Abstract
Several neurological disorders may be amenable to treatment with gene-targeting therapies such as antisense oligonucleotides (ASOs) or viral vector-based gene therapy. The US FDA has approved several of these treatments; many others are in clinical trials. Preclinical toxicity studies of ASO candidates have identified dose-dependent neurotoxicity patterns. These include degeneration of dorsal root ganglia, the cell bodies of peripheral sensory neurons. Quantitative sensory testing (QST) refers to a series of standardized mechanical and/or thermal measures that complement clinical neurologic examination in detecting sensory dysfunction. QST primarily relies on patient self-report or task performance (i.e., button-pushing). This brief report illustrates individualized pragmatic approaches to QST in non-verbal subjects receiving early phase investigational intrathecal drug therapies as a component of clinical trial safety protocols. Three children with neurodevelopmental disorders that include Neuronal Ceroid Lipofuscinosis Type 7, Ataxia-Telangiectasia, and Epilepsy of Infancy with Migrating Focal Seizures are presented. These case studies discuss individualized testing protocols, accounting for disease presentation, cognitive and motor function. We outline specific considerations for developing assessments for detecting changes in sensory processing in diverse patient groups and safety monitoring trials of early phase investigational intrathecal drug therapies. QST may complement information obtained from the standard neurologic examination, electrophysiologic studies, skin biopsies, and imaging. QST has limitations and challenges, especially in non-verbal subjects, as shown in the three cases discussed in this report. Future directions call for collaborative efforts to generate sensory datasets and share data registries in the pediatric neurology field.
Highlights
Drug Administration (FDA) and European Medicines Agencies (EMA) have approved several of these treatments for clinical applications; many others are in clinical trials
We have developed Quantitative sensory testing (QST) protocols for typically-developing children [29], children and adolescents with juvenile idiopathic arthritis [30], complex regional pain syndrome [31–33], and scoliosis [34]; and adult volunteers receiving novel local anesthetics in Phase-1 clinical trials [10]
We show that our protocol can be used as a paragmatic approach to evaluate patient safety and drug toxicity during clinical trials were there is an potential risk for spinal toxicity
Summary
Precision medicine is an emerging area for disease prevention and treatment strategies that takes into account individual variability in genes and environment. Recent advances in ASO drug development have resulted in a rapid transition from bench-to-bedside candidates with the FDA recently approving 12 ASO therapies between the years 2016 and 2020 alone [1]. All of these therapies were optimized for treatment of orphan diseases where druggable genetic targets are present only in small-to-moderate proportions of patients. Preclinical toxicity studies of ASO candidates in rodents and non-human primates have identified dosedependent neurotoxicity patterns. These include acute and subacute dysfunction, inflammation, and degeneration of dorsal root ganglia, the cell bodies of peripheral sensory neurons [2, 3]. It is critical to ensure these therapies are safe and effective in order to translate therapies into the clinic
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