Stories about: Drug discovery

Breaking the allergic asthma cycle…by targeting nerve endings

asthma therapeuticsExisting asthma medications work by suppressing inflammatory signaling by immune cells or by dilating constricted airways. Over time, though, these drugs’ benefits can wane. New research supports a surprising new tactic for controlling asthma: targeting sensory nerve endings in the lungs with a selective drug.

Our lungs are known to contain specialized sensory neurons known as nociceptors that connect to the brainstem. Best known for causing the perception of pain, nocieptors also trigger the cough reflex in the lungs when they detect potential harms like dust particles, chemical irritants or allergens. Nociceptor nerve endings are known to be more plentiful and more readily activated in people with asthma. Now it’s also clear that they help drive allergic inflammation.

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Targeting inflammation in sickle cell disease with fatty acids

sickle cell disease red blood cells
(OpenStax College/Wikimedia Commons)

Painful, tissue-damaging vaso-occlusive crises (a.k.a. pain crises) are one of the key clinical concerns in sickle cell disease (SCD). The characteristic C-shaped red blood cells of SCD become jammed in capillaries, starving tissues of oxygen and triggering searing pain. Over a patient’s life, these repeated rounds of oxygen deprivation (ischemia) can take a heavy toll on multiple organs.

There’s some debate as to why these crises take place—is the sickled cell’s shape and rigidity at fault, or are the blood vessels chronically inflamed and more prone to blockage? Either way, doctors can currently do little to treat vaso-occlusive crises, and nothing to prevent them.

The inflammation view, however, is leading some researchers to ask whether omega-3 fatty acids—which can alleviate inflammation—might be part of the solution. A recent mouse study in the journal Haematologica, led by Mark Puder, MD, PhD, of Boston Children’s Vascular Biology Program, and Carlo Brugnara, MD, of the hospital’s Department of Laboratory Medicine reveals some molecular clues and suggests that human trials of omega-3s might be a good next step.

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Treating chronic pain: From humans to mice and back

"Reverse engineering" reveals the enzyme sepiapterin reductase (SPR)—the large gray molecule in the background—as a new target for pain treatment. This take on Michelangelo's famous Sistine Chapel image symbolizes the link between human pain patients and the mouse model. The lab-designed SPR inhibitor (in green), shown within SPR’s active pocket, is the "bridge" between the two species. (Image: Alban Latremoliere)
“Reverse engineering” reveals the enzyme sepiapterin reductase (SPR)—the large gray molecule in the background—as a new target for pain treatment. This take on Michelangelo’s famous Sistine Chapel image symbolizes the link between human pain patients and the mouse model. The lab-designed SPR inhibitor in green, shown within SPR’s active pocket, is the “bridge” between the two species. (Image: Alban Latremoliere)

Non-narcotic treatments for chronic pain that work well in people, not just mice, are sorely needed. Drawing from human pain genetics, an international team demonstrates a way to break the cycle of pain hypersensitivity without the development of addiction, tolerance or side effects. Their findings were published online today in the journal Neuron.

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Souped-up fish facility boosts drug discovery and testing

closeup of zebrafish-20150526_ZebraFishCeremony-60The care and feeding of more than 250,000 zebrafish just got better, thanks to a $4 million grant from the Massachusetts Life Sciences Center to upgrade Boston Children’s Hospital’s Karp Aquatics Facility. Aside from the fish, patients with cancer, blood diseases and more stand to benefit.

From a new crop of Boston-Children’s-patented spawning tanks to a robotic feeding system, the upgrade will help raise the large numbers of the striped tropical fish needed to rapidly identify and screen potential new therapeutics. It’s all part of the Children’s Center for Cell Therapy, established in 2013. We put on shoe covers and took a look behind the scenes. (Photos: Katherine Cohen)

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What we’ve been reading: Week of May 18, 2015

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From cancer to feet: the power of Twitter in healthcare (MedCity News)
Why does Twitter care about the healthcare industry? Craig Hashi, one of two Twitter engineers dedicated to healthcare, details the opportunities.

MIT’s implantable device could help docs determine best cancer medicine (Boston Business Journal)
Removing the trial and error associated with cancer drug treatments is high on oncologists’ wish lists. Heeding that call, MIT has developed an implantable device (about the size of a grain of rice) that can carry up to 30 different drug doses to a cancerous tumor, and then be removed to test responses.

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First six months of life are best for stimulating child heart growth

heart-regeneration-study2
In these sample sections of mouse heart, the color blue signifies scar tissue. Damage from scarring was minimized by early administration of the drug neuregulin.

Developing a child-centric approach to treating heart failure is no easy task. For one thing, the underlying causes of decreased cardiac function in children vastly differ from those in adults. While most adults with heart failure have suffered a heart attack, heart failure in children is more likely the result of congenital heart disease (CHD), or a structural defect present at birth that impairs heart function. And most therapies designed for adults haven’t proven equally effective in children.

