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.
