PROJECTS AND CORES

Leukodystrophies are rare inherited diseases that affect the white matter of the brain due to the loss or absence of myelin, the lipid membrane that insulates axons in the nervous systems. Recent advances in therapies and available testing have created an urgent need for more robust natural history data, and specifically a better understanding of presymptomatic individuals needing intervention and treatment-associated disease monitoring.

Project 1 seeks to do so in a multi-site fashion through several Specific Aims and focusing on over a dozen Target Disorders that are at or approaching clinical trial readiness.

Note that the list above does not represent the full scope disease-specific work being done under the broader GLIA-CTN. The Myelin Disorders Biorepository Project (MDBP) study protocol, which supports nearly all of the research activities conducted under Project 1, covers not only the leukodystrophies listed above, but essentially any leukodystrophy or leukoencephalopathy.

Aim 1 - Validate meaningful clinical outcome assessments.

Aim 1 will validate meaningful Clinical Outcome Assessments (COA), supporting equity and access, in alignment with patient priorities. To identify COAs, concepts of interest for defined disorders will be assessed through both quantitative and qualitative work with patient advocacy groups and clinician experts. Patient-centric COAs will be administered remotely to validate alternate methods of administration and decrease the disparity brought on through the limitations of in-person assessments.

Aim 2 - define determinates of health outcomes for presymptomatic children benefiting from Newborn screening

Aim 2 will define determinates of health outcomes for presymptomatic children benefiting from newborn screening (NBS). An Electronic Health Record (EHR) approach will be used to identify presymptomatic individuals and track disease-specific visits, labs, procedures, and imaging. Due to known compliance concerns based on Social Determinants of Health (SDOH) that affect health outcomes, we will also use the EHR-based tools to measure core tenants of SDOH. We expect this aim to allow us to deploy NBS monitoring approaches appropriate in a real-world setting and a diverse population.

Aim 3 - assess health trajectories to monitor leukodystrophies in real-world settings

Aim 3 will further leverage Electronic Health Record (EHR) tools to assess health trajectories for leukodystrophies in real-world settings. The extraction of early disease data from medical records is currently limited to a time-consuming manual process which is impractical across many sites and disorders. Therefore, GLIA-CTN researchers will deploy automated assessment of neurologic trajectories methods using data sourced from the EHR systems at our participating sites. We will use control groups with manually-extracted data and apply automated EHR processes for both structured EHR fields as well as free-text fields through the use of functional scores. We expect these aims to refine our ability to enrich large data sets across a growing number of clinical sites.

Overall, we expect Project 1 to prepare the leukodystrophy community for changes in the therapeutic landscape. We are committed to expanding inclusion of a diverse community of subjects through targeted outreach. We align each aim with clear dissemination approaches for our numerous stakeholders, including our advocacy partners, to create a dynamic environment to create therapeutic advances for these rare diseases.

Aicardi-Goutières Syndrome (AGS) is an inborn error resulting in an early-onset leukodystrophy with extensive multisystemic disease and severe morbidity. Off-label use of bariciticib, a janus kinase inhibitor, is now considered standard of care in this disorder. There is a common prodromal period of systemic symptoms, although the diagnosis is typically made after neurologic regression. This results in delayed treatment and irreversible neurologic injury. There is an urgent and unmet need for newborn screening (NBS) to support early diagnosis and intervention to improve outcomes for children affected by AGS.

Through the following Specific Aims, Project 2 seeks to define novel analytic approaches to detect interferon (IFN) related proteins and identify the most sensitive and specific interferon signaling genes (ISGs) in retrospectively collected NBS cards from affected individuals.

Aim 1 - Establish immunoassay approaches for IFN-related protein detection as a NBS biomarker in AGS.

Aim 1 will establish immunoassay approaches for IFN-related protein detection as a NBS biomarker in AGS. Using AGS and control NBS card punches, Project 2 investigators will perform iterative testing of 10 candidate antigens using commercially available ELISA antibodies. The antigen with the best sensitivity and specificity will then be developed into a first-tier newborn screening of AGS.

Aim 2 - Resolve Elevation Patterns of IFN Related Genes in AGS NBS as a Second-Tier Screen.

Aim 2 will resolve elevation patterns of IFN-related genes in AGS NBS as a second tier screen. We already have extensive published experience in ISG use in post-natal AGS samples and the primary goal of this aim is to assess the appropriate cut-off points and genes of interest in a NBS sample. This will be done by evaluating ISG scores and mRNA profiles of at least 48 IFN response genes.

Aim 3 - Pilot use of a two-tiered IFN protein/gene expression assay in a retrospective newborn cohort.

