Potential SMA Therapy Ready for a First Clinical Test

posted Jan 23, 2016, 1:42 PM by Patrice Fletcher

January 12, 2016

Roche's RG7916, an SMA2 splicing modifier, entering Phase 1 study after predecessor put on hold

Roche recently announced that a new investigational medicine for the treatment of spinal muscular atrophy (SMA) — RG7916 — will soon advance to its first clinical trial.

The study will provide information on the safety and tolerability, and investigate the pharmacokinetics (absorption, distribution, metabolism and excretion) of RG7916 in healthy individuals.

In April 2015, the Moonfish clinical trial investigating another drug sharing the same mechanism, called RG7800, was placed on hold as a precautionary measure. An animal study of prolonged exposure to high doses of the drug showed unfavorable results, and the trial remains on hold until the investigation of the findings is complete.

Meanwhile, Roche continued to work on RG7916. Both drugs are SMN2 splicing modifiers — targeting the SMN2 gene, which produces only low levels of the SMN protein due to the splicing of the messenger RNA. Typically, people have up to two copies of the SMN2 gene in each cell. In some cases, individuals have three or more copies. In those with spinal muscular atrophy, additional copies of the SMN2 gene are associated with a milder course of the disorder.

Splicing modifiers can shift the balance of SMN2 splicing from the production of the nonfunctional short-form, toward the production of full-length functional SMN with the ability to rescue the phenotype. Indeed, a study published in the journal Science in 2014 showed that SMN2 splicing modifiers can improve motor function and longevity in a mouse model of spinal muscular atrophy.

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In Spinal Muscular Atrophy, Vascular System May Play a Key Role

posted Jan 23, 2016, 1:26 PM by Patrice Fletcher

December 8, 2015

Study finds insufficient blood supply likely contributes to motor neuron loss


For the first time, scientists have shown that insufficient blood supply is likely to contribute to motor neuron loss in spinal muscular atrophy (SMA), a finding that potentially opens a new avenue into disease research. The study, entitled Vascular defects and spinal cord hypoxia in spinal muscular atrophy,” was published in the Annals of Neurology.

The role that the cardiovascular system, and blood vessels in particular, play in SMA pathogenesis is lacking in research; however, cardiac defects have been described in SMA patients as well as in animal models, while disrupted capillary networks have been reported in skeletal muscle from SMA mice.

The team, led by Professor Simon Parson, chair in Anatomy at the University of Aberdeen, with colleagues at Edinburgh, Oxford and University College London, investigated whether defects associated with vasculature play a role in SMA’s motor neuron pathology. The results demonstrated that the capillary bed in the muscle and spinal cord of pre-symptomatic SMA mice was normal, but did not match post-natal development in control littermates. Furthermore, according to the researchers, “during later symptomatic time-points the extent of the vascular architecture in two mouse models of SMA was only around 50% of that observed in control animals.” The team also analyzed skeletal muscle biopsies from human patients, confirming a similar vascular depletion in severe SMA. The findings, the authors write, mean that “vascular defects are a major feature of severe forms of SMA, present in both mouse models and patients, which results in functional hypoxia of motor neurons. As such, abnormal vascular development and resulting hypoxia may contribute to the pathogenesis of SMA.”

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Impaired Mitochondrial Dynamics Play Role in SMA Pathology

posted Jan 23, 2016, 1:17 PM by Patrice Fletcher   [ updated Jan 23, 2016, 1:18 PM ]

December 1, 2015

Abnormal mitochondrial transport and morphology may cause SMA


The degeneration of spinal motor neurons in spinal muscular atrophy (SMA) may be the direct result of abnormal mitochondrial (energy source of cells) transport and morphology and subsequent reduced mitochondrial health. These are the conclusions of a study preformed by an international team of collaborative researchers led by scientists from the University of Connecticut Health Center (UConn Health) entitled “Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy,” and published in the open access journal Disease Models & Mechanisms.

This important discovery was led by senior researcher Dr. Xue-Jun “June” Li, Ph.D., Assistant Professor, Neuroscience, UConn Health. Dr. Li’s research is focused on modeling neuronal degeneration in motor neuron diseases with stem cells to identify targets and potential therapeutics to rescue motor neuron and axonal degeneration in theses devastating diseases.

Dr. Li and her team utilized human fibroblasts (most common cells in connective tissue) obtained from SMA type 1 patients to establish stem cell lines in which to use experimental techniques (DNA, RNA isolation, PCR, and RT-qPCR , western blot), in order to study the mitochondrial dynamics associated with mutations in the survival motor neuron (SMN) that lead to spinal motor neuron-specific degeneration in SMA patients.

