Spinal muscular atrophy (SMA) is a neuromuscular disorder thought of as arising primarily from the deficiency of the SMN protein in motor neurons. Accordingly, current treatments focus on restoring the protein to these cells or the central nervous system. However, recent data suggests that protein deficiency in skeletal muscle also contributes to disease. This proposal investigates the manner in which SMN ensures healthy muscle, examining the cellular and molecular consequences of low protein in the tissue. In particular, experiments center on the role of SMN in muscle stem cells. If successful, the project will cast important light on the role of muscle in SMA and how SMN functions in this tissue to maintain its health. This could lead to new and improved treatments for this most devastating of pediatric diseases.

"In nearly all cases, the genetic defect is caused by the inheritance of two deleted copies of SMN1, which can rapidly be detected in any genetics laboratory. Instead of inheriting SMN1 gene deletions, a small subset of SMA patients have small DNA changes in the SMN1 gene. In these cases, a nearly identical gene known as SMN2 complicates detecting DNA changes in the SMN1 gene."

Matthew Avenarius, Ph.D., is an Assistant Professor at The Ohio State University in Columbus, OH, has been awarded an MDA Idea Program of $25,000 for one year to detect DNA changes in the SMN1 gene using advance DNA sequencing technologies.

Spinal Muscular Atrophy (SMA) is a group of hereditary diseases affecting motor neurons in the spinal cord and brainstem, which are essential for controlling skeletal muscle activity, causing progressive deterioration and weakness. Individuals with SMA present severe muscle weakness in early childhood with most do not live past the age of 2. Treatment and diagnosis of SMA relies on early detection of mutations in the SMN1 gene. Dr. Avenarius' novel technology to sequence different variants of SMN1 offers the potential to provide a molecular diagnosis of SMA and gain knowledge about these genetic changes.

https://doi.org/10.55762/pc.gr.147550

Tomoyuki Awano, a postdoctoral research scientist in the department of pathology and cell biology at Columbia University Medical Center in New York, was awarded an MDA development grant (DG) totaling $180,000 over a period of three years to search for genes that modify the onset and disease course of spinal muscular atrophy (SMA). (MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.)

SMA is caused by the deletion of the SMN1 gene and a resulting deficiency of functional SMN protein. In humans, a nearly identical gene called SMN2 produces some partially functional SMN protein. Typically, the greater the number of copies a person with SMA has of the SMN2 gene, the less severe the disease.

But sometimes the SMN2 copy number doesn’t predict a person’s disease course.

This has been demonstrated in families, where multiple members are missing the SMN1 gene and have the same number of copies of SMN2, but whose SMA turns out drastically different. In previous work, Awano and colleagues have confirmed that this inconsistency is observed also in mouse models of SMA. A possible explanation is "modifier genes" that influence the disease course via the modulation of different biological pathways.

"Identifying modifier genes will not only reveal a potential target for cures, but will also shed light on the unknown disease mechanisms of SMA," Awano said.

Funding for this MDA grant began February 1, 2012.

Gary Bassell, professor of cell biology and neurology at the Emory University School of Medicine in Atlanta, Ga., was awarded an MDA research grant totaling $405,000 over a period of three years to discover new functions of the SMN protein in spinal muscular atrophy (SMA).

SMA occurs when the gene for SMN (survival motor neuron) is mutated, leaving too little SMN protein to perform its normal functions. While some of those functions are known, Bassell expects there are others that have yet to be described.

SMN binds to a molecule in cells called messenger RNA (mRNA), which carries genetic instructions from the nucleus, where they are stored, to the cytoplasm, where they are used to build proteins. Researchers know that SMN interacts with mRNA in the nucleus, but there is also evidence that the two pair up outside the nucleus, in the cytoplasm, as well. Exactly how SMN functions in this role, and exactly where in the cell the pair are located, is unknown.

“Our central hypothesis is that SMN protein plays a critical role in facilitating regulation of mRNA transport in motor neurons,” Bassell says, particularly the long extensions of these cells called axons, which carry nerve impulses to the muscles.

Bassell will use a mouse model of SMA to study the movements of SMN in cells. Using high-resolution fluorescence microscopy and imaging, he will directly visualize those movements within live nerve axons. His goal is to understand the adverse consequences for mRNA regulation when SMN protein is lost.

“We also will use these state-of-the-art methods to investigate whether specific compounds can correct defects in mRNA regulation in motor neurons from SMA mice,” he says, potentially pointing the way for development of new therapies.

