From the category archives:

Orphan diseases

Hope for Rett syndrome?This post is the first in a two-part series on clinical trials in autism spectrum disorders. Read part 2.

In the world of neurodevelopmental disorders, an exciting trend is the emergence of specific molecular targets and treatments through genetic research. A case in point is IGF-1 therapy for Rett syndrome, a devastating disorder in girls that affects their ability to speak, walk, eat and breathe. It causes autism-like behaviors, intellectual disability and repetitive hand-wringing movements—a hallmark of the disorder.

A Phase I trial, published this week in the Proceedings of the National Academy of Sciences Early Edition, has modest but consistent results suggesting improvements in some salient features of the disorder.

Current treatments for Rett syndrome address only the symptoms and comorbidities, such as seizures, anxiety and scoliosis, but not the disease itself. But in 2007, findings in a mouse model (which even replicated the hand-wringing) changed how scientists think about Rett and other neurodevelopmental disorders, previously thought to be untreatable. Full story »

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Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.

Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.

Babies born with X-linked myotubular myopathy (MTM), which affects about one in 50,000 male births, are commonly referred to as “floppy.” They have very weak skeletal muscles, making it difficult to walk or breathe; survival requires intensive support, often including tube feeding and mechanical ventilation. Most children with MTM never reach adulthood.

One of these children, Joshua Frase, succumbed to MTM on Christmas Eve, 2010. The son of former NFL player Paul Frase, he lived to age 15. But his parents, who continue to actively support MTM research, now see a glimmer of hope for children born with the disease today.

A preclinical study on the cover of last week’s Science Translational Medicine, funded in part by the Joshua Frase Foundation, showed dramatic improvements in muscle strength using gene replacement therapy in mouse and dog models of MTM—paving the way for a potential clinical trial. Full story »

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Abstract model of the genome morphing into human shape representing clinical genomics.The Human Genome Project’s push to completely sequence the human genome ran a tab of roughly $2.7 billion and required the efforts of 20 research centers around the world using rooms full of equipment.

But that was using technology from the 1990s to early-2000s. As by a panel of genomics experts from industry and academia pointed out at last week’s National Pediatric Innovation Summit + Awards, a scientist in a single laboratory today can sequence a genome for as little as $1,000, making sequencing almost a medical commodity.

Now what? How do we go about making clinical genomics an everyday thing? The discussion left the answer to that question—and the other questions it raises—unclear. While the panelists expressed excitement about what’s possible, they cited great uncertainty among doctors, scientists, patients, payers, companies and regulators about how to make clinical genomics work. Full story »

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Cows provided tuberculosis-free milk to Boston Children's Hospital in 1919.

An early innovation: Specially bred cows graze in front of Boston Children’s Hospital in 1919, providing safe, tuberculosis-free milk for patients.

Clinicians wanting to develop new devices and treatments for children face formidable barriers: regulators’ need to protect the most vulnerable coupled with a lack of commercial interest. But determined innovators do have options, including creative funding sources, says Thomas Krummel, MD, director of surgical innovation at Stanford Medical School.

“Technology developed specifically for children has been a low priority,” Krummel began at a two-part talk at Boston Children’s Hospital this summer (read our coverage of the other part). “The FDA barriers are incredibly high, and ultimately, investors just demand returns that pediatric markets won’t necessarily deliver.”

As Krummel detailed, the FDA barriers are there for a reason: a past history of ethical abuses in human subjects research. In 1966, physician Henry Beecher, MD, exposed many examples in The New England Journal of Medicine, such as withholding effective treatment for the sake of research, proceeding with a treatment despite recognized hazards, or failing to disclose risk to patients. Institutional Review Boards (IRBs) arose in the mid-1970s to protect research subjects—protections that are especially strict when that research is done in children.

But there’s also a deep-seated reluctance to break with the status quo. Full story »

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Bone marrow being extracted for a hematopoietic stem cell transplant

A patient’s bone marrow is extracted for a hematopoietic stem cell transplant, or HSCT. Once just a last-resort treatment for cancer, HSCTs are now used for a growing list of conditions, including certain metabolic disorders affecting the brain. (US Navy/Wikimedia Commons)

The history of hematopoietic stem cell transplant (HSCT) starts with severe cancers of the blood or immune system, like relapsed leukemias or lymphomas. Today, HSCTs are no longer solely the treatment of last resort for cancer but is used to treat a growing list of pediatric and adult conditions.

Most of these are cancers and blood disorders, but in recent years, a new frontier has opened up for HSCT: treatment of metabolic diseases, in particular, ones that affect the function of the brain.

Full story »

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Obese child on a scale

Obesity is more common among children with sickle cell disease than thought. Why?

