Stories about: orphan diseases

RNAi isn’t ready to be silenced

In this screengrab from a Nature video, a siRNA, cradled by an argonaute protein, binds to a messenger RNA. (Watch the full video at: https://www.youtube.com/watch?v=cK-OGB1_ELE)
An siRNA, cradled by an argonaute protein, binds to a messenger RNA. (More from Nature at www.youtube.com/watch?v=cK-OGB1_ELE)

RNA interference (RNAi) is a therapeutic technology that blocks gene expression with either small interfering RNAs (siRNA) or microRNAs (miRNA). RNAi’s discovery was considered transformative enough to earn the 2006 Nobel Prize for Physiology or Medicine, but from the start the challenge of delivering RNA-silencing therapeutics to the right tissues has hobbled efforts to use RNAi to treat patients.

Citing this challenge, the pharmaceutical giant Novartis is the latest major company to withdraw from RNAi research, following Merck and Roche. Forbes was prompted to write:

…for certain diseases where an RNAi therapeutant can be more readily introduced, such as the eye, or ‘privileged compartments’ such as the liver, RNAi still has potential. But given that these therapies would be expensive due to the high cost-of-goods involved in synthesizing these agents, they would have to be targeted to diseases where the cost of therapy would be justified by the beneficial medical effects. … to say that RNAi therapy will rival monoclonal antibodies in terms of revenue potential—well, that’s a bit of a stretch.

Barry Greene, COO of Alnylam Pharmaceuticals, a biotech that’s championed RNAi, countered in Fierce Drug Delivery: “Novartis pulling out is an exemplar of Big Pharma not being able to innovate, and historically they have never been able to innovate.”

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Gene therapy strengthens weak muscles in congenital myopathy

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.

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Decoding kidney disease, one gene at a time

blood samples chronic kidney disease
More than a 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.

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How things work: Scientists find cellular channels vital for hearing

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.

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Research registry reveals new mutations in rare childhood blood disorders

A research registry helped Inga Hofmann, MD, PhD, search the genomes of several patients with a rare blood disorder and reveal new mutations behind it. (Michael David Pedersen/Flickr)

To really understand rare conditions, you need a lot of data from a lot of patients. But no one hospital or center usually sees more than a few patients with any given rare disease, precisely because they’re rare.

This is where case registries become important. These research collaborations, which usually span several institutions, typically focus on a single rare disease or a few related conditions, serving as a data warehouse for collecting information from as many patients and as many places as possible.

One such registry based out of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center—the Pediatric Myelodysplastic Syndromes (MDS) and Bone Marrow Failure (BMF) Registry—has recently started to bear fruit, finding that a unique set of mutations in a single gene may play a larger-than-realized role in a group of rare blood diseases.

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Restoring muscle function in a rare, devastating disease: Part 2

Joshua Frase, who died from myotubular myopathy in 2006
Joshua Frase, who died from X-linked MTM, with his father in 2006.

Part 2 of a two-part series. (Read part 1.)

Back in the 1990s, rheumatologist Richard Weisbart, MD, of University of California, Los Angeles (UCLA), was studying lupus in a mouse model and found that the mice were making an antibody that had the intriguing ability to get inside tissues and cells.

Weisbart shifted his work away from studying lupus to studying and refining the antibody, called 3E10, and he and others showed that proteins could be delivered into different tissues of the body simply by attaching them to a fragment of 3E10.

Dustin Armstrong, PhD, a postdoc at Novartis at the time, was trying to find molecules that could activate growth in weakened muscles—without activating possibly cancerous growth in other tissues. He saw Weisbart’s work and contacted UCLA. In 2008, he obtained seed money and founded a company around 3E10-based therapeutics for muscular diseases, now known as Valerion Therapeutics (formerly 4s3 Bioscience).

“There’s a huge need for therapies for genetic muscle diseases, and muscle was a tissue we could target well with our technology,” says Armstrong.

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Inherited autism mutations found via genomic sequencing in Mideast families

Pedigree for a family with 4 children with autism
In this family with 4 children with autism, a combination of genetic mapping and whole-exome sequencing identified a mutation in SYNE1, a known gene never previously associated with autism.