Funding for this MDA grant began Feb. 1, 2013.

MDA has awarded a research grant totaling $387,228 over three years to Lisa Baumbach, associate professor in the departments of neurology, pediatrics and biochemistry at the Miller School of Medicine at the University of Miami. The funds will help Baumbach continue to search for disease-causing genes responsible for infantile (either X-linked or type 1) spinal muscular atrophy (SMA).

X-linked SMA is one of a group of disorders with a wide spectrum of overlapping characteristics that involve the muscle-controlling lower motor neurons. As a group, these diseases are known as infantile lower motor neuron diseases (ILMD). They manifest just prior to birth or in the newborn period, and generally are lethal.

The only identified causal gene for X-linked SMA is UBE-1, but it's suspected there may be others that have yet to be identified in the ILMD group.

Baumbach's new research focuses on finding additional disease genes and biological pathways responsible for causing X-linked SMA and the ILMD group of disorders, and on identifying potential genetic modifiers of the causal genes.

Favorable results could have implications for improving early disease detection and paving the way toward potential therapies.

"We are indebted to MDA staff, MDA supporters and the Board of Directors for their ongoing support," Baumbach said.

Funding for this MDA grant began August 1, 2011.

“In this proposal we aim to identify the genes that modify the severity of SMA and the changes in them that cause modification of severity. The identification of these changes will improve the ability to predict severity with a DNA test and initiate treatment at the appropriate time. In addition, these modifier genes can be novel therapeutic targets that can act independently of current therapies to increase SMN.”

Arthur Burghes, PhD, professor of Biological Chemistry and Pharmacology, Molecular Genetics, and Neurology at The Ohio State University Wexner Medical Center in Columbus, was awarded an MDA research grant totaling $200,000 over two years to study genes that might have the potential to modify the severity of spinal muscular atrophy (SMA).

In SMA, mutations in the survival motor neuron 1 gene (SMN1) prevent a person from making enough survival motor neuron protein (SMN). Lack of this protein is what causes the loss of motor neurons, muscle weakness, and paralysis that define SMA. In addition to the SMN1 gene, there is also a related SMN2 gene, which functions as a “backup” to producing some amount of SMN protein.

Dr. Burghes was previously awarded MDA funding to study how SMN2 copy number might predict severity of SMA. Currently SMN2 copy number is the best predictor of SMA severity and in general, having more SMN2 copies results in less severe SMA. However, both SMA type 2 and type 3 patients have three copies of SMN2. In this new work, Dr. Burghes will study the DNA of siblings who have three copies of SMN2, but one has SMA type 2 while the other has SMA type 3. He aims to identify new genes with the potential to modify the severity of the symptoms of SMA, which may potentially become novel therapeutic targets.

https://doi.org/10.55762/pc.gr.87335

Arthur Burghes, professor of biological chemistry and pharmacology, molecular genetics, and neurology at The Ohio State University Wexner Medical Center in Columbus, was awarded an MDA research grant totaling $188,613 over two years to refine how a genotype can be used to predict the severity of spinal muscular atrophy (SMA). Burghes will develop assays to test whether SMA patients have either intact or defective SMN2 genes, which serve as the backup for the SMN1 gene lost in SMA patients. Since the level of SMN2 determines the disease severity in SMA patients, these assays may be able to better predict how disease may progress in an individual.

Funding for this MDA research grant began Aug. 1, 2015.

Christine DiDonato, assistant professor of pediatrics at Northwestern University in Chicago, Ill., was awarded an MDA research grant totaling $405,000 over a period of three years to test treatment strategies for spinal muscular atrophy (SMA).

SMA is due to the loss of SMN protein, caused by a mutation in the SMN1 gene. Replacing the SMN1 gene, or increasing production from a usually silent "backup" copy of the gene called SMN2, both hold promise for treatment. However, DiDonato says, “it is currently unknown how late in the disease process such therapies can be beneficial, in terms of either improving function or halting disease progression.”

Her research will address that question in a mouse model of the disease by determining the latest time at which SMN protein can be re-introduced and still have effect after disease onset in milder forms of SMA.

In addition, DiDonato says the project “will specifically determine if therapies that only increase SMN within the nervous system can correct all deficits in milder forms of SMA. This research has important implications for SMA therapy development,” since diagnosis of the disease often occurs months or years after birth.

