Stories about: rare disease

Can rare pain syndromes point the way to new analgesics?

analgesic drug discovery could reduce prescription opioid use
Boston Children’s Hospital and Amgen will collaborate to discover and accelerate non-addicting pain drugs.

As the opioid epidemic deepens and drug overdoses increase, effective non-addicting painkillers are desperately needed. Efforts to discover new pain pathways to target with new drugs have thus far had little success. Other promising research is investigating triggerable local delivery systems for non-opioid nerve blockers, but it’s still in the early stages.

A new collaboration between Boston Children’s Hospital and the biopharmaceutical company Amgen is aimed at accelerating new pain treatments. Announced yesterday, it will revolve around patients with rare, perplexing pain syndromes. The scientists hope that the genetic variants they find in these patients will shed new light on pain biology and lead to new ways of controlling pain. 

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Bad to the bone: New light on the brain’s venous system… and on craniosynostosis

cerebral veins and skull development in a normal child
Normal skull and brain venous development in a young child (courtesy Tischfield et al).

A recent study rocked the neuroscience world by demonstrating what in retrospect seems obvious: the brain has its own lymphatic system to help remove waste. A new study, from the laboratory of Elizabeth Engle, MD, at Boston Children’s Hospital, sheds light on another critical, little-studied part of the brain’s drainage system: the dural cerebral veins that remove and reabsorb excess cerebrospinal fluid.

The story of these vessels, the cover article in the next Developmental Cell, is a great example of lab scientists and physicians joining to make fundamental discoveries in biology. Strangely, critical clues come from children with craniosynostosis, a congenital malformation in which the skull plates fuse together too early in prenatal development, resulting in abnormal head shapes and, often, neurologic complications.

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Galloway-Mowat mutations have dual target: kidney cells, neurons

Evidence of disease in GAMOS patients
Disease phenotype of GAMOS patients. Left: Kidney cells show signs of nephrotic syndrome. Right: Anomalies in brain development

With the help of more than 100 clinical collaborators around the world, Friedhelm Hildebrandt, MD has received thousands of blood samples from patients with nephrotic syndrome. They have helped Hildebrandt’s lab determine several underlying causes of this serious kidney disorder, in which high levels of protein are expelled in the urine.

“Nephrotic syndrome is not one disease; in fact, we already know that it is 55 different diseases,” says Hildebrandt, chief of the Division of Nephrology at Boston Children’s Hospital.

Over the course of time, Hildebrandt’s lab has discovered 35 of the more than 55 genes that can cause nephrotic syndrome. Identifying the different genetic pieces of the puzzle can help tailor a precision medicine approach to treating patients.

The latest piece, published earlier this month in Nature Genetics, is a set of four single-gene mutations that cause Galloway-Mowat syndrome (GAMOS) a rare disorder causing early-onset nephrotic syndrome and, often, microcephaly (abnormally small head size). Until now, the genetic changes underlying GAMOS and why they affect two disparate organs — the brain and kidney — have not been well understood. 

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Rare disease therapies: Three strategies to bridge the gap between research and industry

Rare disease research: DNA helix pictured here
Genetic mutations underpin many rare diseases.

Right now, there are about 7,000 rare diseases affecting 10 percent of Americans. Only five percent of these diseases have any FDA-approved treatment options.

Panelists:
David Williams, MD: President, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center; Senior VP, Chief Scientific Officer and Chief of Hematology/Oncology, Boston Children’s
Wayne Lencer, MD: Chief of Gastroenterology, Hematology and Nutrition, Boston Children’s
Phil Reilly, MD, JD: Venture Partner at Third Rock Ventures
Alvin Shih, MD, MBA: Chief Executive Officer at Enzyvant

Even at a place like Boston Children’s Hospital, where doctors regularly see children with rare diseases from all over the world, there are big challenges when it comes to drug discovery and treatment.

“Roughly 70 percent of drugs to treat children are used off-label,” says David Williams, Boston Children’s chief scientific officer. “That’s because these drugs were initially developed for adults and have not been tested formally in children.”

In order to cure rare diseases in children and adults, scientists must bridge the gap between research and industry. On May 25, Boston Children’s Technology and Innovation Development Office (TIDO) and MassBio held a candid panel discussion about what it will take to advance the development of rare disease therapies. Here are three of the biggest takeaways

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Patients’ brain tissue unlocks the cellular hideout of Sturge-Weber’s gene mutation

A diagram of the skull and brain showing the leptomeninges, which is affected by Sturge-Weber syndrome
Sturge-Weber syndrome causes capillary malformations in the brain. They occur in the brain’s leptomeninges, which comprise the arachnoid mater and pia mater.

A person born with a port-wine birthmark on his or her face and eyelid(s) has an 8 to 15 percent chance of being diagnosed with Sturge-Weber syndrome. The rare disorder causes malformations in certain regions of the body’s capillaries (small blood vessels). Port-wine birthmarks appear on areas of the face affected by these capillary malformations.

