US FDA Grants Expanded Approval of ELEVIDYS Gene Therapy for DMD Patients Ages 4 and Above

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Spinal Muscular Atrophy (SMA)


The research picture has brightened considerably in the last decade for people with chromosome 5-related spinal muscular atrophy (SMA) types 0 through 4.

Since 1995, scientists have known that a deficiency of functional SMN protein (SMN stands for survival of motor neuron) is the underlying cause of chromosome 5 SMA. Two nearly identical genes carry the genetic instructions for making SMN protein: SMN1 and SMN2. Proteins made from the SMN1 gene are full-length, functional, and appear to be necessary for the survival and proper function of motor neurons. By contrast, proteins made using instructions from the SMN2 gene are shorter and tend to be less stable but can compensate for a lack of SMN protein when the SMN1 gene is not functioning.

In SMA types 0 through  4, flaws (mutations) in each of the two copies of the SMN1 genes result in insufficient production of full-length, functional SMN protein. Fortunately, a certain amount of full-length SMN protein can be made from the SMN2 gene. Many people have multiple copies of the SMN2 gene. These extra SMN2 copies can lessen the impact of a flaw in both SMN1 copies. In chromosome 5-related SMA, the more copies of SMN2 a person has, the milder the course of SMA is likely to be.

Researchers are seeking to exploit this unique redundancy through development of strategies that restore levels of full-length SMN protein.

Raising SMN levels through gene replacement

One of the research strategies to treat chromosome 5-related SMA is based on transferring SMN1 genes into the body to raise the level of full-length SMN protein. Back in 2010, young mice with an SMA-like disease received intravenous injections of genes containing instructions for making SMN protein, packaged inside modified type 9 adeno-associated viruses (AAV9 vehicles). The AAV9 vehicle eventually reached its target — motor neurons in the spinal cord — and increased levels of SMN protein were subsequently found in the animals' brains, spinal cords, and muscles. The mice showed dramatic improvement of motor function and brain-to-muscle signaling, and a significant increase in survival. Promising results could be seen in pigs and monkeys as well.

Brian Kaspar at Nationwide Children's Hospital in Columbus, Ohio, discusses gene transfer in SMA in a May 2010 podcast.

More recently, Novartis collaborated with AveXis to develop the drug Zolgensma, which proved to be effective for pediatric patients under the age of 2. Zolgensma is a non-infectious viral vector (AAV9) that delivers replacement genes to patients with an SMN1 gene mutation. This therapy — the first-ever gene-replacement therapy approved by the US Food and Drug Administration (FDA) to treat any neuromuscular disease —  is a one-time intravenous administration that, once given, halts the progression of SMA. For more information, read MDA Celebrates FDA Approval of Zolgensma for Treatment of Spinal Muscular Atrophy in Pediatric Patients.

Raising SMN levels using antisense oligonucleotides or small molecules

Several research strategies involve manipulating the genetic instructions provided by the SMN2 gene so that more full-length SMN protein can be made. The SMN2 gene is similar in structure to the SMN1 gene. However, most of the protein made from the SMN2 gene is short and not functional. This research approach uses small molecule drugs that target the SMN2 gene to change how the SMN2 RNA is put together, with the goal of increasing production of full-length, functional SMN protein.

A successful strategy is using antisense oligonucleotides to cause more full-length SMN production from SMN2 genes. The antisense oligonucleotides alter how the SMN2 RNA is put together to increase the amount of full-length, functional SMN protein. In 2010, MDA-supported scientists announced that mice with an SMA-like condition showed a "robust and long-lasting increase" in full-length SMN protein in their spinal cords and in motor neurons after the experimental antisense treatment.

On Dec. 23, 2016, the FDA approved this antisense therapy, Spinraza (nusinersen), for the treatment of SMA. Spinraza is designed to increase the quantity of the full-length and functional SMN2 gene product. For more, see Spinraza is Approved.

Genetic information moves from its storage form as DNA to a set of instructions known as RNA, from which protein molecules are made. Most of the RNA instructions from the SMN1 gene tell the cell to make full-length SMN protein. Most of the instructions from the SMN2 gene tell the cell to make short SMN protein.

Novartis is conducting a phase 2 trial in patients diagnosed with SMA type 1 to test a drug called branaplam (aka LMI070). Branaplam is designed to increase the amount of the functional SMN protein by increasing the quantity of the full-length SMN2 gene product, similarly to Spinraza’s mechanism.

Roche-Genentech, together with PTC Therapeutics and the SMA Foundation, initiated a phase 3 clinical trial for risdiplam (formerly known as RG7916). Risdiplam, similarly to other splicing modifier drugs, increases the quantity of the full-length SMN2 gene product that can compensate for a mutated SMN1 gene’s lack of functionality.1

X-linked SMA research

An X-chromosome gene has been identified that, when mutated, causes X-linked SMA. The gene codes for the UBE1 protein, which is part of a cellular waste disposal system. Without functional UBE1 protein, this important waste disposal system malfunctions.