DiDonato will measure strength, endurance and gait in mice that begin SMN protein production at various time points. Using these techniques, she will ask “whether we can halt, slow or reverse disease progression when SMN is returned after symptoms are clearly evident, and at advancing points of disease.”

She notes that “great strides have been made in SMA research and therapeutic development. There are now several drugs that have entered clinical trials for SMA, so it is a very exciting time. Our research will provide important information for SMN-based therapies for milder forms of SMA.”

Funding for this MDA grant began Feb. 1, 2013.

Christine DiDonato, associate professor at the Ann & Robert H. Lurie Children’s Hospital of Chicago, was awarded an MDA research grant totaling $300,000 over a period of three years to decipher the mechanisms underlying muscle dysfunction in spinal muscular atrophy (SMA). 

SMA is caused by insufficient levels of the survival motor neuron (SMN) protein. DiDonato and colleagues have developed SMA mice in which they have specifically increased SMN protein levels in motor neurons (nerve cells that lose function in SMA). The mice have normal functioning motor neurons, but they still have very clear functional deficits, thus unmasking muscle problems caused by low SMN levels in this tissue. This has important long-term implications for SMN-based therapies under current clinical investigation that target only the central nervous system. 

DiDonato aims to characterize the muscle defects in SMA, identify altered molecular pathways in skeletal muscle that are responsible for muscle weakness and atrophy, and develop strategies to enhance muscle function.

The knowledge gained from this work is critical to understanding SMN’s role in skeletal muscle and devising ways in which skeletal muscle can be maintained and its function enhanced. It could point the way to the development of therapies that can be used independently or in conjunction with other therapies for SMA.

Funding for this MDA research grant began Aug. 1, 2016.

Constantin d’Ydewalle, a postdoctoral fellow at Johns Hopkins School of Medicine in Baltimore was awarded an MDA development grant totaling $180,000 over three years to test a gene therapy designed to increase levels of SMN protein in spinal muscular atrophy (SMA). The work, co-funded by the American Association of Neuromuscular & Electrodiagnostic Medicine Foundation for Research and Education (AANEM), may lead to the development of a new treatment that could be useful by itself or in combination with other therapies in development.

Funding for this MDA development grant began Aug. 1, 2015.

Kevin Foust, assistant professor in the department of neuroscience at Ohio State University in Columbus, was awarded an MDA research grant totaling $293,378 over three years to investigate disruption of gut bacteria in spinal muscular atrophy (SMA). The gut microbiome is the collection of organisms that inhabit a healthy gastrointestinal (GI) tract. Dysbiosis, or changes in the gut microbiome, disrupts GI motility, nutrient uptake and lipid metabolism, creating a spiral that impacts patient health.  Foust will examine the microbiome in mouse models of SMA and determine the effects of antibiotics, probiotics and fecal transplants on the SMA mouse microbiome. This study may help guide patients in the use of probiotics or other measures in order to maintain normal gastrointestinal function and nutritional health.

Funding for this MDA research grant began Aug. 1, 2015.

Laxman Gangwani, associate professor in the department of biomedical sciences at Texas Tech University Health Sciences Center in El Paso, Texas, was awarded an MDA research grant totaling $280,500 over three years to identify therapeutic targets in spinal muscular atrophy (SMA).

While promising SMA therapies are being tested in patients — and one, Spinraza, recently was granted FDA approval — it is important to continue to identify new and different approaches that could be used in combination with other therapies already approved or currently in the pipeline.

With colleagues, Gangwani has shown that the activation of a motor neuron-specific version of an enzyme called JNK3 mediates neurodegeneration in SMA and that inhibiting it provides neuroprotection and ameliorates disease symptoms.

Now the team will examine the effects of pharmacological inhibition of the JNK enzyme using JNK inhibitors in an SMA mouse model.

If successful, Gangwani’s work could lead to the identification of drug candidates for further development and testing as potential treatments for SMA.

Funding for this MDA research grant began Feb. 1, 2017.

"While enhancing SMN as a means to treating SMA is undoubtedly a major development, the therapeutic strategy has its limitations. Indeed, early clinical results and the outcome of studies in model mice have shown that one major caveat stems from the timing of treatment; unless patients are treated shortly after birth, they tend not to benefit."

Narendra Jha, Ph.D., is a Postdoctoral Scientist at Columbia University Medical Center in New York, NY, has been awarded an MDA Development Grant totaling $220,000 for three years to identify factors that mediate the effects of SMN on the neuromuscular system, specifically muscle and nerve.

