Advances and limitations for the treatment of spinal muscular atrophy
Abstract Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | BMC Pediatrics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12887-022-03671-x |
| _version_ | 1798044492940443648 |
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| author | John W. Day Kelly Howell Amy Place Kimberly Long Jose Rossello Nathalie Kertesz George Nomikos |
| author_facet | John W. Day Kelly Howell Amy Place Kimberly Long Jose Rossello Nathalie Kertesz George Nomikos |
| author_sort | John W. Day |
| collection | DOAJ |
| description | Abstract Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment. |
| first_indexed | 2024-04-11T23:04:46Z |
| format | Article |
| id | doaj.art-23d4045b62054d5a94312babfd720376 |
| institution | Directory Open Access Journal |
| issn | 1471-2431 |
| language | English |
| last_indexed | 2024-04-11T23:04:46Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Pediatrics |
| spelling | doaj.art-23d4045b62054d5a94312babfd7203762022-12-22T03:58:03ZengBMCBMC Pediatrics1471-24312022-11-0122111510.1186/s12887-022-03671-xAdvances and limitations for the treatment of spinal muscular atrophyJohn W. Day0Kelly Howell1Amy Place2Kimberly Long3Jose Rossello4Nathalie Kertesz5George Nomikos6Department of Neurology, Stanford UniversitySpinal Muscular Atrophy FoundationPfizer, IncCasma Therapeutics, IncScholar Rock, IncScholar Rock, IncScholar Rock, IncAbstract Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment. https://doi.org/10.1186/s12887-022-03671-xSpinal muscular atrophySurvival motor neuron-1 geneSurvival motor neuronNusinersenOnasemnogene abeparvovec-xioiRisdiplam |
| spellingShingle | John W. Day Kelly Howell Amy Place Kimberly Long Jose Rossello Nathalie Kertesz George Nomikos Advances and limitations for the treatment of spinal muscular atrophy BMC Pediatrics Spinal muscular atrophy Survival motor neuron-1 gene Survival motor neuron Nusinersen Onasemnogene abeparvovec-xioi Risdiplam |
| title | Advances and limitations for the treatment of spinal muscular atrophy |
| title_full | Advances and limitations for the treatment of spinal muscular atrophy |
| title_fullStr | Advances and limitations for the treatment of spinal muscular atrophy |
| title_full_unstemmed | Advances and limitations for the treatment of spinal muscular atrophy |
| title_short | Advances and limitations for the treatment of spinal muscular atrophy |
| title_sort | advances and limitations for the treatment of spinal muscular atrophy |
| topic | Spinal muscular atrophy Survival motor neuron-1 gene Survival motor neuron Nusinersen Onasemnogene abeparvovec-xioi Risdiplam |
| url | https://doi.org/10.1186/s12887-022-03671-x |
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