PROJECTS

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. Although they are caused by disparate molecular etiologies, similar functional impairments are common across all leukodystrophies and generally appear to be associated with disease progression. Clinical outcome assessments (COA) are critically lacking, with very few validated tools available for use in clinical trials.

This project will advance the clinical trial readiness for multiple leukodystrophies by creating an outcomes assessment “toolbox” and multi-center data integration systems. Further, this project will catalyze ongoing efforts within the leukodystrophy community by bringing together more dozens of patient advocacy groups, industry stakeholders, and existing research consortia.

Project 1 will focus on the following five disorders that have either ongoing newborn screening programs or are considered to be at a state of clinical trial readiness.

• Aicardi-Goutières Syndrome

• Adrenoleukodystrophy/Adrenomyeloneuropathy

• Alexander Disease

• Metachromatic Leukodystrophy

• Pelizaeus-Merzbacher Disease (PMD)

This selection is further justified by preliminary epidemiological data suggesting that these five conditions alone account for nearly 40% of all individuals diagnosed with a leukodystrophy. The investigators would to to emphasize, however, that the knowledge and tools developed through this project will be applicable to all other leukodystrophies and even other rare disorders causing similar clinical manifestations.

This longitudinal study will provide a body of data and management approaches that will inform and empower the projects below, along with broader goals of our scientific, advocacy and commercial stakeholders. The anticipated impact of this project to define the best tools to understand natural history in individuals with leukodystrophy.

X-linked adrenoleukodystrophy (ALD), a debilitating neurological disorder caused by mutations in the ABCD1 gene, is one of the few leukodystrophies for which newborn screening is available and recommended by the federal government. Adult-onset Adrenomyeloneuropathy (AMN) is the most common phenotype of ALD, as adult males with pathogenic changes in ABCD1 and more than half of female ALD heterozygotes develop AMN over time. Despite advances in the treatment for the childhood onset cerebral form of ALD, no treatment is currently available for AMN. Additionally, the slow and variable rate of disease progression and lack of understanding of clinical outcome assessments (COA) have hampered efforts to design clinical trial readiness.

In this project, investigators will explore novel disease rating scales and measures of ataxia, a key component of the gait abnormalities seen in AMN. The results of this project will be vital for the facilitation of clinical studies for therapies that are currently under development for adults with AMN.

Aim 1 - Assess the validity of an adult AMN rating scale.

In the first aim, investigators will optimize and validate an existing disease rating scale for Adrenomyeloneuropathy (AMN). Assessments will be conducted at Massachusetts General Hospital (MGH) and Kennedy Krieger Institute (KKI). Investigators hope to compare the trajectory between this rating scale and the patient-report outcomes (PROs) obtained in Project 1, representing a critical step needed for clinical trials to test the effectiveness of future interventions. Investigators hypothesize that the application of a disease-specific rating scale that accounts forall nervous system compartments affected in AMN (brain, spinal cord, and peripheral nerve) will be more comprehensive and therefore correlate better with disease progression than individual clinical outcome assessments (COAs) obtained in Project 1.

Aim 2 - Assess the rate of change in quantitative ataxia measures as compared to exsting quantitative performance measures

Given the impact of balance problems in adult AMN, investigators will perform detailed assessments of ataxia measures using force plates to assess amplitude sway in both males and females. Investigators expect to establish ataxia measurement as a useful clinical outcome assessment (COA) for AMN, and explore its validity, reliability and reproducibility in this population.

Aim 3 - Determine whether remote assessment with wearable technology systems are comparable with quantitative performance measures of gait and balance obtained using force plate technology.

The final aim seeks to validate wearable devices as effective tools to obtain meaningful outcomes data. Investigators have previously utilized the Opal, a research-grade wearable device designed to aid in gait and balance research. These measures can be performed in the comfort of the research subject’s own home. Investigators hypothesize that these remotely assessed variables will be comparable to those obtained through in-person assessments performed in the laboratory and may serve as meaningful outcome measures in the context of future clinical trials.