Although there have been therapeutic advances developed to address SMA, there is still a need to better understand the basic biology of SMA. The outcome of Dr. Jha's project will help with two potential discoveries: 1) unravel how low SMN protein can lead to SMA and 2) refined treatments of the disease.

https://doi.org/10.55762/pc.gr.147553

Stephen Kolb, an assistant professor in the Departments of Neurology and of Molecular & Cellular Biochemistry at Ohio State University, has been awarded an MDA human clinical trial grant totaling $183,354 over three years as supplemental funding for the SMA NeuroNEXT biomarkers study. This study is being conducted by the U.S. National Institutes of Health (NIH) to compare children with and without spinal muscular atrophy (SMA) during the first two years of life. Its purpose is to determine measurements of SMA progression during this period so that these measurements (“biomarkers”) can be used to assess the effects of experimental treatments in future trials. The MDA funding will allow additional training of evaluators of motor function.

Funding for this MDA human clinical trial grant began June 1, 2014.

Our laboratory has been at the leading edge in the identification of non-neuronal defects in spinal muscular atrophy (SMA). We have shown that SMN depletion leads to defects in fatty acid metabolism. This novel finding raises the intriguing question of whether liver metabolic alterations are an important facet of SMA disease pathogenesis. Here we will perform a more in-depth investigation to examine fatty acid metabolism in SMA. The proposed experiments will address the triggering events in liver steatosis in SMA and whether the liver is an important player in the overall picture of SMA disease etiology. The research will have important implications in the care and disease management of patients with SMA.

https://doi.org/10.55762/pc.gr.157042

Rashmi Kothary, a senior scientist in the Regenerative Medicine Program at Ottawa Hospital Research Institute in Canada, has been awarded an MDA research grant totaling $253,800 over three years to further investigate a potential new treatment approach for spinal muscular atrophy (SMA) . Kothary and colleagues will continue to develop inhibitors of an enzyme called rho kinase to see if they are beneficial in this disease. Early experiments in mice have shown promise.

Funding for this MDA research grant began May 1, 2014.

“There has to be great optimism about the emerging therapies for the treatment of SMA. There has been tremendous progress in this area over the past few years. With this progress comes the opportunity to better understand all the ramifications of SMN depletion. What is the new landscape of SMA in the longer-lived patients?”

Rashmi Kothary, senior scientist and deputy scientific director at Ottawa Hospital Research Institute in Ontario, was awarded an MDA Research Grant totaling $300,000 over 3 years to study abnormal fatty acid metabolism that’s a feature of spinal muscular atrophy (SMA). SMA is a an inherited motor neuron disease leading to muscle wasting and difficulties in controlling movement. There has been major progress in identifying the responsible gene, and in generating model systems.

Dr. Kothary’s work has shown that although SMA is largely considered a motor neuron disease, other cell types and tissues have intrinsic problems in the disease context and can contribute to the pathogenesis. Smn depletion leads to major glucose and lipid metabolism defects due to pancreatic and liver abnormalities in a mouse model of SMA.

As new therapies for SMA emerge, these metabolic defects may become more prominent features of the disease as patients are living longer. Additionally, understanding the metabolic abnormalities in SMA patients is important for future drug development, as they may affect drug pharmacokinetics and lead to possible increased risk of liver toxicity. Dr. Kothary and colleagues plan to use their SMA mouse model to get a better understanding of the multi-organ nature of the disorder.

MDA awarded a research grant totaling $381,582 over a period of three years to Christian Lorson, a professor in the departments of veterinary pathobiology, and molecular microbiology & immunology, at the University of Missouri in Columbia. The funds will help support Lorson’s research into targeting skeletal muscle as a therapeutic strategy in spinal muscular atrophy (SMA).

“Recently, several labs have shown the power of gene replacement — gene therapy — in SMA mice,” Lorson said. “Building upon these results, we will use a similar gene therapy strategy to investigate additional pathways that may provide insight into the SMA disease process, and also to identify novel therapeutic targets.”

Many therapeutic strategies under development for SMA involve replacement of the missing SMN protein; the aim of such strategies is to prevent loss of nerve cells called motor neurons.

Lorson and colleagues will use two different mouse models of SMA to test various gene therapy vectors (delivery vehicles) that instead target skeletal muscle. Their work is expected to determine whether such a therapy based on modulating activity of a non-SMN protein can reduce disease severity and extend survival.

