Novel Approaches, Therapeutics, and Devices Accelerate Breakthroughs

By using structure-guided design, researchers in the John Laboratory at Children’s Hospital of Philadelphia developed a novel approach for developing new antibiotics that are able to reach resistant bacteria.

This newly established method reported in eLife takes a cue from the Trojan horse strategy in Homer’s epic poem, The Odyssey, by creating prodrugs, or blocking agents, that conceal the antibiotics and then allow them to be revealed and released — by the bacteria themselves — once the antibiotics arrive at the site of infection. By learning how the mechanism by which the bacteria remove the prodrug, the research team designed a better way of delivering the effective compound without releasing the prodrug early and missing the intended target, which has been a major challenge in the effort to develop effective antibiotics.

“We’ve created a sort of ‘Trojan horse’ that would allow antibiotics to reach desired tissues undisturbed, until the bacteria itself activates the drug, effectively releasing an ‘army’ of antibiotics,” said senior author Audrey Odom John, MD, PhD, chief of the Division of Infectious Diseases. “Using structure-guided design, we have developed a new way to design better antibiotics. Given the growing concern over antimicrobial resistance, we think this is an important step forward.”

Mitochondrial disease comprises a group of energy deficiency disorders that impair mitochondrial respiratory chain function — a function necessary to make energy to power cells in the body. Healthcare providers often recommend vitamins and supplements to patients but do so with no definitive knowledge about how much to recommend, or what formulation to recommend, or if there is any value to combining several types of vitamins or supplements.

In a preclinical study, led by Marni Falk, MD, executive director of CHOP’s Mitochondrial Medicine Frontier Program, the researchers identified a group of three drugs that may be a potential effective treatment for mitochondrial disease. The findings showed that a combination of glucose, nicotinic acid, and N-acetylcysteine — all vitamins or supplements that are available over the counter — appears to be beneficial for patients with mitochondrial respiratory chain disorders.

“The variable combinations of therapies used to manage mitochondrial disease patients tend to include empirically-based ‘cocktails’ of vitamins and nutrients whose safety and efficacy are difficult to objectively evaluate and compare,” Dr. Falk said. “Our preclinical study demonstrates that identifying the right combination of therapies that is rationally designed based on addressing the unique cellular deficiencies of major mitochondrial disease classes can provide clear, measurable survival benefits over individual therapies that each address only part of the cellular problem.”

The Food and Drug Administration approved crizotinib, also known by its brand name Xalkori, a first generation ALK inhibitor, for the treatment of pediatric patients with a rare form of non-Hodgkin’s lymphoma known as ALK-fusion positive relapsed/refractory anaplastic large cell lymphoma (ALCL). Approximately 90 percent of pediatric ALCL cases are ALK-positive. The approval was based on a pivotal study led by CHOP researchers through the Children’s Oncology Group.

Yael Mossé, MD, an oncologist in CHOP’s Cancer Center and co-leader of the Genes, Genomics, and Pediatric Disease Research Affinity Group, has researched ALK alterations in the context of several cancers and was the principal investigator for several studies that led to the FDA approval of this cancer treatment drug.

“The approval of Xalkori marks an important moment for pediatric patients with ALK-positive ALCL who suffer a relapse during or after standard upfront chemotherapy, and who now have another treatment option that may one day prove to be an integral component of curative therapy,” Dr. Mossé said “This is a big step forward and one that will give hope to many patients and families.”

Approximately 40,000 infants each year are affected by congenital heart disease, the most common birth defect in the United States. These tiny patients face several open-heart surgeries over their lifetimes to correct issues related to their dysfunctional pulmonary valves. However, with a new non-surgical device approved by the FDA, less invasive procedures can now reduce the many risks associated with open heart surgery.

CHOP was the lead enrolling site in the clinical trial that led to the FDA approval of the Harmony™ Transcatheter Pulmonary Valve. This medical technology advancement allows for pulmonary valve replacement via a minimally invasive catheter-based procedure. The device consists of a self-expanding metal frame combined with valve leaflets that can be implanted inside a patient’s heart and will require less anesthesia, reduce the risk of infection, and lead to a faster recovery, than open heart surgery.

“The approval of this device will allow us to provide a non-surgical option to patients with congestive heart disease, reducing or eliminating the need for multiple open heart surgeries over the course of a patient’s lifetime,” said CHOP site PI, Matthew Gillespie, MD, interventional cardiologist in the Cardiac Center, director of CHOP’s Cardiac Catheterization Laboratory, and co-director of its Center for Pediatric Heart Valve Disorders. “Researchers in the Cardiac Center at CHOP are committed to bringing our expertise to the development of cutting-edge treatments, which will improve the lives of our patients and their families.”

Image courtesy of Medtronic.

Researchers with CHOP’s Cancer Center, in collaboration with 154 other hospitals in the Children’s Oncology Group, revealed that the drug blinatumomab, a bispecific T-cell engaging antibody, is less toxic than chemotherapy for high-risk relapsed B-cell acute lymphoblastic leukemia (B-ALL). The findings reported in JAMA suggest blinatumomab as the standard of care for patients with the high-risk, difficult-to-treat cancer.

Blinatumomab links a patient’s CD3+ T cells to CD19+ leukemia cells, inducing an immune response that destroys the cancer cells. The Food and Drug Administration approved this targeted treatment for patients — adults and children — with relapsed/refractory B-ALL and minimal residual disease (MRD)- positive B-ALL.

“When it comes to high-risk cancers like relapsed B-ALL, we have reached a plateau in what we can accomplish with more intense chemotherapy, which comes with numerous toxic side effects,” said co-senior author Stephen Hunger, MD, chief of the Division of Oncology, and director of the Center for Childhood Cancer Research. “This study shows that blinatumomab can replace chemotherapy in certain subsets of B-ALL because it is less toxic and leads to better outcomes. Additional studies will examine this therapy in other disease stages of B-ALL to see if it has a similar benefit.”

CHOP researchers, including Joseph St. Geme, MD, physician-in-chief and chair of the Department of Pediatrics at CHOP, have identified two proteins that could be used for a potential vaccine against nontypeable Haemophilus influenzae (NTHi). The most common cause of bacterial respiratory tract infections, NTHi can cause middle ear infections, sinus infections, and exacerbations of chronic obstructive pulmonary disease (COPD) and other underlying lung disease, resulting in significant morbidity in both children and adults.

The scientists focused their research on two proteins — HMW1 and HMW2 — involved in NTHi colonization of the nasopharynx (upper part of throat, behind nose), the first step in the pathogenesis of NTHi disease. These proteins help the bacteria adhere to respiratory cells and are present in approximately 75 to 80 percent of NTHi strains.

The study findings reported in the Proceedings of the National Academy of Sciences of the United States of America showed that administering these two adhesive proteins stimulated protective immunity against not only the parent strain of NTHi from which the adhesive proteins were derived, but also other diverse NTHi strains, highlighting the vaccine potential.

“Currently there are no vaccines or other approaches to protect against infection due to this organism,” said senior author Dr. St. Geme. “Our study has identified two proteins that stimulate both an antibody response and a broader cell-mediated immune response that protect against diverse strains of NTHi influenzae and thus may be valuable for inclusion in a vaccine to protect against a full range of NTHi disease.”