Ask many doctors about their image of a child with sickle cell disease (SCD), and they’ll describe a short, skinny child, perhaps almost malnourished. For decades, that image was accurate.

That perception needs to change, though. A group of sickle cell specialists from hospitals in New England—members of the 11 institutions in the New England Pediatric Sickle Cell Consortium (NEPSCC)—recently made a surprising observation: Nearly a quarter of children with SCD are overweight or obese. The question is, why?

The answer may start with their red blood cells (RBCs). Full story »

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Collection of blood samples

Analyzing blood samples, researchers have found that over one third of chronic kidney diseases are caused by single mutations on single genes
(Image: Graham Colm)

Part 2 of a two-part series on kidney disease. Part 1 is here.

Friedhelm Hildebrandt, MD, receives around one blood sample in the mail per day from a patient with chronic kidney disease. Over 10 years, he’s collected more than 5,000 samples from patients all over the world—in hopes of finding the genetic mutations that cause them and, ultimately, new treatments.

Consider the mutation in an 8-month-old boy from Turkey, who had fluid collection under his skin and elevated protein in his urine—signs that his kidneys were failing. Doctors identified his disease as a form of nephrotic syndrome, one of the three main types of chronic kidney disease. The disease was proving to be hard to treat: Ten weeks of steroids had produced no result, and an immunosuppressant hadn’t been effective enough to justify its harsh side effects.

Only within the last year, genetic research has revealed that more than 30 percent of childhood chronic kidney diseases—like this child’s—stem from single mutations in single genes.
Full story »

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A mechanosensory hair bundle in the cochlea. Each sensory cell, of which the human ear has about 16,000, has tiny hairs tipped with TMC1 and TMC2 proteins. When sound vibrations strike the bundle, it wiggles back and forth, opening and closing the TMC channels. When open, the channel allows calcium into the cell, initiating an electrical signal to the brain relayed by the 8th cranial nerve. (Image: Yoshiyuki Kawashima)

A mechanosensory hair bundle in the cochlea. Each sensory cell, of which the human ear has about 16,000, has tiny hairs tipped with TMC1 and TMC2 proteins. When sound vibrations strike the bundle, it wiggles back and forth, opening and closing the TMC channels. When open, the channel allows calcium into the cell, initiating an electrical signal to the brain relayed by the 8th cranial nerve. (Image: Yoshiyuki Kawashima)

Ending a 30-year search by scientists, researchers have identified two proteins in the inner ear that are critical for hearing, which, when damaged by genetic mutations, cause a form of delayed, progressive hearing loss.

The proteins are essentially transducers: They form channels that convert mechanical sound waves entering the inner ear into electrical signals that talk to the brain. Corresponding channels for each of the other senses were identified years ago, but the sensory transduction channel for both hearing and the sense of balance had been unknown.

The channels are the product of two related genes known as TMC1 and TMC2. TMC1 mutations were first reported in people with a prominent form of hereditary deafness back in 2002 by Andrew Griffith, MD, PhD, of the National Institute on Deafness and Other Communication Disorders (NIDCD) and collaborators. Children with recessive mutations in TMC1 are completely deaf at birth. Full story »

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(Wikimedia Commons)

(Wikimedia Commons)

Craig Gerard, MD, PhD, is chief of the Division of Respiratory Diseases at Boston Children’s Hospital.

In the 24 years since the cystic fibrosis (CF) gene was identified, the median life expectancy has risen from 25 to 39 years. Novel therapies are largely responsible for this progress, and there is hope that the pace will continue, as the first oral medications directed at correcting the gene defect have been approved by the FDA. However, it is still unclear how and when to pharmacologically treat this complicated patient population, especially during childhood.

Prior to the recent treatments developed by Vertex Pharmaceuticals, therapies for CF largely consisted of antibiotics, drugs to break up mucus secretions and chest physiotherapy. The new drugs, known as correctors and potentiators, partially “fix” the CF gene defect at the protein level, lowering the amount of chloride secreted in sweat and increasing lung function. Full story »

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(Teak Sato/Wikimedia Commons)

Research on rare disorders, or in new fields, often follows a particular trajectory. It tends to start out fragmented, carried out by one or two isolated researchers at a few institutions.

But as researchers find each other, identify more patients and start to collaborate systematically, patterns of disease biology emerge, researchers start speaking the same language and new treatments materialize.

The field of complex vascular anomalies—a set of conditions characterized by blood vessels that have not developed normally—is in this kind of early days. In large part this is because they are relatively rare. In addition, few centers worldwide have the multidisciplinary experience to provide comprehensive care to these rare patients.

But a new coalition forming around vascular anomaly research and care could help unravel the biology of vascular anomalies and fashion better treatments for these children by bringing to bear the resources and knowledge of specialists from across the continent. Full story »

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