Funding for this MDA grant began February 1, 2012.

Chris Lorson, professor of veterinary pathology, and molecular biology and immunology at the University of Missouri in Columbia, was awarded an MDA research grant totaling $300,000 over a period of three years to optimize an approach currently in clinical trials for spinal muscular atrophy (SMA) by delivering an enhanced form of drug combined with other potential synergistic therapies. This work could provide evidence for an innovative combinatorial approach to SMA that would address a broad range of patient needs.

Funding for this MDA research grant began Feb. 1, 2016.

John Manfredi, chief scientific officer at Sfida BioLogic in Salt Lake City, Utah, was awarded an MDA research grant totaling $161,995 over a period of two years to study the potential of new compounds for treatment of spinal muscular atrophy (SMA). The new grant complements previous MDA-funded research by Manfredi into potential therapeutics for SMA.

SMA is caused by the loss of muscle-controlling nerve cells called motor neurons. These neurons have long extensions, called axons, which must remain in communication with muscle in order to promote normal movement. Manfredi and colleagues have identified several small molecules that promote the growth of axons of motor neurons. They have shown that these compounds can improve movement in flies with movement defects, and also have shown their potential in a fish model of SMA. They will now move on to test them in a mouse model of SMA.

“Importantly,” says Manfredi, “previous tests of the compounds in healthy adult rats and mice showed that the chemicals are nontoxic, metabolically stable, capable of entering the central nervous system” and remain active for a long time. All these are important for a compound to become a useful drug. Testing the ability of these compounds as potential treatments for SMA is the next step.

“Given the drug-like characteristics of the compounds, positive results in the SMA mice will nominate the compounds for clinical development,” Manfredi says. They also may shed light on whether these or similar compounds have potential in other diseases of axon degeneration, including amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease.

Funding for this MDA grant began Feb. 1, 2013.

MDA awarded a grant totaling $79,277 to John Manfredi, chief scientific officer at Sfida BioLogic Inc., in Salt Lake City, Utah, for continued research into new drug compounds that promote the growth and function of motor neurons (nerve cells), and that may have potential as therapeutics for treatment of spinal muscular atrophy (SMA).

Manfredi's research team aims to determine the therapeutic potential of their compounds using a zebra fish research model that has been genetically engineered to simulate aspects of SMA. Results will determine whether the drugs merit future testing in more sophisticated and expensive models of the disease.

The compounds identified by Manfredi and colleagues "exhibit attractive pharmaceutical properties," Manfredi said. "They are not toxic; they penetrate the central nervous system; they exhibit appropriate half-lives in tissues; they can be administered orally; their permeability and solubility characteristics are drug-like; and they can be economically synthesized."

The group also will test a sample of their compounds alongside a collection of biochemically similar, commercially available drugs. If the commercial drugs show effects in the zebra fish model of SMA, the results will support the hypothesis that their SMA-relevant effects are due to shared biochemical activity with the investigators' novel drugs. Positive results also could lead to development of the commercial compounds as SMA therapeutics.

"The funding provided by MDA is absolutely critical for evaluating the potential of our company’s proprietary compounds to treat spinal muscular atrophy," Manfredi said. "Indeed, if these or derivative compounds prove to be efficacious for the treatment of SMA, MDA can legitimately claim responsibility for their success."

Funding for this MDA grant began August 1, 2010.

Steven Markus, assistant professor at Colorado State University in Fort Collins, Colo., was awarded an MDA research grant totaling $300,000 over a period of three years to study alterations in the dynein gene and their effects in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Alterations in the dynein gene disrupt the transportation highway in the cell responsible for delivering cargo to appropriate locations to promote cell growth, maintenance and division. Defects in this process compromise the survival and maintenance of several cell types, most notably motor neurons that communicate information from the spinal cord to muscles throughout the body. Markus’ work to elucidate the molecular basis for dynein dysfunction in motor neuron disease could lay the foundation to identify effective, targeted therapies.

Funding for this MDA research grant began Feb. 1, 2016.

"This project will directly test a novel treatment to address neuromuscular weakness in SMA patients. This treatment is not a cure but rather a symptomatic approach to increase acetylcholine release from neuromuscular synapses."