Stimulating heart muscle cells to regenerate is one way cardiac researchers at Boston Children’s Hospital’s Translational Research Center hope to restore function to children’s ailing hearts. In this area, children actually have an advantage over adults: their young heart cells are better suited for regrowth.

Reporting in the April 1 Science Translational Medicine, Brian Polizzotti, PhD, and Bernhard Kuhn, MD, demonstrate that not only does the drug neuregulin trigger heart cell regeneration and improve overall heart function in newborn mice, but its effects are most potent for humans within the first six months of life.

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Six emerging trends in vaccine development

boy receiving vaccine-shutterstock

Vaccines to protect against infectious disease are the single most effective medical product, but developing new ones is a challenging and lengthy process, limiting their use in developing countries where they are most needed. Once a new vaccine is developed, it undergoes animal testing, which is time-consuming and does not necessarily reflect human immunity.

“It can take decades from the start of vaccine development to FDA approval at huge cost,” says Ofer Levy, MD, PhD, a physician and researcher in the Division of Infectious Diseases at Boston Children’s Hospital. “We are working on making the process faster and more affordable.”

A variety of new strategies are emerging to facilitate vaccine development and delivery:

1. Modular approaches to vaccine production

The Multiple Antigen Presenting System (MAPS) is one innovative modular method to more efficiently produce vaccines that provide robust immunity.

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New Human Neuron Core to analyze ‘disease in a dish’

Human Neuron CoreLast week was a good week for neuroscience. Boston Children’s Hospital received nearly $2.2 million from the Massachusetts Life Sciences Center (MLSC) to create a Human Neuron Core. The facility will allow researchers at Boston Children’s and beyond to study neurodevelopmental, psychiatric and neurological disorders directly in living, functioning neurons made from patients with these disorders.

“Nobody’s tried to make human neurons available in a core facility like this before,” says Robin Kleiman, PhD, Director of Preclinical Research for Boston Children’s Translational Neuroscience Center (TNC), who will oversee the Core along with neurologist and TNC director Mustafa Sahin, MD, PhD, and Clifford Woolf, PhD, of Boston Children’s F.M. Kirby Neurobiology Center. “Neurons are really complicated, and there are many different subtypes. Coming up with standard operating procedures for making each type of neuron reproducibly is labor-intensive and expensive.”

Patient-derived neurons are ideal for modeling disease and for preclinical screening of potential drug candidates, including existing, FDA-approved drugs. Created from induced pluripotent stem cells (iPSCs) made from a small skin sample, the lab-created human neurons capture disease physiology at the cellular level in a way that neurons from rats or mice cannot.

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Five new developments in hemophilia

Ellis Neufeld hemophiliaEllis Neufeld, MD, PhD, is a hematologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

From new longer-acting drugs to promising gene therapy trials, much is changing in the treatment of hemophilia, the inherited bleeding disorder in which the blood does not clot. Hemophilia Awareness Month comes at a time of both progress and remaining challenges.

1. Many more treatment products are being introduced, including some that last longer.

People with hemophilia lack or have defects in a “factor”—a blood protein that helps normal clots form. Of the approximately 20,000 people with hemophilia in the U.S., about 80 percent have hemophilia A, caused by an abnormally low level of factor VIII, and most of the rest have hemophilia B, caused by abnormally low levels of factor IX. Many patients with severe hemophilia give themselves prophylactic IV infusions of the missing factor to prevent bleeding (which otherwise can lead to crippling joint disease when blood seeps into the joint and enzymes released from blood cells erode the cartilage).

Hemophilia factors traditionally have such a short half-life that we tend to treat patients every other day with factor VIII and twice a week with factor IX. The first two longer-lasting products came onto the market within the past year, and more are on the way. So now, with factor IX, it is possible to get an infusion just once a week and not bleed. This is really changing how we think about the disease. So far, the longer-acting factor VIII products are not yet long-lasting enough to make as dramatic a difference in the frequency of infusions. And creating really long-acting factors remains a challenge.

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Can rare disease genes be protective?

Carriers of the rare disease Niemann-Pick C1 may be protected against Ebola.
Carriers of the rare disease Niemann-Pick C1 may be protected against Ebola.
First of several posts to commemorate (Feb 28, 2015).

Evolution is a strange thing: sometimes it favors keeping a mutation in the gene pool, even when a double dose of it is harmful—even fatal. Why? Because a single copy of that mutation is protective in certain situations.

A classic example is the sickle-cell mutation: People carrying a single copy don’t develop sickle cell disease, but they make enough sickled red blood cells to keep the malaria parasite from getting a toe-hold. (Certain other genetic disorders affecting red blood cells have a similar effect.)

Or consider cystic fibrosis. Carriers of mutations in the CFTR gene—some 1 in 25 people of European ancestry—appear to be protected from typhoid fever, cholera and possibly tuberculosis.

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