Natural History Study and Identification of Patient-Centric Clinical Outcome Assessments in TUBB4A-LD (NIH R21) - ABSTRACT TUBB4A-associated leukodystrophy (TUBB4A-LD) is a rare pediatric hypomyelinating disorder caused by sporadic mutations in the TUBB4A gene, which encodes β-tubulin 4A (Tubb4A) protein. Affected individuals experience significant motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. TUBB4A-LD is a life-threatening diagnosis for which there is currently no treatment or cure. Promising therapies, such as antisense oligonucleotides (ASO) and in-vivo gene therapy, are nearing pediatric clinical trials, highlighting the urgent need for foundational tools to design patient-centric trials that are both safe and capable of evaluating treatment efficacy. Key challenges remain in clinical trial design and include gaps in (i) understanding the overall disease course, in particular systemic complications (e.g., cardiac involvement), and (ii) the lack of validated patient-centric clinical trial endpoints to ensure safety and measure efficacy in TUBB4A-LD drug candidate trials, respectively. We propose to address this urgent gap in clinical trial readiness by leveraging our partnership with disease/outcome experts, caregivers, and advocacy partners in the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN). We will longitudinally map the systemic complications of TUBB4A-LD and develop a novel quantitative measure of systemic burden (TUBB4A-S) (Aim 1). This effort will guide clinical trial readiness by enabling determination of safe inclusion and exclusion criteria, identification of individuals at-risk of AEs as well as appropriate assignment of relatedness of AEs to disease. In addition, this work will also inform evidence- based clinical guidelines for TUBB4A-LD. Disease severity and complexity in TUBB4A-LD affected individuals will require patient-centric approaches to identify concepts of interest (COI) most meaningful to patients and families. Our team has already identified patient priorities and COIs. In Aim 2, we will identify and measure COAs able to capture patient-centric COIs, to define meaningful changes in COA measures with clear context of use (COU). The approach will be framed in accordance with guidance from the FDA as measures of health events and COI important to the patient community. Together, these efforts are expected to establish a sharable resource to validate clinical trial endpoints applicable to TUBB4A-LD candidate drug trials. Also, this work will create a knowledge base on systemic complications of TUBB4A-LD to define standards of care and inform clinical trial design including, trial eligibility, at-risk prediction and adverse event attribution.