Stephen Meriney, PhD, professor of Neuroscience and Psychiatry at the University of Pittsburgh, was awarded an MDA research grant totaling $302,587 over three years to develop a combinatorial drug approach to discover possible therapeutics for spinal muscular atrophy (SMA). His work is focused on testing a novel calcium channel agonist (an agonist produces the same reaction as the molecule that usually binds the receptor) to boost motor neuron signal strength. He will also study combining this drug with the current antisense oligonucleotide therapy (ASO) for SMA.

In SMA, the leading genetic cause of death in infants, very little full-length survival motor neuron protein (SMN) is made due to a mutated or missing survival motor neuron 1 gene (SMN1). Without the protein, there is a loss of motor neurons in the spinal cord, resulting in weakness and atrophy of the voluntary muscles. In 2016, the U.S. Food and Drug Administration  approved Biogen’s nusinersen (brand name Spinraza) to treat SMA. Spinraza is an ASO drug designed to increase production of the needed SMN protein. While transformative, the treatment does not completely cure the disease and most patients still experience deficits.

Starting his career with an MDA fellowship, Dr. Meriney went on to define the deficits at the neuromuscular junction (NMJ), followed by a focus on trying to strengthen the NMJ as a type of add-on therapy. The goal of this proposed work is to test whether a novel calcium channel agonist drug could boost the signal sent from the nerve to the muscle to achieve increased strength in SMA. Dr. Meriney will test this drug in a mouse model of SMA already receiving an ASO to determine whether the agonist can provide additional benefit in combination with a therapy such as Spinraza.

https://doi.org/10.55762/pc.gr.84557

Umrao Monani, associate professor at Columbia University Medical Center in New York City, was awarded an MDA research grant totaling $300,000 over a period of three years to study how junctions between neurons and muscle are affected in spinal muscular atrophy (SMA).

SMA is due to a gene mutation that causes a deficiency in a protein calledSMN. Without it, the nerve cells that control muscles, called motor neurons, die off and muscles weaken. One of the first effects of lack of SMN is seen at the neuromuscular synapse, the place on the surface of the muscle where the motor neuron contacts it and sends its signal to control muscle contraction.

“We are interested in investigating the role of SMN in the formation, function, maintenance and repair of these structures,” says Monani. “We will use model mice, in which defects of the neuromuscular synapses become apparent when the SMN protein is depleted, to determine how SMN might shape synaptic structure and function.

"By examining molecular changes that occur normally in the motor neurons and muscle as the synapses mature, and by looking for differences when SMN is reduced, we hope to identify specific mediators of the SMA disease process. Understanding how low SMN levels translate into a disease that affects the motor system is not only of enormous scientific interest but is also likely to teach us how best to effectively treat SMA and other diseases of the motor neurons,” he says.

Funding for this MDA grant began August 1, 2013.

Jacqueline Montes, assistant professor of Rehabilitation and Regenerative Medicine in the Program for Physical Therapy at Columbia University Medical Center in New York, New York, was awarded an MDA clinical trial travel grant totaling $60,000 to help support the costs of patients traveling to participate in a trial to study oxidative capacity and exercise tolerance in ambulatory SMA.

In a previous study, Dr. Montes’ team found that exercise does not improve function or fitness in ambulatory SMA children and adults despite increases in exercise ability. Understanding the underlying mechanisms preventing the expected improvements is necessary to design appropriate treatment strategies for SMA patients to benefit from exercise.

There has been laboratory evidence to suggest that mitochondria are affected by lack of SMN. A reduction in oxidative capacity disproportionate to lean mass and disease severity would further support evidence of mitochondrial depletion in SMA. Alternative exercise training strategies and/or concomitant targeted therapeutic intervention may be necessary to achieve an aerobic conditioning effect.

The results from this 6-month observational study of 42 patients (14 ambulatory SMA, 14 ambulatory mitochondrial myopathy, and 14 healthy controls) would provide preliminary data, using non-invasive methods, on oxidative capacity in ambulatory SMA patients and disease controls to aid in the design of exercise intervention studies. Furthermore, this information would link previous laboratory and preclinical findings of mitochondrial depletion in SMA to the clinical condition and provide important information for future studies designed to improve oxidative capacity and fitness in SMA patients.

https://doi.org/10.55762/pc.gr.80672

Lyndsay Murray, a lecturer in anatomy at  the University of Edinburgh in Scotland, has been awarded an MDA development grant totaling $152,280 over three years to determine the earliest changes in gene activity that occur in spinal muscular atrophy (SMA). By conducting experiments in mice with and without an SMA-like disorder, Murray and colleagues will study the genetic changes that occur prior to the death of nerve cells in the SMA-like condition. The work is expected to lead to new ideas of how to protect nerve cells that carry SMA-causing abnormalities.

