Author Interviews, Brain Injury, Brigham & Women's - Harvard / 03.01.2021
Nanoparticles May Enable Delivery of Drugs Across Blood Brain Barrier
MedicalResearch.com Interview with:
[caption id="attachment_56348" align="alignleft" width="100"]
Dr. Joshi[/caption]
Nitin Joshi, Ph.D.
Engineering in Medicine/Department of Medicine
Brigham and Women's Hospital
[caption id="attachment_56349" align="alignleft" width="100"] Dr. Karp[/caption]
Dr. Jeffrey M Karp Ph.D
Principal Investigator
Professor of Medicine at Brigham and Women’s Hospital
Harvard Medical School
MedicalResearch.com: What is the background for this study? Would you explain what is meant by the blood brain barrier? How will nanoparticles facilitate transport of drugs into the brain?
Response: Over the past few decades, researchers have identified promising therapeutic agents that can target the biological pathways involved in brain diseases. Unfortunately, clinical translation of these therapeutics is limited by their inability to cross the blood brain barrier (BBB) and enter the brain at therapeutically effective levels. The BBB is a highly selective semipermeable border of cells that prevents molecules in the circulating blood from non-selectively crossing into the brain tissue. We have developed a simple targeted nanoparticle platform that can stably encapsulate therapeutic agents and enable their therapeutically effective delivery into the brain. In this work, we have demonstrated the utility of this platform for the treatment of traumatic brain injury (TBI), which is a leading cause of death and disability in children and young adults, with millions of people suffering TBI each year in accidents, sports, and military conflicts. Following primary injury, which is a result of the mechanical impact to the brain, secondary injury gradually occurs over months to years and can lead to neurological dysfunctions, including Alzheimer’s and Parkinson’s diseases.
After TBI, the BBB is physically breached for a short time and previous approaches to achieve therapeutically effective transport of drugs across the BBB have been severely limited to utilizing this very short window. However, the extent to which the BBB is physically breached in TBI varies greatly across the patient population. Therefore, current approaches are applicable to only a subset of injuries with substantially breached BBB. Moreover, BBB can self-repair within a few hours to weeks post-injury to restore its integrity. Hence, physical breaching of BBB offers a limited window for therapeutic interventions, which is not ideal as the secondary injury can last months to years and may require repeated dosing over long term.
The nanoparticle platform developed in this work can enable therapeutically effective delivery of drugs into the brain, irrespective of the state of the BBB. We achieved this by precise engineering of the surface properties of nanoparticles, which maximized their transport across the BBB. The therapeutic used in this study was a small interfering RNA (siRNA) molecule designed to inhibit the expression of the tau protein, which is believed to play a key role in neurodegeneration. Poly(lactic-co-glycolic acid), or PLGA, a biodegradable and biocompatible polymer used in several existing products approved by the U.S. Food and Drug Administration was used as the base material for nanoparticles. We systematically engineered and studied the surface properties of the nanoparticles to maximize their penetration across the intact, undamaged BBB in healthy mice. This led to the identification of a unique nanoparticle design that maximized the transport of the encapsulated siRNA across the intact BBB and also significantly improved the uptake by the brain cells.
Dr. Joshi[/caption]
Nitin Joshi, Ph.D.
Engineering in Medicine/Department of Medicine
Brigham and Women's Hospital
[caption id="attachment_56349" align="alignleft" width="100"] Dr. Karp[/caption]
Dr. Jeffrey M Karp Ph.D
Principal Investigator
Professor of Medicine at Brigham and Women’s Hospital
Harvard Medical School
MedicalResearch.com: What is the background for this study? Would you explain what is meant by the blood brain barrier? How will nanoparticles facilitate transport of drugs into the brain?
Response: Over the past few decades, researchers have identified promising therapeutic agents that can target the biological pathways involved in brain diseases. Unfortunately, clinical translation of these therapeutics is limited by their inability to cross the blood brain barrier (BBB) and enter the brain at therapeutically effective levels. The BBB is a highly selective semipermeable border of cells that prevents molecules in the circulating blood from non-selectively crossing into the brain tissue. We have developed a simple targeted nanoparticle platform that can stably encapsulate therapeutic agents and enable their therapeutically effective delivery into the brain. In this work, we have demonstrated the utility of this platform for the treatment of traumatic brain injury (TBI), which is a leading cause of death and disability in children and young adults, with millions of people suffering TBI each year in accidents, sports, and military conflicts. Following primary injury, which is a result of the mechanical impact to the brain, secondary injury gradually occurs over months to years and can lead to neurological dysfunctions, including Alzheimer’s and Parkinson’s diseases.
After TBI, the BBB is physically breached for a short time and previous approaches to achieve therapeutically effective transport of drugs across the BBB have been severely limited to utilizing this very short window. However, the extent to which the BBB is physically breached in TBI varies greatly across the patient population. Therefore, current approaches are applicable to only a subset of injuries with substantially breached BBB. Moreover, BBB can self-repair within a few hours to weeks post-injury to restore its integrity. Hence, physical breaching of BBB offers a limited window for therapeutic interventions, which is not ideal as the secondary injury can last months to years and may require repeated dosing over long term.
