Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanistic insights into spinal muscular atrophy suggest new paths for treatment

13.01.2015

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.cshlp.org

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.cshl.edu.

Jaclyn Jansen | EurekAlert!

More articles from Health and Medicine:

nachricht Routing gene therapy directly into the brain
07.12.2017 | Boston Children's Hospital

nachricht New Hope for Cancer Therapies: Targeted Monitoring may help Improve Tumor Treatment
01.12.2017 | Berliner Institut für Gesundheitsforschung / Berlin Institute of Health (BIH)

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Long-lived storage of a photonic qubit for worldwide teleportation

12.12.2017 | Physics and Astronomy

Multi-year submarine-canyon study challenges textbook theories about turbidity currents

12.12.2017 | Earth Sciences

Electromagnetic water cloak eliminates drag and wake

12.12.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>