Researchers find that in mouse models of the disease subcutaneous drug administration is sufficient to treat SMA
Today, a team of researchers from Cold Spring Harbor Laboratory (CSHL) sheds new light on the underlying pathology of spinal muscular atrophy (SMA), a rare but devastating disease that causes muscle weakness and paralysis and is the leading genetic cause of infant deaths. The newly obtained insights may prove valuable as scientists currently work to define optimal treatment strategies for patients.
Spinal muscular atrophy is the leading genetic causes of death for infants, but there is currently no approved treatment. A team of scientists from Cold Spring Harbor Laboratory has a potential drug to treat the disease that is injected into the cerebrospinal fluid of patients. But the researchers have discovered that in mouse models the drug is effective even when injected subcutaneously, and it is not necessary in the central nervous system. Shown here are spinal sections from three different mice with spinal muscular atrophy. Systemic drug treatment (middle panel) increases the presence of motor neurons (red spots) over the untreated mice (left panel). Surprisingly, the results are very similar when treatment is excluded from the central nervous system (right panel), suggesting a possible new path for spinal muscular atrophy drug treatment.
Credit: A. Krainer/ Cold Spring Harbor Laboratory
SMA is a motor neuron disease, meaning that it leads to the degeneration of nerves that control muscles and voluntary movement. These neurons require a protein known as Survival of Motor Neuron (SMN). Normally, all cells contain the instructions for two variants of the protein, called SMN1 and SMN2. In healthy patients, SMN1 is abundant, while SMN2, due to a quirk of molecular editing, is produced primarily in a shortened, unstable form.
In patients with SMA, however, the instructions to produce SMN1 are faulty and cells no longer generate the protein. Therefore, cells are forced to rely on small amounts of full-length SMN2 protein that are produced alongside the shorter, nonfunctional version.
CSHL Professor Adrian Krainer, in collaboration with Isis Pharmaceuticals, has developed a drug that allows the correct editing to occur, thereby greatly increasing the amount of functional SMN2 protein in neurons. The drug, known as an antisense oligonucleotide (ASO), showed great promise in preclinical mouse models of SMA. It is now in Phase 3 clinical trials in SMA patients.
The drug is delivered directly into the cerebrospinal fluid of infants and children with SMA. "It is largely believed in our field that SMN is essential in the central nervous system (CNS) - not in peripheral tissues like the limbs or liver - so most efforts have been focused on increasing full-length SMN levels in the CNS," explains Krainer. "But over the last few years, evidence has been building that challenges our assumptions about the pathology of the disease. The question is: do we need to increase SMN levels in the CNS, in peripheral tissues, or both?"
In their new work, reported today in Genes & Development, the researchers developed a method to restore SMN production only in peripheral tissues, allowing them to define the role of the drug both inside and outside of the CNS. The team treated well-established mouse models of SMA with the ASO subcutaneously. Consistent with previous results, the drug increased SMN levels in both the CNS and peripheral tissues; in newborn mice, but not in older mice, some of the drug injected in the periphery can reach the CNS. The treatment effectively cured the animals.
The team then injected a "decoy" oligonucleotide into the CNS, along with the subcutaneous injection of the SMA ASO. "Our decoy was thus able to inactivate the drug only in the CNS," explains Krainer. "Full-length SMN2 was still produced in peripheral tissues, but there was no increase in SMN2 made in the CNS, where we expected it to be important." But the results were striking and unanticipated. "We were amazed to find that our decoy had absolutely no effect on motor neurons or recovery. Contrary to our initial assumptions, increasing SMN levels in the CNS is not essential to rescue the SMA phenotypes in these mouse models of the disease."
The work has implications as researchers and clinicians work to develop optimal treatment strategies for SMA. "Already, our ASO is showing great potential in the clinic," says Krainer. "There is a possibility that modifying the way the drug is administered may produce even better outcomes; alternatively, our observations may reflect unique idiosyncrasies of the mouse models, but even then it will be important to understand the underlying mechanisms."
This work was supported by the US National Institutes of Health, the St. Giles Foundation and Cold Spring Harbor Laboratory, as well as a Cancer Center Support Grant to CSHL and the National Natural Science Foundation of China.
"Motor-neuron-cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models" appears online in Genes and Development on January 12, 2015. The authors are: Yimin Hua, Ying Hsiu Liu, Kentaro Sahashi, Frank Rigo, C. Frank Bennett, Adrian Krainer. The paper can be obtained online at: http://genesdev.
About Cold Spring Harbor Laboratory Celebrating its 125th anniversary in 2015, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to 8 Nobel Prize winners, the private, non-profit Laboratory is more than 600 researchers and technicians strong. The Meetings & Courses program hosts more than 12,000 scientists from around the world each year on its campuses in Long Island and in Suzhou, China. The Laboratory's education arm also includes an academic publishing house, a graduate school and programs for middle and high school students and teachers. For more information, visit http://www.
Jaclyn Jansen | EurekAlert!
Collagen nanofibrils in mammalian tissues get stronger with exercise
14.12.2018 | University of Illinois College of Engineering
New discoveries predict ability to forecast dementia from single molecule
12.12.2018 | UT Southwestern Medical Center
The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.
Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
14.12.2018 | Power and Electrical Engineering
14.12.2018 | Physics and Astronomy
14.12.2018 | Physics and Astronomy