Leveraging modulation of polyamine metabolism for therapeutic advantage in genetic disorders

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ABSTRACT We are at the forefront of investigating novel neurodevelopmental disorders associated with polyamines. Our overarching hypothesis is that mutations in genes of the polyamine pathway result in pathologically unbalanced polyamine profiles in affected individuals that lead to neurodevelopmental disorders. Specifically, Bachmann- Bupp Syndrome (BABS) is an autosomal dominant genetic disorder caused by heterozygous de novo variants in the ornithine decarboxylase 1 (ODC1) gene, and Snyder-Robinson Syndrome (SRS) is an X-linked genetic disorder that results from mutations in the spermine synthase (SMS) gene. Both ODC1 and SMS are sentinel genes in the regulation of polyamine metabolism. However, the precise pathways linking polyamines to these neurodevelopmental disorders are not well defined. Based on our preliminary in vitro, animal, and clinical patient data, we hypothesize that dysregulated polyamines (putrescine, spermidine, spermine) can be normalized, and BABS and SRS phenotypes can be reversed through pharmacological intervention. Importantly, we have compelling data showing that BABS patients accumulate active ODC enzyme and produce large amounts of putrescine, and we showed that the FDA-approved ODC inhibitor DFMO (Eflornithine) significantly improves BABS patient symptoms. We further hypothesize that similar gain-of- function (GOF) or loss-of-function (LOF) variants in other polyamine genes (e.g., eIF5A, DHPS, DOHH, SMOX, AZ, AZI) exist, potentially giving rise to yet unknown polyamine disorders. Unfortunately, very little is known about the underlying mechanisms that govern the phenotypes of polyamine-linked neurodevelopmental disorders. In light of these facts, the overall goals of this application are to unravel the molecular mechanisms and metabolic pathways that link polyamines to BABS and SRS and test polyamine-targeting agents (DFMO, Me2Spm, others) in transgenic BABS and SRS murine models and human patient-derived primary cells and lymphoblastoid cell lines. The following Specific Aims are designed to pursue these goals. Aim 1: Characterize and pharmacologically treat genetic mouse models that mimic ODC1 gain-of-function mutations of individuals with BABS to interrogate the molecular mechanisms that govern the human BABS patient phenotype. Aim 2: Optimize pharmacologic treatment in cells from SRS-affected individuals and in a novel genetic mouse model that mimics a common mutation in SRS patients. Aim 3: Expand the clinical understanding of BABS and SRS to improve clinical care of a growing family of rare diseases. As the primary purpose of this proposal is to define molecular mechanisms and metabolic pathways that govern BABS and SRS as well as to test the effectiveness of treatments in relevant models, it is critical that we use disorder-specific mouse models. We will use our BABS and SRS murine models and patient-derived cell lines, as we have previously published, to determine the in vivo effectiveness of polyamine inhibitor treatments. Our study provides the rare opportunity to potentially cure or at least ameliorate the symptoms of BABS and SRS, two human genetic disorders.