After experimental analysis of the SMA type 1 stem cells, the following findings were observed:

  • Following long-term culture of the cells, SMA spinal motor neurons degenerated.
  • During the early stages of the disease model of SMA spinal motor neurons, the mitochondrial number, area, and transport were significantly reduced in certain parts of the neuronal cells.
  • Experimentally removing SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics.
  • The use of N-acetylcysteine (NAC), an antioxidant, blocked the impaired mitochondrial transport and morphology, and then rescued motor neuron degeneration in SMA long-term cultures.
  • NAC reduced mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC may rescue cell death and motor neuron degeneration by improving mitochondrial health.

When discussing these findings Dr. Li and her team wrote, “in this study, we reveal that mitochondrial deficits including mitochondrial transport, distribution, and morphology are early pathological changes in human SMA models, which are implicated in the motor neuron-specific degeneration in SMA patients. Better understanding of how and why mitochondrial dynamics and function are altered in SMA spinal motor neurons will provide valuable insights into identifying potential therapeutic targets for rescuing motor neuron degeneration in SMA.”

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Spinal Muscular Atrophy Study Points to Blood Vessel Defects

posted Jan 23, 2016, 1:10 PM by Patrice Fletcher   [ updated Jan 23, 2016, 1:11 PM ]

November 17, 2015

Researchers find that vascular defects also play role in motor neuron loss


U.K. researchers funded by the SMA Trust have found that insufficient blood supply may well contribute to motor neuron loss in spinal muscular atrophy (SMA). The study entitled, Vascular defects and spinal cord hypoxia in spinal muscular atrophy,” was published in the latest edition of the Annals of Neurology.

This potentially important discovery was led by Dr. Simon Parson, PhD, Chair in Anatomy at the University of Aberdeen.  Dr. Parson’s research interests are focused on determining the relationship between SMN protein deficiency and blood vessel defects, utilizing a variety of model species and tissues, to further understand the molecular mechanisms involved in tissue-specific defects in SMA, hopefully leading to novel treatment strategies for this childhood disease.

In this study, Dr. Parson and his colleagues used an experimental mouse model of SMA to investigate whether defects associated with the animal’s vasculature contributed to motor neuron pathology in SMA. After a series of experiments, primary study findings showed that the SMA mouse spinal cord was accompanied by significant functional defects in the blood-spinal cord barrier, indicating that defects in the animals’ vasculature may contribute to SMA  pathogenesis.

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Key SMA Patient Trial of Skeletal Muscle Activator Getting Underway

posted Jan 23, 2016, 1:04 PM by Patrice Fletcher   [ updated Jan 23, 2016, 1:04 PM ]

November 10, 2015

Cure SMA pins hopes on study of Cytokinetics' CK-2127107 in teens and adults


Cytokinetics has announced additional details about a planned Phase 2 clinical trial of CK-2127107 in patients with spinal muscular atrophy (SMA). Investigators believe CK-2127107, a skeletal muscle activator, has the potential to improve muscle function, either alone or in combination with other drugs.

The company, in collaboration with its partner Astellas, recently held an investigator meeting to finalize the details of the trial. The first trial will enroll 75 patients — both ambulatory and non-ambulatory teens and adults with SMA type II, III or IV — across 10 to 12 centers in the U.S. The trial will measure respiratory and muscle function in the population to test the drug’s safety and efficacy.

Both Cytokinetics and Astellas work with Cure SMA — an organization dedicated to supporting SMA research — to pursue its four therapeutic approaches: two addressing the underlying survival motor neuron (SMN) protein deficiency that occurs in SMA, and two addressing the muscle and nerve weakness caused by the SMN deficiency. Researchers are hopeful that CK-2127107 will show positive results to preserve muscle strength in human clinical trials, and possibly lend itself to combination with SMA therapies currently in development.

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Isis Pharmaceuticals Announces Open-Label Extension Study SHINE in Pediatric SMA Patients

posted Jan 23, 2016, 12:57 PM by Patrice Fletcher

October 22, 2015

Isis Pharmaceuticals, Inc. recently announced the official launch of an open-label extension study, called SHINE, which will be continuing treatment of the same infants and children diagnosed with spinal muscular atrophy (SMA) who had previously participated in Phase III studies ENDEAR and CHERISH. The infants whi had participated in ENDEAR will continue to receive 12mg of investigational product ISIS-SMNRx every 4 months, while those from CHERISH will receive treatment every 6 months. Following the launch of SHINE, Isis will be receiving a milestone payment worth $11 million from Biogen.

Candidate Drug Provides Benefit in Spinal Muscular Atrophy Animal Models

posted Jun 5, 2013, 4:22 PM by Patrice Fletcher   [ updated Jul 23, 2014, 8:48 PM ]

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 improve function in two spinal muscular atrophy (SMA) mouse models. They have determined the minimum effective dose and drug action, thus contributing to dose selection and exposure estimates for the first studies with RG3039 in humans. As in cellular assays, the animal studies have shown that drug treatment leads to improvement in nuclear gem/Cajal body numbers in motor neurons.