Aside from the visible symptoms of Sturge-Weber, there are also some more subtle and worrisome ones. Sturge-Weber syndrome can be detected by magnetic resonance imaging (MRI). Such images can reveal a telltale series of malformed capillaries in regions of the brain. Brain capillary malformations can have potentially devastating neurological consequences, including epileptic seizures.

Frustratingly, since doctors first described Sturge-Weber syndrome over 100 years ago, the relationship between brain capillary malformations and seizures has remained somewhat unexplained. In 2013, a Johns Hopkins University team found a GNAQ R183Q gene mutation in about 90 percent of sampled Sturge-Weber patients. However, the mutation’s effect on particular cells and its relationship to seizures still remained unknown.

But recently, some new light has been shed on the mystery. At Boston Children’s Hospital, Sturge-Weber patients donated their brain tissue to research after it was removed during a drastic surgery to treat severe epilepsy. An analysis of their tissue, funded by Boston Children’s Translational Neuroscience Center (TNC), has revealed the cellular location of the Sturge-Weber mutation. The discovery brings new hope of finding ways to improve the lives of those with the disorder.

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With no time to lose, parents drive CMT4J gene therapy forward

CMT4J
Talia Duff’s disorder, CMT4J, is a rare form of Charcot-Marie-Tooth. It has been modeled in mice that will soon undergo a test of gene therapy, largely through her parents’ behind-the-scenes work.

In honor of Rare Disease Day (Feb. 28), we salute “citizen scientists” Jocelyn and John Duff.

When Talia Duff was born, her parents realized life would be different, but still joyful. They were quickly adopted by the Down syndrome parent community and fell in love with Talia and her bright smile.

But when Talia was about four, it was clear she had a true problem. She started losing strength in her arms and legs. When she got sick, which was often, the weakness seemed to accelerate.

Talia was initially diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an autoimmune disease in which the body attacks its own nerve fibers. Treated with IV immunoglobulin infusions to curb the inflammation, she seemed to grow stronger — but only for a time. Adding prednisone, a steroid, seemed to help. But it also caused bone loss, and Talia began having spine fractures.

“We tried a lot of different things, but she never got 100 percent better,” says Regina Laine, NP, who has been following Talia in Boston Children’s Hospital’s Neuromuscular Center the past several years, together with Basil Darras, MD.That’s when we decided to readdress the possibility that it was genetic.”

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Honoring rare disease ‘citizen scientists’

citizen scientists

The global theme of this year’s Rare Disease Day (February 28) is research, and in keeping with that, we salute a very important group of people: citizen scientists. These can-do patients and family members are putting previously undiagnosed rare diseases on the map and driving the search for treatments. Citizen scientists play multiple roles: They keep scientists focused on therapeutic development, conduct online research to connect ideas, set up patient networks and data registries, raise money and start companies. They’ve earned a voice in clinical trial design and were instrumental in the passage of the 21st Century Cures Act.

Meet a few citizen scientists who have inspired us recently.

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Rare blood disorder sideroblastic anemia slowly reveals its genetic secrets

congenital sideroblastic anemia
Regardless of the gene, all patients with sideroblastic anemia have sideroblasts: red blood cell precursors with abnormal iron deposits in mitochondria, shown here ringing the cell nucleus. (Paulo Henrique Orlandi Mourao/Wikimedia)

A decade ago, Brooks McMurray’s routine check-up was anything but routine. The suburban Boston boy’s spleen was enlarged. His red blood cell count was low and the cells were very small and very pale, which suggested a serious iron deficiency anemia. The family pediatrician referred McMurray, now a 19-year-old college freshman, to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

There hematologists discovered the boy had unexpectedly high iron levels. Together with pathologist Mark Fleming, MD, DPhil, they solved the mystery. McMurray has congenital sideroblastic anemia, an inherited blood disorder so rare that fewer than 1,000 cases have been reported worldwide. Iron was getting stuck in the wrong place in the precursor red blood cells developing in his bone marrow.

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2017 predictions for biomedicine

2017 predictions for biomedicine

David Williams, MD, is Boston Children’s Hospital’s newly appointed Chief Scientific Officer. He is also president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and director of Clinical and Translational Research at Boston Children’s. Vector connected with him to get his forecast on where biomedical research and therapeutic development will go in the year ahead.

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Why we’re glad the Cures Act passed: Its provisions benefit children

Cures Act children
Via @POTUS

Amy Judge DeLong is manager of Federal Government Relations at Boston Children’s Hospital.

In the midst of a seismic shift in Presidential administrations and anticipation of the incoming Congress, a landmark medical research bill with several provisions important to children cleared the lame duck session of Congress. The 21st Century Cures Act (Cures) is the end result of nearly three years of bipartisan Congressional activity. Last week, it was signed into law.

Cures includes scores of provisions aimed at strengthening National Institutes of Health funding for medical research and accelerating review efforts at the Food and Drug Administration. The law cleared Congress with overwhelming majorities, an example of bipartisanship that may be challenged in the months ahead.

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