Funding for this MDA development grant began May 1, 2014.

Lyndsay Murray, a lecturer in anatomy at the University of Edinburgh, in Scotland, United Kingdom, was awarded an MDA research grant totaling $292,174 over a period of three years to investigate how the mechanisms underlying spinal muscular atrophy (SMA) influence how therapies work at different stages of the disease.   

In animal model studies, it has been shown that while treatment can nearly rescue an individual from the disease when given before symptoms begin, the benefits are drastically reduced when therapies are given after symptom onset. Most therapies currently in clinical trials for SMA are treating patients after symptoms have appeared, which is thought to limit their effectiveness.

With colleagues, Murray will conduct studies in a mouse model of SMA that are aimed at determining why the benefits of therapeutics are so limited after symptoms have started, and finding ways in which to maximize the benefits of these therapies during symptomatic stages of the disease. The work is expected to inform development of more effective therapies and increase understanding of when and why they have to be administered.

Funding for this MDA research grant began Aug. 1, 2016.

Bennett Novitch, assistant professor of neurobiology at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over a period of three years to study the development of motor neurons that control respiration and their significance for spinal muscular atrophy (SMA).

SMA is due to the loss of motor neurons (nerve cells that control muscle activity), and in the most severe forms of SMA, the motor neurons controlling respiration are affected early in the disease.

“These observations raise the possibility that these respiratory defects might have a developmental origin [that is, they may arise in the developing embryo or fetus],” Novitch says, “resulting either from the improper formation of respiratory motor neurons, or their integration into functional motor circuits. This issue has been difficult to address, however, as our knowledge of the developmental origins of respiratory motor neurons and their assembly into circuits is incomplete.”

In this study, Novitch will study development of respiratory motor neurons and their organization into motor circuits that carry out both inspiration and expiration (breathing in and out). He also will study the gene networks that control this development. Better understanding of these networks, and the developmental processes they control, may lead to better understanding of how respiratory motor neurons are affected in SMA.

“Our study will provide new insights into the root causes of SMA and potentially lead to the discovery of new therapeutic targets. Moreover, by studying the process by which respiratory motor circuits are initially formed, we will gain vital information on how this activity may be recapitulated to rebuild damaged circuits to help patients maintain their ability to breathe independently,” he says.

Funding for this MDA grant began August 1, 2013.

Franco Pagani, at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy, was awarded an MDA research grant totaling $224,950 over a period of three years to investigate a new therapeutic strategy for spinal muscular atrophy (SMA). Pagani will study a small RNA molecule called Exon Specific U1 (ExSpeU1), which may be able to correct the splicing defect in the SMN2 gene, resulting in restored SMN protein levels. His work could result in a therapy that will achieve higher SMN protein levels than drugs currently in clinical trials for SMA.

Funding for this MDA research grant began Feb. 1, 2016.

Livio Pellizzoni, associate professor at Columbia University Medical Center in New York, was awarded an MDA research grant totaling $200,000 over two years to elucidate the underlying mechanisms of spinal muscular atrophy (SMA). Although several strategies to restore SMN levels have shown promising results in preclinical studies and are currently being tested in clinical trials, it remains essential to understand the still elusive mechanisms by which low SMN causes SMA and to define other therapeutic targets that can be pursued in parallel to SMN-enhancing approaches. To address these issues, Pellizzoni will determine whether disruption of a novel function of SMN in RNA regulation contributes to SMA pathology in a well-established mouse model that recapitulates many features of the human disorder. This work has the potential to identify new research avenues for the development of therapeutic approaches that could complement current strategies for upregulation of SMN.

Funding for this MDA research grant began Feb. 1, 2016.

Natalia Rodriguez Muela, a postdoctoral fellow at Harvard University in Cambridge, Mass., was awarded an MDA development grant totaling $179,985 over a period of three years to deepen our understanding of what goes wrong in spinal muscular atrophy (SMA), a progressive disease caused by low levels of SMN protein. The work will focus on how the SMN protein is degraded in the cell in SMA. If the degradation pathway can be blocked, it could point to a potentially new, exciting approach to treat SMA.

Funding for this MDA research grant began Feb. 1, 2016.

