Orally delivered compounds selectively modify RNA splicing, prevent deficits in SMA models

August 7, 2014, University of Southern California

Today the journal Science published results of a preclinical study demonstrating that treatment with orally available RNA splicing modifiers of the SMN2 gene starting early after birth is preventing deficits in a mouse model of Spinal Muscular Atrophy (SMA). Scientists from Roche Pharma Research and Early Development (pRED), PTC Therapeutics, Inc., the SMA Foundation, the University of Southern California and Harvard University collaborated to demonstrate that continuous treatment of SMA mice with these compounds increased life span, normalized body weight and prevented both disease-related motor dysfunction and neuromuscular deficits.

"Although still preclinical, these results demonstrate how SMN2 splicing modifiers could correct the molecular deficit that causes SMA," said Luca Santarelli, Head of Neuroscience, Ophthalmology and Rare Diseases at Roche. "This study represents an important step towards developing a potential therapeutic option for this devastating and currently untreatable condition. Early clinical trials are currently underway to determine the safety and tolerability of this approach."

"The investigational compounds used in this study represent the first orally available SMN2 splicing modifiers for SMA," commented Stuart W. Peltz, CEO of PTC Therapeutics, Inc. "Using the experience and expertise in RNA biology we have gained at PTC over the last 16 years, we used our alternative splicing technology to identify and subsequently optimize investigational compounds that target the SMN2 splicing to produce the SMN protein. Our unique partnership with Roche and the SMA Foundation has allowed this project to rapidly move into clinical development."

The study used chemical screening and optimization to identify orally available small molecules that selectively alter the splicing of the SMN2 pre-mRNA to produce stable full-length SMN protein. The SMN2 splicing modifiers described in the Science article penetrated into all mouse tissues tested, including brain, spinal cord and muscle, and thus improved SMN2 RNA splicing to increase SMN protein production in these disease-relevant tissues. As a result of the SMN protein increase, the compounds prevented the progression of SMA in a severe mouse model. These compounds also corrected SMN2 RNA splicing and increased SMN protein levels in cell cultures obtained from SMA patients, including stem cell-derived motor neurons. A Phase I clinical program to assess safety and tolerability with investigational compounds was initiated in early 2014.

"The findings of this preclinical study contribute significantly to our understanding of SMA and provide further evidence suggesting that our strategy to upregulate SMN with small molecules could be effective," said Loren Eng, President of the SMA Foundation. "We are proud to have seeded this important work – we believe it could have a meaningful impact on the lives of patients who suffer from SMA."

SMA is a genetic disease caused by mutation or deletion of the SMN1 (survival of motor neuron) gene. It affects one in approximately 10,000 live births and in the most severe forms is associated with a high rate of childhood mortality. SMA is characterized by progressive loss of motor neurons, muscle weakness and atrophy. The disease affects mainly proximal muscles including intercostal muscles (chest muscles), and patients often die due to respiratory complications.

Explore further: First animal model of adult-onset SMA sheds light on disease progression, treatment

More information: "SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy," by N.A. Naryshkin et al Science, www.sciencemag.org/lookup/doi/ … 1126/science.1250127

Related Stories

First animal model of adult-onset SMA sheds light on disease progression, treatment

September 9, 2013
A research team at Cold Spring Harbor Laboratory (CSHL) has used a recently developed technology they call TSUNAMI to create the first animal model of the adult-onset version of spinal muscular atrophy (SMA), a devastating ...

Low oxygen levels may decrease life-saving protein in spinal muscular atrophy

August 21, 2012
Investigators at Nationwide Children's Hospital may have discovered a biological explanation for why low levels of oxygen advance spinal muscular atrophy (SMA) symptoms and why breathing treatments help SMA patients live ...

Gene therapy extends survival in an animal model of spinal muscular atrophy

May 22, 2014
To make up for insufficient amounts of SMN protein, the cause of the inherited neuromuscular disease spinal muscular atrophy (SMA), researchers have successfully delivered a replacement SMN1 gene directly to the spinal cords ...

Long-term correction of severe spinal muscular atrophy by antisense therapy

October 5, 2011
A new study from Cold Spring Harbor Laboratory (CSHL) reports surprising results that suggest that the devastating neuromuscular disease, spinal muscular atrophy (SMA), might not exclusively affect the motor neurons in the ...

Candidate drug provides benefit in SMA animal models

June 4, 2013
In a new publication that appears in Human Molecular Genetics, the laboratory of Christine DiDonato, PhD reports on their pharmacological characterization of the drug RG3039, demonstrating that it can extend survival and ...

Recommended for you

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.