The nanoparticle platform developed in this work can enable therapeutically effective delivery of drugs into the brain, irrespective of the state of the BBB. We achieved this by precise engineering of the surface properties of nanoparticles, which maximized their transport across the BBB. The therapeutic used in this study was a small interfering RNA (siRNA) molecule designed to inhibit the expression of the tau protein, which is believed to play a key role in neurodegeneration. Poly(lactic-co-glycolic acid), or PLGA, a biodegradable and biocompatible polymer used in several existing products approved by the U.S. Food and Drug Administration was used as the base material for nanoparticles. We systematically engineered and studied the surface properties of the nanoparticles to maximize their penetration across the intact, undamaged BBB in healthy mice. This led to the identification of a unique nanoparticle design that maximized the transport of the encapsulated siRNA across the intact BBB and also significantly improved the uptake by the brain cells. 
Dr. Chua[/caption]
Isaac Chua, MD, MPH
Division of General Internal Medicine and Primary Care
Brigham and Women's Hospital
MedicalResearch.com: What is the background for this study?
Response: Patient surveys have shown that most people prefer to die at home at the end-of-life. However, during the initial wave of the COVID-19 pandemic, anecdotal evidence from our colleagues and findings from a prior study published in the Journal of the American Geriatrics Society suggested that majority of COVID-19 decedents died in a medical facility. However, less is known about care intensity at the end-of-life according to place of death among patients who died of COVID-19. Therefore, we characterized end-of-life care by place of death among COVID-19 decedents at Mass General Brigham (MGB), the largest health system in Massachusetts. 
Dr. Halpern-Felsher[/caption]
Bonnie Halpern-Felsher, PhD, FSAHM (pronouns: she/her)
Professor of Pediatrics
Taube Endowed Research Faculty Scholar
Professor (by courtesy), Epidemiology and Population Health
Professor (by courtesy), Psychiatry and Behavioral Sciences
Director of Fellows’ Scholarship, Department of Pediatrics
Director of Research, Division of Adolescent Medicine
Co-leader, Scholarly Concentrations, Pediatrics Residency Program
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: To examine adolescent and young adult e-cigarette use during the COVID-19 pandemic.
There were 4 main findings:
Dr. Ganson[/caption]
Kyle T. Ganson, PhD, MSW
Assistant Professor, Factor-Inwentash Faculty of Social Work
University of Toronto
Toronto, Canada
[caption id="attachment_55902" align="alignleft" width="132"]
Dr. Nagata[/caption]
Jason Nagata, MD, MSc
Assistant Professor of Pediatrics
University of California, San Francisco
San Francisco, California, USA
MedicalResearch.com: What is the background for this study?
Response: A quarter of young adults in the US have reported being unemployed during the COVID-19 pandemic. Young adults may be especially affected by employment loss as they often work in industries most adversely affected by social distancing.
MedicalResearch.com: What are the main findings?
Response: Among a sample of nearly 5,000 young adults age 18 to 26 in the US, we found that since March 2020, young adults who lost their job or were part of a household that experienced employment loss were more likely than those with secure employment to experience four common symptoms of anxiety and depression. This was also true of young adults who expected an employment loss in the next four weeks. The study also found that symptoms of anxiety and depression were common among the sample of young adults. In the seven days prior to the survey, 75% reported being nervous, anxious or on edge, 68% reported not being able to stop or control worrying, 67% reported having little interest or pleasure in doing things, and 64% reported feeling down, depressed, or hopeless.
Dr. Al Rifai[/caption]
Mahmoud Al Rifai, MD, MPH
Cardiovascular Disease Fellow
Baylor College of Medicine Houston, TX
[caption id="attachment_55680" align="alignleft" width="150"]
Dr. Virani[/caption]
Salim S. Virani, MD, PhD, FACC, FAHA, FASPC
Professor, Section of Cardiovascular Research
Director, Cardiology Fellowship Training Program
Baylor College of Medicine
Staff Cardiologist, Michael E. DeBakey Veterans Affairs Medical Center
Co-Director, VA Advanced Fellowship in Health Services Research & Development at the Michael E. DeBakey VA Medical Center
Investigator, Health Policy, Quality and Informatics Program
Michael E. DeBakey Veterans Affairs Medical Center HSR&D Center of Innovation Houston, TX
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: E-cigarettes have gained popularity since their introduction in the U.S. market nearly 20 years ago and their use has increased especially among younger adults. On the other hand, public health efforts aimed at curbing tobacco use over the past few decades have resulted in a decrease in cigarette use. However, state-specific laws and regional cultural differences with regards to perception of these products may result in variability in tobacco use patterns. We therefore evaluate temporal changes in e-cigarette and cigarette use in each U.S. state between the years 2016 to 2018.
Dr. Spann[/caption]
Marisa N. Spann, PhD, MPH
Columbia University Irving Medical Center
New York, New York
MedicalResearch.com: What is the background for this study?
Response: Prior research has demonstrated that higher maternal pre-pregnancy body mass index is associated with adverse long-term outcomes for offspring including obesity, poorer cognitive and social abilities, and increased risk of psychiatric disorders.
MedicalResearch.com: What are the main findings?
Response: In this study, we investigated the association of maternal pre-pregnancy body mass index with fetal growth and neonatal functional connectivity and found that maternal pre-pregnancy BMI has a significant positive correlation with fetal weight and with greater thalamic connectivity of the brain. 
