A multimodal approach to identify clinically relevant parameters to monitor disease progression in a preclinical model of neuropediatric disease

Abstract

While research has accelerated the development of new treatments for pediatric neurodegenerative 20 disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of 21 convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical 22 trials. Here, we unveil a new translational platform for tracking disease progression in an animal model of a 23 pediatric neurodegenerative disorder, CLN6-Batten disease. Instead of looking at a handful of parameters or a single 24 "needle in a haystack", we embrace the idea that disease progression, in mice and patients alike, is a diverse 25 phenomenon best characterized by a combination of relevant biomarkers. Thus, we employed a multi-modal 26 quantitative approach where 144 parameters were longitudinally monitored to allow for individual variability. We 27 use a range of noninvasive neuroimaging modalities and kinematic gait analysis, all methods that parallel those 28 commonly used in the clinic, followed by a powerful statistical platform to identify key progressive anatomical and 29 metabolic changes that correlate strongly with the progression of pathological and behavioral deficits. This 30 innovative, highly sensitive platform can be used as a powerful tool for preclinical studies on neurodegenerative 31 diseases, and provides proof-of-principle for use as a potentially translatable tool for clinicians in the future. 32 33 [Main Text: ] 34

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

“…In recent years, the methods to quantify exon skip and dystrophin levels have significantly improved with, for instance, the availability of digital droplet PCR (ddPCR) [17], automated, sensitive and accurate immunofluorescence analysis (IFA) [18], and capillary Western immunoassay (Wes) [10]. In addition, more sensitive methods for quantification of functional endpoints have become available, including magnetic resonance imaging (MRI) [19] and fully automated kinematic analysis (ie, MotoRater analysis for mouse models), with which 95 different parameters related to fine motor capabilities and gait can be assessed [20][21][22].…”