Aim 3 will pilot the use of a two-tiered IFN protein/gene expression assay in a retrospective newborn cohort. This will entail 50,000 existing deidentified newborn screening blood spots as well as blinded positive controls undergoing the testing procedures as outlined in Specific Aims 1 and 2, as well as genetic testing.

Aim 1 - Determine meaningful change in quantitative remote measures of gait and ataxia in LBSL.

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. Investigators 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: determine whether GFAP concentrations vary by disease subtypes.

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 1. It is important to understand whether MRS correlates with COAs, as this will determine strategies to assess whether MRS brain lactate has a prognostic value.

Aim 3 - Develop tools to assess the MRS metabolite signature to predict change in Performance Outcomes.

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 two-year period.

The last decade has revolutionized leukodystrophy therapeutics, with approval of gene therapy for both adrenoleukodystrophy (ALD) and metachromatic leukodystrophy (MLD), as well as and active trials in Alexander Disease, Pelizaeus Merzbacher Disease, Vanishing White Matter Disease. Transformative work on modified adeno-associated virus (AAV) capsids with improved cerebral tropism have the potential to further change the therapeutic landscape, which includes active Canavan Disease (CD) AAV9 trials. These highly innovative therapies are highly likely to be applied to other ultrarare leukodystrophy, which - ironically - are amongst the least trial-ready within our portfolio.

To redefine approaches to provide clinical trial readiness in ultrarare disorders using Canavan Disease as a template, the GLIA-CTN seeks to pursue the following aims.

Aim 1 - Development of predictive models in ultrarare LDs with multi-variate disease signatures

To address the need for early disease trajectory prediction for accurate stratification in trials, Aim 1A will focus on characterizing the heterogeneous trajectory of Canavan Disease (CD) as an example of an ultrarare disease. CD benefits from an ongoing, prospective natural history study, biospecimens, and real-world data such as age at onset, developmental milestones, disease progression, biochemical results and genotype. Retrospective clinical assessment tools, including the Canavan Disease Scale, will be applied to medical encounters to capture function. In Aim 1B, we will develop two complementary models for risk stratification: A staged model and a machine-learning approach. The ability of these models to accurately assign disease subtype will be compared across two independent test and validation cohorts. Our team includes experienced biostatisticians and data engineers able to define databases and models. The anticipated outcome and metric of success is creation of dynamic disease prediction tools using approaches generalizable to other ultrarare leukodystrophies.

Aim 2 - Measure Leukodystrophy manifestations and comorbidities to prepare for real-world safety monitoring.

Leukodystrophy families emphasize the impact of systemic disease burden on quality of life. In Aim 2A, we will define this burden of disease manifestations and comorbidities using patient- and observer-reported outcomes (PRO/ObsRO) and correlate these with traditional functional measures. Investigators will emphasize inclusion of the ultrarare leukodystrophies, including CD and other ultrarare conditions with imminent trials, such as multiple sulfatase deficiency (MSD).

In Aim 2B, project investigators will focus on capturing disease burden using electronic health record (EHR) tools, focusing on events that might be termed “pre-existing condition” in a future clinical trial. This regulatory-ready database will help anticipate events, define safety criteria, and better guide families. The anticipated outcome is an understanding of pre-existing conditions that may otherwise be misattributed during a clinical trial.

Aim 3 - Establish real-world protocols to capture AAV toxicities and permit longitudinal safety monitoring.

Finally - The GLIA-CTN recognizes that there is no standardized approach to monitoring for emerging gene therapy-related complications.

To address this gap, Aim 3A will leverage the GLIA-CTN infrastructure to develop a standardized clinical dashboard using the Epic Population Health suite, including HealthyPlanet®, around common AAV complications, including automated grading of laboratory values using Common Terminology Criteria for Adverse Events (CTCAE) criteria. We will first test this platform in a historical cohort of subjects at the Children’s Hospital of Philadelphia (CHOP) that received intravenous AAV-based therapy, and then implement this monitoring dashboard within the medical systems of EPIC sites accross the GLIA-CTN network that are currently conducting AAV trials (e.g. CANaspire trial). This clinical dashboard, which can be implemented across all Epic-based sites, is integrated with REDCap via an existing Application Programming Interfaces (API) to collect real-time clinical data.

With AAV-based therapies representing a defined therapeutic drug class with increasing clinical development efforts in the leukodystrophies, Aim 3B will focus on development of a shared registry for post-AAV monitoring to support cross-application comparisons. This platform will capture AAV-related complications such as thrombotic microangiopathy (TMA), cardiac, dorsal root ganglia, and liver toxicities. The anticipated outcome is shareable tools for safety monitoring.