Scientists are now studying the UBE1 gene and protein with an eye to identifying therapeutic targets in X-linked SMA.

Targeting muscle

Motor neurons are a specialized type of nerve cell that dies in people with SMA. These motor neurons are the wires that connect the brain and spinal cord to the muscles, and their death leads to muscle weakness and paralysis in SMA. One approach researchers are pursuing for SMA focuses on protecting muscles from paralysis and increasing their strength. Although this approach does not fix the underlying genetic problem in SMA, drugs that enhance muscle function could likely be used in combination with other therapies that act on the SMN genes.

Cytokinetics is developing drugs that increase the ability of the muscle to contract. These drugs have shown early promise in patients with a similar motor neuron disease called amyotrophic lateral sclerosis (ALS). Together with Astellas, Cytokinetics is developing a similar drug called reldesemtiv (CK-2127107) for SMA. This drug has been tested in a phase 2 clinical trial to determine the drug’s potential pharmacodynamic effect (the drug’s mechanism of action), and to evaluate its tolerability and safety in patients. The goal is to show positive results preserving muscle strength. Researchers hope that reldesemtiv can be combined with other therapies to achieve maximal therapeutic benefits for patients.

SRK-015, developed by Scholar Rock for SMA patients, enhances muscle growth by inhibiting myostatin (a muscle growth inhibitor naturally in the body). A phase 1 clinical trial of SRK-015 in healthy volunteers resulted in no adverse effects, successful inhibition of myostatin, and a relatively long half-life. Its success supported the advancement toward a phase 2 clinical trial.

BIIB110, developed by Biogen, is a hybrid inhibitor that acts on both myostatin and activins, but not on BMP9. Myostatin, activins, and BMP9 are related growth factors with shared signaling pathways. Previous attempts at inhibition of myostatin have resulted in safety concerns thought to be related to off-target effects on BMP9. Combined inhibition of both myostatin and activins but not BMP9 may boost the effect of the drug on muscle function, while improving the safety profile. Currently, BIIB110 is in phase 1 clinical trial.  

Newborn screening

SMA is largely caused by a deletion of a section in the SMN1 gene, called exon 7. As discussed earlier, the presence of SMN2 genes is known to be a modifier of disease severity. The higher the number of SMN2 copies, the milder the SMA disease course and the later the disease onset. But in any case, early treatment is a game changer in the course of the disease as it can completely alter the prognosis. Early diagnosis and treatment is crucial. Because Spinraza (nusinersen), a disease-modifying therapy, was approved by the FDA in 2016, SMA could enter the list of diseases recommended for screening at birth. On July 2, 2018, the secretary of the US Department of Health and Human Services approved the recommendation to adopt SMA for newborn screening.2 For more information, visit Baby's First Test - SMA.  

Chromosome 14-related research

Flaws in the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene on chromosome 14 can lead to a rare form of SMA called SMA-LED, which predominantly affects muscles in the legs. The DYNC1H1 gene works as a "motor" to transport cellular components. Mutations in the DYNC1H1 gene result in disruptions to the motor's function. Much work is yet to be done on this newly discovered cause of SMA.


Motor neurons are the nerve cells that degenerate in SMA, leading to muscle weakness and paralysis. While some research is focused on strategies to increase SMN levels to help motor neurons, other scientists are focusing on broad neuroprotection. This research aims to prevent motor neurons from becoming dysfunctional and dying rather than altering the genetics of the SMN genes. Neuroprotective strategies could likely be used in combination with other drugs that address the underlying genetic problem in SMA.

Biomarkers for SMA

For many diseases, there are indicators in the body that change when a person has a disease or when the disease gets worse or better. These indicators are called “biomarkers” and can be found by testing the blood or urine, or by using other more sophisticated types of testing, such as nerve conduction tests commonly used to diagnose motor neuron disorders. One area of active research within the SMA field is to identify biomarkers that could be used to indicate how SMA patients are progressing and whether they are responding to a potential treatment. Because motor function tests can be variable and difficult to conduct, especially in young infants, identification of biomarkers would be useful in the evaluating the efficacy of potential new therapies for SMA.

SMA biomarkers are currently being evaluated in the NIH NeuroNEXT clinical trial, titled SMA Biomarkers in the Immediate Postnatal Period of Development. In this trial, infants with and without SMA are being followed over time, and a variety of testing is being conducted to determine whether any reliable biomarkers can be identified for SMA. 

For an in-depth discussion of several research strategies in SMA, read SMA: Full Speed Ahead, and see the SMA Research section from the Quest series In Focus: Spinal Muscular Atrophy.


  1. Ratni, H. et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J. Med. Chem. (2018). doi:10.1021/acs.jmedchem.8b00741
  2. Baker, M. et al. Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps. JAMA Neurol. (2019). doi:10.1001/jamaneurol.2019.1206

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