Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

Overview

Journal J Neuromuscul Dis

Publisher Sage Publications

Specialty Neurology

Date 2023 Jul 17

PMID 37458045

Authors

Jacqueline Glascock

Basil T Darras

Thomas O Crawford

Charlotte J Sumner

Stephen J Kolb

Christine DiDonato

Bakri Elsheikh

Kelly Howell

Wildon Farwell

Marta Valente

Marco Petrillo

Jessica Tingey

Jill Jarecki

Affiliations

Soon will be listed here.

Abstract

Background: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a significant unmet need in SMA.

Objectives: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA.

Methods: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions.

Results: The Working Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed.

Conclusions: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.

Citing Articles

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Insights into spinal muscular atrophy from molecular biomarkers.

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Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.

Brkusanin M, Kosac A, Brankovic-Sreckovic V, Jovanovic K, Peric S, Karanovic J Front Neurol. 2024; 15:1394001.

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References

Gagliardi D, Meneri M, Saccomanno D, Bresolin N, Comi G, Corti S . Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature. Int J Mol Sci. 2019; 20(17). PMC: 6747516. DOI: 10.3390/ijms20174152. View

Maretina M, Valetdinova K, Tsyganova N, Egorova A, Ovechkina V, Schioth H . Identification of specific gene methylation patterns during motor neuron differentiation from spinal muscular atrophy patient-derived iPSC. Gene. 2021; 811:146109. DOI: 10.1016/j.gene.2021.146109. View

DAmico A, Mercuri E, Tiziano F, Bertini E . Spinal muscular atrophy. Orphanet J Rare Dis. 2011; 6:71. PMC: 3231874. DOI: 10.1186/1750-1172-6-71. View

Crawford T, Paushkin S, Kobayashi D, Forrest S, Joyce C, Finkel R . Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. PLoS One. 2012; 7(4):e33572. PMC: 3338744. DOI: 10.1371/journal.pone.0033572. View

Strauss K, Farrar M, Muntoni F, Saito K, Mendell J, Servais L . Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med. 2022; 28(7):1381-1389. PMC: 9205281. DOI: 10.1038/s41591-022-01866-4. View

Ruhno C, McGovern V, Avenarius M, Snyder P, Prior T, Nery F . Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Hum Genet. 2019; 138(3):241-256. PMC: 6503527. DOI: 10.1007/s00439-019-01983-0. View

Mercuri E, Lucibello S, Perulli M, Coratti G, de Sanctis R, Pera M . Longitudinal natural history of type I spinal muscular atrophy: a critical review. Orphanet J Rare Dis. 2020; 15(1):84. PMC: 7132885. DOI: 10.1186/s13023-020-01356-1. View

Bromberg M, Swoboda K . Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002; 25(3):445-7. PMC: 4334581. DOI: 10.1002/mus.10050. View

Rutkove S, Aaron R, Shiffman C . Localized bioimpedance analysis in the evaluation of neuromuscular disease. Muscle Nerve. 2002; 25(3):390-7. DOI: 10.1002/mus.10048. View

10.

Kariyawasam D, DSilva A, Howells J, Herbert K, Geelan-Small P, Shin-Yi Lin C . Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen. J Neurol Neurosurg Psychiatry. 2020; . PMC: 7803907. DOI: 10.1136/jnnp-2020-324254. View

11.

Mercuri E, Darras B, Chiriboga C, Day J, Campbell C, Connolly A . Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018; 378(7):625-635. DOI: 10.1056/NEJMoa1710504. View

12.

Yanyan C, Yujin Q, Jinli B, Yuwei J, Hong W, Fang S . Correlation of PLS3 expression with disease severity in children with spinal muscular atrophy. J Hum Genet. 2013; 59(1):24-7. DOI: 10.1038/jhg.2013.111. View

13.

Sturm S, Gunther A, Jaber B, Jordan P, Al Kotbi N, Parkar N . A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Br J Clin Pharmacol. 2018; 85(1):181-193. PMC: 6303280. DOI: 10.1111/bcp.13786. View

14.

Lewelt A, Krosschell K, Scott C, Sakonju A, Kissel J, Crawford T . Compound muscle action potential and motor function in children with spinal muscular atrophy. Muscle Nerve. 2010; 42(5):703-8. PMC: 2964439. DOI: 10.1002/mus.21838. View

15.

Strauss K, Farrar M, Muntoni F, Saito K, Mendell J, Servais L . Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nat Med. 2022; 28(7):1390-1397. PMC: 9205287. DOI: 10.1038/s41591-022-01867-3. View

16.

Wirth B, Karakaya M, Kye M, Mendoza-Ferreira N . Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next. Annu Rev Genomics Hum Genet. 2020; 21:231-261. DOI: 10.1146/annurev-genom-102319-103602. View

17.

Verhaart I, Robertson A, Wilson I, Aartsma-Rus A, Cameron S, Jones C . Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017; 12(1):124. PMC: 5496354. DOI: 10.1186/s13023-017-0671-8. View

18.

Glascock J, Sampson J, Connolly A, Darras B, Day J, Finkel R . Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. J Neuromuscul Dis. 2020; 7(2):97-100. PMC: 7175931. DOI: 10.3233/JND-190468. View

19.

Walter M, Wenninger S, Thiele S, Stauber J, Hiebeler M, Greckl E . Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 - A Prospective Observational Study. J Neuromuscul Dis. 2019; 6(4):453-465. PMC: 6918909. DOI: 10.3233/JND-190416. View

20.

Zheleznyakova G, Nilsson E, Kiselev A, Maretina M, Tishchenko L, Fredriksson R . Methylation levels of SLC23A2 and NCOR2 genes correlate with spinal muscular atrophy severity. PLoS One. 2015; 10(3):e0121964. PMC: 4378931. DOI: 10.1371/journal.pone.0121964. View