University of Maryland School of Medicine (UMSOM) Professor of Diagnostic Radiology & Nuclear Medicine, Linda Chang, MD, MS, received the National Institute on Drug Abuse (NIDA) 2021 Avant Garde Award (DP1) for HIV/AIDS and Substance Use Disorder Research -- a National Institutes of Health (NIH) Director's Pioneer Award. This prestigious award supports researchers with exceptional creativity, who propose high-impact research with the potential to be transformative to the field. Her proposed project will involve a team of experts in brain imaging, infectious diseases, addiction, animal research, and gene-editing technology with the goal to essentially eradicate all traces of HIV from the body, and treat commonly co-existing substance use disorders. 2021 Avant Garde Awardees are expected to receive more than $5 million over five years.
"I am extremely pleased, and feel very fortunate to have received this award," says Dr. Chang, who has a secondary appointment in the Department of Neurology at UMSOM. "This project takes my work in a new direction. I believe my track record of being able to work across multiple disciplines with various researchers to initiate new areas of research and getting good results, along with the outstanding collaborators and resources at UMB, gave the proposal reviewers confidence that my team and I can significantly advance this new project."
About 38 million people around the world live with HIV, according to the Centers for Disease Control and Prevention. Although antiretroviral therapies can treat HIV to the point of undetectable viral levels and lead to long, healthy lifespans, these medications must be taken for life to prevent 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 can reemerge.
From start to finish, Dr. Chang's plan is to remove HIV from the genome, even in tough to reach spots like the brain, get more of the antiretroviral therapies into the brain, and stimulate the reward system in the brain to reduce drug cravings. The work will start out in mice before it can be tested in people.
Dr. Chang plans to use the gene-editing technology known as CRISPR to cut out copies of the hidden HIV genes in the genomes of mice, so they can be eradicated by antiretroviral drugs.
However, getting the CRISPR therapy into the brain can be difficult because of 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 seek out HIV in the brain, Dr. Chang and her team will temporarily disrupt the blood-brain barrier to allow more of the antiretroviral drugs or the CRISPR compounds to cross over the blood-brain barrier using an unique resource at the University of Maryland--the MRI-guided focused ultrasound system. This technique uses the MRI scan to help guide 2,000 pinpointed beams of high energy sound waves, along with microscopic bubbles, to non-invasively and temporarily open an area of the brain with the goal of eliminating the hidden reservoirs of virus in the brain's immune cells.
About half of the people with HIV use substances, like drugs or alcohol, or have substance use disorders. Even tobacco or cannabis use in people with HIV is at 2-3 times that of the general population. Together with Victor Frenkel, PhD, an Associate Professor in the Department of Radiology and the Director of Translational Focused Ultrasound, and Donna Calu, PhD., Assistant Professor in the Department of Anatomy and Neurobiology, Dr. Chang will use low energy MR-guided focused ultrasound to suppress brain activity in the reward center of the brain, the nucleus accumbens. They hope this approach will suppress drug cravings in people with HIV who have substance use disorders.
The different components of this project will first be tested in mouse or rat models before moving onto clinical studies. As HIV does not normally infect mice, researchers use "humanized" mice that have weak immune systems, which are replaced with human blood stem cells that become human immune cells that can be infected with HIV. Although these humanized mice make lots of T cells-- a main cell for HIV infection--they don't make the immune cells that HIV uses to hide in the brain, known as microglia. Recently, Dr. Chang's collaborator Howard E. Gendelman, MD, Margaret R. Larson Professor of Internal Medicine and Infectious Diseases Chair at University of Nebraska Medical Center, and his lab created a modified humanized mouse that has an extra human gene that allows the human blood stem cells to now make microglia.
"These new mice mean that these experiments can be done in a fraction of the time and cost and without the other hurdles that come along 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 UMSOM's Institute of Human Virology.
He adds, "There have been many attempts to eradicate HIV in the body, and it is thought they have not been successful, in part because we cannot get to the HIV reservoirs in the brain. If this works, we will be much closer to a practical cure for HIV." Dr. Heredia will be collaborating with Dr. Chang on this project using HIV-infected humanized mice that he has developed for his other ongoing projects.
For the addiction studies, Dr. Chang's team will use the expertise and rodent models of addiction developed and optimized by Mary Kay Lobo, PhD, Professor of Anatomy and Neurobiology, and Dr. Calu. The mice will self-administer fentanyl, a powerful, synthetic opioid.
Dr. Frenkel and Dheeraj Gandhi, MBBS, Professor of Diagnostic Radiology and Nuclear Medicine and Clinical Director of Center of Metabolic Imaging and Therapeutics at UMSOM, are the team's MRI-guided focused ultrasound and clinical research experts.
"My hearty congratulations to Dr. Chang and her colleagues and collaborators. If anything is called 'cutting edge' this work surely qualifies for that praise. We wish this group all the success possible," said Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Director, Institute of Human Virology (IHV), University of Maryland School of Medicine, a Global Virus Network (GVN) Center of Excellence, and GVN Co-Founder and International Scientific Advisor.
Dr. Chang is an expert in using brain imaging to study how HIV or drug use affect the brain in adults and during adolescence, and how exposure to drugs in the womb affects childhood development. She has also conducted clinical trials for treating HIV-associated cognitive disorders and substance use disorders.
Dr. Chang joined UMSOM in 2017 through the Dean's initiative Special Trans-Disciplinary Recruitment Award 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 clinical and basic science research bringing UMSOM among other top-tier medical research schools.
"Dr. Chang's arrival to UMSOM spurred the exact kind of collaborative efforts we had hoped to foster through our recruitment program in order to accelerate discoveries, treatments and cures for the world's most pressing diseases," says E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM. "I look forward to following her team's progress on this ambitious project in the hope that one day we can eradicate HIV."
Dr. Chang served on the National Advisory Council on Drug Abuse for NIDA and is a current member on the Council of Councils at the NIH.
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