4-hydroxymandelate for HPDL deficiency, a novel mitochondrial encephalopathy

Abstract HPDL encodes the mitochondrial enzyme 4-hydroxyphenylpyruvate dioxygenase-like, which converts the tyrosine metabolite 4-HPPA to 4-hydroxymandelate (4-HMA). HPDL biallelic mutations lead to a mitochondrial encephalopathy (ME) syndrome with two distinct presentations: neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA, MIM619026) and Autosomal Recessive Spastic Paraplegia 83 (SPG83, MIM619027). Genotype analysis suggests that truncating mutations correlate with NEDSWMA, while missense mutations correlate with SPG83. Preclinical mouse models show that 4-HMA is a critical precursor for the mitochondrial coenzyme Q10 cofactor involved in the electron transport chain. Ina mouse Hpdl knockout model, 4-HMA supplementation prevented and ameliorated ME features and death, suggesting that HPDL-deficiency syndromes (HDS) may be a treatable mitochondrial disease. This application lays the groundwork for a clinical trial to assess the benefit of 4-HMA or a derivative to treat NEDSWMA and SPG83. We identified over 200 patients with HDS worldwide, and 40 patients in the United States. We have an active patient registry to prepare for a future interventional clinical trial using 4-HMA supplementation in HDS patients. For this proposal, we plan to enroll 10 patients with the NEDSWMA phenotype in a natural history study. We have found that 4-HMA is a measurable biomarker and can be readily measured from blood samples. Here we propose to leverage our existing patient registry by testing 4-HMA and urine organic acids as biomarkers of disease status (Aim 1) and conducting an 18 month natural history (Aims 2 and 3). The result of this work may provide a strong preclinical proof of concept IND-enabling dataset, blood and urine biomarkers, and fit-for-purpose outcome measures to support a subsequent single-site clinical trial.