Project 3: Clinically Meaningful Outcomes in LBSL

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Summary/Abstract for Project 3: Clinically meaningful outcomes in LBSL Clinical trial readiness is particularly difficult to achieve in ultra rare disorders such as leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). Several therapeutics are undergoing active preclinical development, including antisense oligonucleotides, but a small patient population and lack of validated outcome measures limits the ability to test these discoveries in a clinical trial. To address this unmet need we plan to investigate possible measurable clinical outcome assessments (COAs) including wearable devices which would allow remote collection of data as well as MRS measures to identify if MRS lactate could serve as a biomarker. Aim 1 will determine meaningful change in quantitative remote measures of gait and ataxia in LBSL. Participating families will be trained in the use of remote methods for data collection, including OPAL wearable devices to measure gait and ataxia. Data from the OPAL device will be reviewed alongside patient and observer reported outcomes to determine Meaningful Score Difference / Meaningful Score Regions. We expect to see that changes in the mobility score will reflect meaningful changes in disease burden and provide an outcome measure for therapeutics which are being actively developed in the laboratory. Aim 2 will determine if measures of proton MRS lactate can serve as a monitoring biomarker in LBSL. Patients will undergo MRS studies at one of the approved centers at baseline, one year follow-up, and two years follow-up each within 2-3 weeks of completing the remote balance and gait assessments listed for aim one. It is important to understand whether MRS correlates with COAs as this will determine strategies to determine if MRS brain lactate has a prognostic value (aim 3). Aim 3 will develop tools to assess the MRS metabolite signature to predict change in Performance Outcomes (PerfOs) in LBSL. Patients will have COAs and MRS studies as described in aims 1 and 2 and the data collected will be used to determine whether MRS Lactate or a combination of lactate and other MRS metabolites at baseline will predict change in PerfOs over a 2-year period. The proposed work will generate multiple publications, explore the value of brain lactate and/or an MRS metabolite signature as potential first biomarkers in LBSL, and support the selection of clinical trial endpoints.