A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen

Abstract

Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0-20 years with and without treatment with the antisense oligonucleotide nusinersen.

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

“…For example, Finkel et al (2022) analyzed data from the CS3A and ENDEAR studies and found that in infants with SMA, lower NF-H levels in CSF were associated with increased nusinersen dosage, which in turn correlated with better treatment outcomes [ 165 ]. Studies that have evaluated the effects of nusinersen treatment on NF levels in SMA-affected adolescents and adults have yielded conflicting results, suggesting a need for further, standardized studies on these populations [ 109 , 111 , 115 , 121 , 147 – 149 , 166 , 167 ]. Factors that may have contributed to these variable results include whether NF was measured in blood plasma, serum, or CSF, and whether the NF-H and/or NF-L subunit was measured.…”

Role of circulating biomarkers in spinal muscular atrophy: insights from a new treatment era

“…Among the various putative circulating biomarkers under investigation, Nfs stand out as promising candidates, particularly in children with type 1 and 2 SMA (83,98,99). These biomarkers have exhibited favorable responsiveness to treatments such as nusinersen and gene therapy.…”

“…In children with SMA type 1, plasma levels pNf-H and Nf-L exhibit a substantial increase during the initial months of life when compared to age-matched controls, indicating active and rapid motor neuron degeneration and death at early stages of the disease (83,98,99). Additionally, serum Nfs levels are inversely associated with SMN2 copies number, and directly correlate with earlier age of diagnosis and symptom onset and lower baseline motor function (34).…”

“…Additionally, serum Nfs levels are inversely associated with SMN2 copies number, and directly correlate with earlier age of diagnosis and symptom onset and lower baseline motor function (34). Over time, pNf-H levels decline in untreated SMA children, but persistently remain higher compared to healthy controls of the same age, probably due to the active axonal degeneration (99). Recent data have revealed notable fluctuations in pNf-H levels among both SMA patients and mouse models, highlighting the necessity for a comprehensive interpretation of this biomarker's measurements (100).…”

Molecular markers of disease severity and response to nusinersen therapy in 5q spinal muscular atrophy (literature review)

“…Вероятно, такую связь не удалось обнаружить в результате методологических ограничений включенных в обзор исследований: максимальная длительность большинства наблюдений не превышала 2 лет, из 12 исследований в 9 число пациентов со СМА до деления на подгруппы составляло 30 и менее, в 4 исследованиях -менее 15. С другой стороны, несколько авторов указывают на то, что в старшей возрастной группе уровень нейрофиламентов не позволяет отличить группу пациентов со СМА от контроля [12,14,15], а наибольшее повышение исходного уровня и выраженность его снижения отмечаются в возрасте до 2 лет, а затем уровень быстро достигает плато, как это было показано для pNfH [18]. Таким образом, даже если бы такая связь была обнаружена, наиболее вероятно, нейрофиламенты не удалось бы эффективно использовать в клинической практике с целью оценки прогноза и мониторинга ответа на терапию для каждого конкретного пациента, поскольку случайные индивидуальные колебания уровня нейрофиламентов могут быть больше обнаруженных различий в их концентрации на уровне больших выборок.…”