Gem loss is a cellular hallmark of fibroblasts derived from SMA patients; gem numbers inversely correlate with SMA disease severity. In addition, the laboratory has shown improved functional outcomes, including treadmill walking and gait dynamics, in animals receiving the drug. The laboratory has been testing RG3039 in SMA mouse models with disease phenotypes ranging from mild to severe.

The collective results suggest that RG3039 positively modifies motor unit pathologies and dysfunction, and that it may have therapeutic benefit for SMA.

A new approach to spinal muscular atrophy?

posted Jun 5, 2013, 4:16 PM by Patrice Fletcher   [ updated Jul 23, 2014, 9:00 PM ]

April 9, 2013  |  Contact: David Orenstein |  401-863-1862

 Spinal muscular atrophy is a debilitating neuromuscular disease that in its most severe form is the leading genetic cause of infant death. By experimenting with an ALS drug in two very different animal models, researchers at Brown University and Boston Children’s Hospital have identified a new potential mechanism for developing an SMA treatment.

Anne Hart

“We’re not suggesting ... that SMA patients should ask their doctors for Riluzole, but we are suggesting that this pathway would be useful for therapeutic development.”

PROVIDENCE, R.I. [Brown University] — There is no specific drug to treat spinal muscular atrophy (SMA), a family of motor neuron diseases that in its most severe form is the leading genetic cause of infant death in the United States and affects one in 6,000 people overall. But a new multispecies study involving a drug that treats amyotrophic lateral sclerosis (ALS) has pinpointed a mechanism of SMA that drug developers might be able to exploit for a new therapy.

The research, published in the Journal of Neuroscience, reports that the drug Riluzole advanced neural cell development in a mammalian model of SMA and restored neuromuscular function and mobility in a Caenorhabditis elegans worm model of the disease.

Riluzole has already been tested as a therapy in a very small study of severely affected SMA patients. It failed to help. Nevertheless, what makes the new research encouraging, said Anne Hart, professor of neuroscience at Brown and senior author on the paper, is that the study traces the beneficial action of Riluzole to specific “SK2” potassium channels in worm neurons. Humans have these channels too, and if they can be more precisely targeted by a new drug, she said, that could make a more meaningful difference, at least for some patients.

“We’re not suggesting based on this that SMA patients should ask their doctors for Riluzole,” Hart said, “but we are suggesting that this pathway would be useful for therapeutic development.”

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Anne Hart“We’re not suggesting ... that SMA patients should ask their doctors for Riluzole, but we are suggesting that this pathway would be useful for therapeutic development.”

SMA: Trial Tests Antisense Therapy in Infants

posted Jun 3, 2013, 8:26 PM by Patrice Fletcher

May 7, 2013

Isis Pharmaceuticals has launched a phase 2 trial to test its experimental antisense drug ISIS-SMNRx in infants with spinal muscular atrophy

A phase 2 clinical trial to test multiple doses of the experimental drug ISIS-SMNRx in infants with spinal muscular atrophy (SMA)has opened at four trial sites in the United States and Canada. Enrollment is expected to begin soon.

ISIS-SMNRx, developed by Isis Pharmaceuticals in Carlsbad, Calif., with Adrian Krainer at Cold Spring Harbor (N.Y.) Laboratory, is based on antisense technology. Antisense molecules are used to block segments of genetic instructions that create proteins, thereby changing the way these instructions are "read" by cells.

The study, which is expected to enroll eight infants with SMA, is designed to enable investigators to determine the optimal dose for a larger planned phase 2-3 study in infants, and also to provide safety and tolerability data on the experimental drug.

Kathie Bishop, executive director of clinical development at Isis, announced the opening of the trial April 23, 2012, at MDA's Scientific Conference in Washington, D.C.

Goal is to produce full-length SMN protein

In the most common form of SMA, genetic mutations in the SMN1 gene lead to a deficiency of SMN ("survival of motor neuron") protein. (Motor neurons are the muscle-controlling nerve cells that are lost in SMA.)

Children and adults with SMA carry one or more copies of a gene called SMN2, which is similar in makeup to SMN1. Usually, SMN protein made from the genetic instructions carried by the SMN2 gene is shorter, relatively nonfunctional and unstable compared to the protein made from SMN1 genes. Sometimes however, natural variations in the cellular protein-building process cause a different "readout" of the SMN2 genetic instructions; the result when this happens is production of full-length, functional SMN protein.

Antisense therapy aims to change the way cells process genetic instructions carried by SMN2, so that the result is always full-length SMN.

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A case of spinal muscular atrophy type 0 in Japan.

posted May 17, 2013, 7:56 AM by Patrice Fletcher

September 2012

A case of spinal muscular atrophy type 0 in Japan.

[Article in Japanese]

Source                                                                                                                                   Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Tokyo. 


The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature.

Information found at PubMed.gov

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