Autism clearly runs in some families, yet few inherited genetic causes have been found. A major reason is that these causes are so varied that it’s hard to find enough people with a given mutation to establish a clear pattern. Now, three large Middle Eastern families with autism spectrum disorders (ASDs) have led the way to a few more mutations, potentially broadening the number of genetic tests available to families.

What’s fascinating is that the mutations, described earlier this week in Neuron, affect genes known to cause severe, often lethal genetic syndromes. Milder mutations in the same genes, found through genomic sequencing, primarily cause autism.

Researchers Tim Yu, MD, PhD, Maria Chahrour, PhD, and senior investigator Christopher Walsh, MD, PhD, of Boston Children’s Hospital, started with three large families that had two or more children with an ASD, in which the parents were first cousins. Cousin marriages are a common tradition in the Middle East that greatly facilitates the identification of inherited mutations—as does large family size.

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Visionary research on Rett syndrome

Mice with the mutation causing Rett syndrome (middle panel) have an excess of inhibitory connections as compared with normal mice (left panel) and mutated mice reared with no visual stimulation (right panel). Inhibitory connections were also reduced by manipulating the NMDA receptor, restoring a more normal balance of inhibition/excitation. (IMAGE COURTESY MICHELA FAGIOLINI/BOSTON CHILDREN’S HOSPITAL)

Research just published in Neuron offers some interesting clues about Rett syndrome, a tragic disease that causes initially healthy girls to lose their ability to speak and to develop motor and respiratory problems. Working with a mouse model, the Boston Children’s Hospital lab of Michela Fagiolini, PhD, explored how the causative mutations, affecting the MECP2 gene, disrupt brain circuitry and function. The team found that the circuit damage can be undone by targeting the NMDA receptor, tipping the brain toward the right balance of inhibition and excitation. They’re now exploring possible pharmaceutical approaches.

The study also suggests that changes in the visual system are a tip-off to what’s going on in the brain as a whole.

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When health care access is as complicated as the patients

The Complex Care Service makes morning rounds. (L-R: CCS attending physician Melinda Morin, MD; pediatric resident Grant Rowe, MD, PhD; Tracy Allen, nurse practioner, CCS; Kristin Buxton, nurse practitioner, baclofen pump program.)

This is the second post of a two-part series on children with complex medical needs. (Read the first post.) Details on some patients have been changed for privacy reasons.

Led by attending physican Mindy Morin, MD, MBA, the Complex Care Service team starts down the 9th floor hall at Boston Children’s Hospital, pushing a cart carrying a computer and folders full of paperwork. They’ve just spent about an hour discussing each patient; now it’s time for morning rounds on the floor.

All the patients—some children, some adults—have illnesses affecting multiple systems in their body. Many are dependent on ventilators, feeding tubes and other technology. They are seen by physicians from multiple departments at the hospital. Morin and her colleagues provide the glue.

Some patients are asleep, their families off at work; some are attended by families who sleep in the room with them; others are rarely visited. Some smile and blow raspberries, some have limited or no social interaction. In one room, Morin lingers to talk politics with an adult patient who is still seen at Boston Children’s for his congenital condition.

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First-ever drug trial reverses some signs of aging in progeria

Trial participant Megan Nighbor (courtesy Progeria Research Foundation)

The children came from all over the world: 28 families from 16 countries, speaking over a dozen languages. They faced a grim prognosis: death at an average age of 13 from cardiovascular disease.  Not the congenital heart defects we so commonly see in babies coming to Boston Children’s Hospital, but the kind of disease you might find in an 80-year-old: atherosclerosis, heart attacks, strokes.

The children represented three-quarters of the then-known world population with Hutchinson-Gilford Progeria Syndrome, or progeria—a rare, fatal genetic condition in which children seem to age prematurely. When they began arriving at the Clinical Translational Study Unit at Boston Children’s in 2007, most had already lost body fat and hair, had the thin, tight skin typical of elderly people, and were suffering from hearing loss, osteoporosis, hardening of the arteries, stiff joints and failure to grow.

They came every four months, two flying in per week on the dime of the Progeria Research Foundation (PRF).

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