can infect.” , says collaborator Alonso Heredia, PhD, associate professor of medicine and scientist at the Institute of Human Virology at UMSOM.
He adds: âThere have been many attempts to eradicate HIV from the body, and it is believed that they have not been successful, in part because we cannot access the reservoirs of HIV in the brain. If that works, we will be much closer to a practical cure for HIV. “Dr Heredia will collaborate with Dr Chang on this project using humanized mice infected with HIV that he has developed for his other ongoing projects.
For addiction studies, Dr Chang’s team will use the expertise and rodent addiction models developed and optimized by Mary Kay Lobo, Ph.D., professor of anatomy and neurobiology, and Dr Calu. The mice will self-administer fentanyl, a strong synthetic opioid.
Dr Frenkel and Dheeraj Gandhi, MBBS, professor of diagnostic radiology and nuclear medicine and clinical director of the Center for Metabolic and Therapeutic Imaging at UMSOM, are the team’s experts in MRI-guided focused ultrasound and clinical research.
“My sincere congratulations to Dr Chang and his colleagues and collaborators. If anything is called ‘cutting edge’, this work certainly deserves this praise. We wish this group every success,” said Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor of Medicine, Co-Founder and Director, Institute of Human Virology (IHV), University of Maryland School of Medicine, Global Virus Network (GVN) Center of Excellence and Co-Founder and International of GVN Scientific Advisor.
Dr Chang is an expert in using brain imaging to study how HIV or drug use affects the brain in adults and during adolescence, and how drug exposure in the womb affects the brain. childhood development. She has also conducted clinical trials for the treatment of cognitive impairment associated with HIV and substance use disorders.
Dr Chang joined UMSOM in 2017 at the initiative of the Dean Special Transdisciplinary Recruitment Fellowship Program (STRAP). The STRAP initiative was part of UMSOM’s multi-year research strategy ACCEL-Med (Accelerating innovation and discovery in medicine) to increase the quality and reputation of research in clinical and basic sciences, bringing UMSOM among other leading medical research schools.
âDr. Chang’s arrival at UMSOM has spurred the exact kind of collaborative efforts we were hoping to foster through our recruiting program to accelerate discoveries, treatments and cures for the most urgent diseases in the world. world, âsaid E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and Distinguished Professor and Dean John Z. and Akiko K. Bowers, UMSOM. “I look forward to monitoring his team’s progress on this ambitious project in the hope that one day we can eradicate HIV.”
Dr. Chang served on the National Drug Abuse Advisory Board for NIDA and is currently a member of the NIH Board of Advisors.
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