Accelerating Precision Therapy and Clinical Trial Readiness For Pla2g6-Associated Neurodegeneration (plan)

Introduction: PLAN is a rare, life-limiting neurodegenerative disorder due to biallelic mutations in PLA2G6. There are currently no effective disease-modifying treatments, though gene therapy is in development. Developing robust disease biomarkers to evaluate efficacy in future clinical trials therefore constitutes research priority.

Methods: We used a multimodal approach to develop a range of PLAN-specific biomarkers, including (a) a large, international retrospective natural history study of >300 cases (b) a disease-specific clinical rating scale (c) prospective, longitudinal quantitative neuroimaging and (d) biomarker discovery through proteomics by mass spectrometry and Single Molecular Array (SIMOA).

Results: The PLAN natural history study (n=310) has provided key data about disease progression, including survival curves (Figure 1) and time to loss of ambulation. The new Childhood-onset PLAN Disease Rating Scale (CoPLAN DRS) was developed and validated with very high interrater reliability (n=35, 45 assessments, intraclass correlation coefficient of 0.98) and significant positive correlation with age (Figure 2). Brain iron in the globus pallidus quantified through Quantitative Susceptibility Mapping (QSM) (n=28) on brain MRI scans showed significant positive correlation with age (Figure 3). Several robust biomarkers were identified, including a novel disease biomarker, Nicastrin. Cerebrospinal fluid and plasma Tau and Neurofilament Light (NfL) were significantly raised compared to controls, with a significant negative correlation between NfL and disease progression (Figure 3).

Conclusion: We have developed a multimodal toolkit of clinical, radiological and multiomic biomarkers that will be imperative for future precision medicine clinical trials.