Aim 1: Obtain longitudinal GFAP measurements in various sample types.

The first aim seeks to obtain longitudinal GFAP measurements in CSF and plasma samples of 40 Alexander Disease patients across multiple sites. Investigators will test sample stability over various shipping and storing conditions and assay reliability through intra- and inter-assay measurements.

Aim 2: determine whether GFAP concentrations vary by disease subtypes.

This aim seeks to determine whether GFAP concentrations vary by clinical subtypes of Alexander Disease. The disorder presents at various ages, with different clinical phenotypes, and investigators hope to determine whether these features accurately predict GFAP elevations.

Aim 3: Determine whether GFAP levels predict functional outcome measures.

The final aim will further explore whether GFAP levels predict functional outcome measures in Alexander Disease. To address this question, investigators will leverage the longitudinal motor, cognitive, and swallowing tools defined as part of Project 1.

Aicardi Goutières Syndrome (AGS) is a rare genetic disorder of excessive interferon (IFN) production, resulting in severe, systemic inflammatory injury and potentially profound disabilities. Most individuals affected by AGS exhibit some degree of neurologic impairment, ranging from mild spastic paraparesis to severe global developmental delay. Additionally, interferon over-expression results in systemic manifestations and recurrent aseptic fevers with severe, chronic irritability. AGS therapeutic trials are limited by heterogeneous patient populations and the lack of disease-specific outcome measures.

Recent clinical studies have demonstrated that current outcome assessment tools do not adequately capture the impact of the disease and the subsequent improvement. In this proposal, we will begin to bridge those gaps by identifying clinically distinct subgroups of AGS, designing an AGS-specific clinical rating scale, and exploring the relationship of a novel biomarker to clinical disease.

Aim 1: Characterize Clinically Distinct AGS Subgroups

The first project aim seeks to define distinct cohorts based on statistically relevant disease features that best predict clinical trajectory and outcomes. Investigators will identify subgroups that represent the distinct clinical manifestations seen in AGS. Using statistical modeling approaches, investigators define discrete subsets within the AGS population. This analysis will be based on neurologic level at presentation, age of onset, genotype, systemic complications, and variables defined by content validity analysis in collaboration with our advocacy partners. The proposed cohorts will be assessed using the prospective data collection tools developed in Project 1 to determine whether they remain longitudinally consistent.

The expected outcome of this aim is to establish an instrument to accurately categorize individuals into distinct subgroups at time of presentation, defining cohorts based on statistically relevant disease features that best predict outcome.

Aim 2: Define a Novel disease Rating Scale to Assess Longitudinal Change

Disease-specific clinical rating scales can be useful in demonstrating therapeutic benefit in disorders with a heterogeneous phenotype, as is seen in individuals with AGS. We propose to identify domains in established Clinical Outcome Assessments (COA) and Patient-Reported Outcomes (PRO) to create a novel disease-specific rating scale. This aim will also test validity and feasibility in subsequently enrolled individuals affected by AGS.

We hypothesize that application of a disease-specific clinical rating scale at defined time points will more closely correlate with disease progression compared to a daily symptom diary and traditional clinical outcome assessment tool results obtained in Project 1.

Aim 3: Explore proportionality between a prospective biomarker and clinical outcomes in AGS

Interferon Signaling Gene (ISG) signature, a score of gene expression related to interferon signaling, is currently used in the context of clinical trials, however its relationship to clinical outcomes has yet to be determined. We propose exploring the longitudinal relationship of ISG scores to clinical presentation, age of onset, genotype, systemic complications, and prospectively identified variables. We will compare the trajectory between ISG scores and clinical function, including a patient-reported outcomes and clinical outcome assessments.

We hypothesize that ISG scores gathered at defined time points will correlate with disease progression. This aim will lay the groundwork for potential use of this biomarker in the context of future clinical trials.