Kentaro Sahashi, a postdoctoral research scientist at the Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y., was awarded an MDA development grant (DG) totaling $180,000 over a period of three years to study the roles of the SMN protein in spinal muscular atrophy (SMA). (MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.)

SMA is caused by mutations in the SMN1 gene, resulting in a deficiency of SMN protein. Humans have a closely-related SMN2 gene that also expresses functional SMN protein, but only in minute amounts due to differences in splicing, a cellular editing process that occurs during protein production.

In mice with an SMA-like disease, Sahashi and colleagues plan to use synthetic molecules called antisense oligonucleotides (ASOs) to influence and evaluate different SMN2 splicing patterns and determine whether they have potential therapeutic value.

The investigators plan to study the effects of ASOs in different tissues, administered via different delivery methods, and at different developmental stages. They expect to gain insight into the roles of the SMN protein in the SMA disease process, as well as an understanding of its normal functions in both the central nervous system and peripheral tissues.

"This in turn," Sahashi said, "will contribute to the ongoing development of targeted therapeutics and the establishment of a useful therapeutic time window."

Funding for this MDA grant began February 1, 2012.

MDA has awarded a research grant totaling $219,000 over three years to Claudio Sette, associate professor for the department of public health and cell biology at the University of Rome Tor Vergata in Rome, Italy. The new funds will help support Sette’s study of the molecular mechanisms underlying spinal muscular atrophy (SMA).

SMA is caused by mutations in the SMN1 gene, which leads to a deficiency of the protein SMN (for "survival of motor neuron") and subsequent degeneration and death of the motor neurons in the spinal cord. Although SMN2, a gene almost identical to SMN1, is present in humans, it's unable to compensate for SMN1's loss due to differences in the two genes' protein-building instructions. With the exception of the case in which an occasional error may result in a functional or partially functional protein, SMN2-derived proteins are short, highly unstable, and for the most part nonfunctional.

Sette and colleagues intend to test a variety of ways to modulate the SMN2 gene, forcing it to mimic the SMN1 gene and process its protein-building instructions in such a way as to lead to the production of functional SMN protein and prevention of motor neuron degeneration and death. Results from Sette’s work should increase understanding of the molecular mechanisms responsible for SMA — in particular, the molecular defects responsible for motor neuron degeneration. In addition, the group’s studies may lead to new therapeutic approaches for treatment of the disease.

Funding for this MDA grant began February 1, 2011.

Ashlyn Spring, PhD, a postdoctoral fellow in Biological and Genome Sciences at the University of North Carolina at Chapel Hill, was awarded an MDA development grant totaling $210,000 over three years to study the relationship of immune system dysfunction in spinal muscular atrophy (SMA).

SMA is caused by a mutated or missing survival motor neuron 1 gene (SMN1) that prevents the body from making enough survival motor neuron protein (SMN), ultimately leading to the loss of motor neurons, muscle weakness, and paralysis seen in SMA. Previous findings suggest that the immune system is also dysfunctional in patients with SMA, making them more susceptible to infection. However, while major strides have been made in developing and approving therapies to treat the genetic mutations behind SMA, little is known about how the immune system dysfunction affects other tissues.

In this project, Dr. Spring, a first-time MDA grantee, will use fly, mouse, and human cell line models of SMA to investigate how the immune system’s response to infections is impacted in the disease. This work will lead to an understanding of why SMN1 mutations change immune system function as well as help identify targets for new therapeutics to improve treatment of SMA in the future.

https://doi.org/10.55762/pc.gr.87333

New gene targeting treatments that increase survival motor neuron (SMN) protein expression can substantially improve motor function in spinal muscular atrophy (SMA) patients when given before disease onset, but have modest effects when given post-symptomatically. Unfortunately emerging data indicates that for the most common and severe SMA type I, precipitous motor axon neurodegeneration is ongoing neonatally. We postulate that temporarily halting axonal degeneration could enhance the efficacy of SMN induction therapeutics. The sterile-a and Toll/interleukin 1 receptor (TIR) motif containing protein 1 (SARM1) is a NADase that triggers motor axon degeneration. Our preliminary data indicate that genetic knock out of SARM1 is associated with prevention of proximal motor axon loss neonatally in SMA mice. In this study, we will assess the durability of this effect and the therapeutic potential of SARM1 inhibition together with SMN induction in severe SMA mice. These studies will provide proof of concept to support the development of a novel combinatorial treatment for SMA patients.

https://doi.org/10.55762/pc.gr.157037