What’s New in Research

Researchers at Brigham and Women’s Hospital (BWH) have developed an efficient and effective delivery vehicle for gene therapy, and have used it to shrink tumors by nearly 90 percent in a pre-clinical model of triple-negative breast cancer. The new technique uses a hydrogel – a super-glue-like gel that spontaneously forms when two solutions mix – and self-assembled nanoparticles consisting of two microRNAs that suppress and target tumor tissue. This platform can be injected locally, allowing the researchers to increase dosage at the site of the tumor while decreasing the risk of the therapy accumulating in the kidneys, liver or other organs. In mouse models, the adhesive containing self-assembled nanoparticles injected using this approach has been far more potent, selective and specific to tumor cells than conventional chemotherapeutic drugs and have lengthened survival time. The team’s results are published in Nature Materials.

“Cancer is usually viewed as a systemic disease requiring systemic therapy but here we show that local therapy is actually very potent,” said senior author Natalie Artzi, PhD, a researcher in the Department of Medicine, Biomedical Engineering Division, and the Harvard-MIT Division for Health Sciences and Technology. “The results are outstanding and demonstrate the power of local, sustained delivery, and the promise of gene therapy in cancer treatment.”

The researchers note that this approach can be used to deliver other combinations of microRNAs or other types of genetic material, including antisense DNA or small interfering RNA, to treat a wide-range of diseases. As a next step, the team will test the technique for biocompatibility and efficacy in larger animal models and will scale up their platform to screen for additional potentially therapeutic microRNAs and cancer therapies that can be combined to improve treatment.

To learn more about this work, watch a “whiteboard video” that tells the story of the research project and its findings.

Treating Rare Brain Tumors with Precision Medicine

Sandro Santagata, MD, PhD, of the Department of Pathology, teamed up with colleagues at Massachusetts General Hospital to test whether a targeted therapy could help treat a patient with a rare brain tumor known as a papillary craniopharyngioma. Building on the promise of a genomics study published in 2014, Santagata and his colleagues report on one of the first examples of precision medicine being used to successfully treat a primary tumor of the central nervous system. Their results have been published in JNCI.

In their Nature Geneticsstudy published in 2014, Santagata and colleagues found that nearly all papillary craniopharyngioma tumors – rare tumors that arise at the base of the skull – harbor mutations in the gene BRAF. Drugs that block the function of the mutant BRAF protein have been very effective for the treatment of melanoma skin cancers Papillary craniopharyngiomas are challenging to treat and manage, and can lead to very serious treatment-related complications for the patient, making a more targeted approach highly attractive. Following the genomics study, Santagata teamed up with colleagues at MGH who were treating a patient who had presented with a tumor that recurred despite surgical resection and decompression. After 35 days of treatment with BRAF inhibitors, the patient’s tumor shrunk by 85 percent.

In addition, when analyzing samples taken from the patient’s blood before and after treatment, the researchers were able to detect circulating BRAF mutant DNA. This finding raises the possibility that in the future, “liquid biopsies” that allow clinicians to detect circulating mutant DNA could be performed before surgery to support that a tumor that harbors a BRAF mutation.

“It is quite remarkable how quickly we have been able to go from identifying the genetic driver of papillary craniopharyngiomas to testing a precision medicine treatment in a patient that needed help,” said Santagata. “It was only last year that we first described in Nature Genetics that nearly all papillary cranionpharyngiomas have mutations in BRAF. This is the same mutation that is found in many melanomas, allowing us to use treatment strategies that have been so promising in melanoma patients.”

A fruit fly model of a rare, neurodegenerative disease is helping researchers trace the series of steps that lead to neuronal cell death. Damage to astrocytes – star-shaped cells found in the brain and spinal cord – is found in many neurodegenerative conditions, but it’s been unclear exactly what role astrocyte dysfunction plays in the development of disease.

Researchers have developed a genetic model that is yielding new insights into what happens when astrocytes go awry. The research team developed a fruit fly model of Alexander disease, a neurodegenerative disease that primarily affects astrocytes, and was able to narrow in on the molecular signals leading to neuronal cell death, identifying nitric oxide (NO) as a critical mediator. The team verified their results in a mouse model and also found evidence of activation of the same pathway in samples from patients with Alexander disease. Their results have been published in Nature Communications.

“We’re excited to be contributing to a growing area of study of how astrocytes contribute to neurodegeneration, and to have uncovered a role for NO as a neuronal cell death signaling molecule,” said corresponding author Mel B. Feany, MD, PhD, a senior pathologist in the Department of Pathology. “Our findings define a potential mechanism for neuronal cell death in Alexander disease and possibly other neurodegenerative diseases with astrocyte dysfunction.”

Graduation of Doctors-in-Training Does Not Affect Their Patients’ Rates of Emergency Department Use and Hospitalizations

Primary care physician Sonja Solomon, MD, and her colleagues studied whether patients experienced more emergency department visits and hospitalizations in the period after residents who had provided them with primary care completed their training. The team’s results appeared in the Journal of General Internal Medicine.

Across the US, approximately one million patients each year who receive their primary care from resident physicians must begin care with a new primary care provider (PCP) when those residents complete their training. Solomon and her colleagues examined over 4,000 patients cared for by residents in a large teaching practice over three years. They found:

Emergency department visits and hospitalizations were not higher in the period following graduation than in the period before graduation

Rates of emergency department visits and hospitalizations were not higher among patients of senior (graduating) residents compared to junior (non-graduating) residents

The rates of emergency department visits and hospitalizations among patients cared for by residents were much higher than national averages in all time periods examined. In each four-month period examined, eight percent of patients were hospitalized and 18 percent of patients visited the emergency room.

“The year-end graduation of resident physicians has been posited to be a time of vulnerability for those residents’ primary care patients,” said Solomon. “Our study calls into question the assumption that patients are adversely affected by the transition to a new resident PCP. At the same time, it highlights an unmet need for interventions to decrease acute care utilization by residents’ patients throughout the academic year.”

Ribas et al.’s paper made the cover of Lab on a Chip and was selected as a “Lab on a Chip Recent Hot Articles.”

Joao Ribas, a graduate student in the lab of Ali Khademhosseini, and senior postdoc Yu Shrike Zhang worked together with colleagues to develop a miniature microscope from off-the shelf components, including a webcam, for biomedical applications. They describe the capabilities of the mini-microscope in a paper that made the cover issue of Lab on a Chip and was recently selected as a “Lab on a Chip Recent Hot Articles.”

Using built-in fluorescence, the mini-miscroscope designed by Ribas, Zhang and colleagues can be used to detect a variety of features of cells and tissues including live/dead cell viability and oxygen levels. The team used the mini-microscope to evaluate the toxicity of a drug on a laboratory model of the liver (liver-on-a-chip) and on the beating of heart cells in culture (heart-on-a-chip). The researchers were able to achieve a resolution as high as two micro-meters. The team estimates a total cost of less than $10 for all of the microscope’s component parts.

“Its versatile nature and low cost make this mini-microscope a convenient tool with many biomedical applications,” said Ribas. “We envision it’s usage in a wide variety of applications, potentially replacing conventional, bench-top microscopy in situation where long-term and large-scale imaging analysis is required.”