Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease

Rajasekaran, Surender; Bupp, Caleb; Leimanis-Laurens, Mara L.; Shukla, Ankit; Russell, Christopher; Junewick, Joseph; Gleason, Emily; VanSickle, Elizabeth; Edgerly, Yvonne; Wittmann, Bryan M.; Prokop, Jeremy W.; Bachmann, André S.

doi:10.7554/elife.67097

Cited by 19 publications

(25 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional support may be required for more severely affected patients. As more is known about treatment with DFMO, the natural history of neurocognitive findings in this syndrome may change (Rajasekaran et al, 2021 ). Diagnoses like autism spectrum disorder (ASD) and intellectual disability (ID) may become more apparent as cognitive and behavioral development progresses functionality to the level of being able to make that diagnosis with more confidence.…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype: Four new cases and hope for treatment in Bachmann‐Bupp syndrome

VanSickle

Michael

Bachmann

et al. 2021

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Bachmann‐Bupp syndrome (BABS) is a rare syndrome caused by gain‐of‐function variants in the C‐terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non‐congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late‐onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

show abstract

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype: Four new cases and hope for treatment in Bachmann‐Bupp syndrome

VanSickle

Michael

Bachmann

et al. 2021

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

show abstract

“…Importantly, DFMO is clinically approved for the treatment of African trypanosomiasis (41), and its use as a maintenance therapy for pediatric neuroblastoma patients has provided valuable data on safety and administration (42,43). DFMO has a decades-long history of safe administration in clinical trials and has recently been repurposed to treat patients with Bachmann-Bupp syndrome (BABS), a newly identified genetic disorder resulting from an ODC gain-of-function variant (44,45). The presentation of BABS emulates that of SRS in several aspects, including developmental delay, hypotonia, dysmorphic features, and non-specific brain MRI findings (46), most of which dramatically improved with DFMO treatment (44).…”

Section: Discussionmentioning

confidence: 99%

“…DFMO has a decades-long history of safe administration in clinical trials and has recently been repurposed to treat patients with Bachmann-Bupp syndrome (BABS), a newly identified genetic disorder resulting from an ODC gain-of-function variant (44,45). The presentation of BABS emulates that of SRS in several aspects, including developmental delay, hypotonia, dysmorphic features, and non-specific brain MRI findings (46), most of which dramatically improved with DFMO treatment (44). Our studies in SRS patient-derived cell lines indicate that DFMO effectively reverses the aberrantly elevated SPD/SPM ratio that is the main biochemical hallmark of SRS.…”

Section: Discussionmentioning

confidence: 99%

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome: mechanism of action and therapeutic potential

Murray-Stewart

Foley

Holbert

et al. 2023

Preprint

View full text Add to dashboard Cite

Snyder-Robinson Syndrome (SRS) is caused by mutations in the spermine synthase (SMS) gene, the enzyme product of which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonic musculature, and seizures, along with other more variable symptoms. Currently, medical management focuses on treating these symptoms without addressing the underlying molecular cause of the disease. Reduced SMS catalytic activity in cells of SRS patients causes the accumulation of spermidine, while spermine levels are reduced. The resulting exaggeration in spermidine-to-spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity in the patient. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this polyamine imbalance and investigate the potential of this approach as a therapeutic strategy for affected individuals. Here we report the use of difluoromethylornithine (DFMO; eflornithine), an FDA-approved inhibitor of polyamine biosynthesis, in re-establishing normal spermidine-to-spermine ratios in SRS patient cells. Through mechanistic studies, we demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of existing spermidine into spermine in cell lines with hypomorphic variants of SMS. Further, DFMO treatment induces a compensatory uptake of exogenous polyamines, including spermine and spermine mimetics, cooperatively reducing spermidine and increasing spermine levels. In a Drosophila SRS model characterized by reduced lifespan, adding DFMO to the feed extended lifespan. As nearly all known SRS patient mutations are hypomorphic, these studies form a foundation for future translational studies with significant therapeutic potential.

show abstract

“…ODC gain-of-function mutations have been associated with hyper-proliferative diseases, including cancer, infections, overgrowth, neural overproliferation, and the ODC-linked neurodevelopmental disorder, Bachmann–Bupp syndrome. − Recently, Prokop et al have identified ODC G84R as a variant associated with intellectual disability and seizures. Activity assays using recombinant ODC indicated that G84R is a loss-of-function mutation, and the authors hypothesized that ODC partial loss-of-function may lead to neural depletion .…”

Section: Discussionmentioning

confidence: 99%

Structure and Enzymatic Activity of an Intellectual Disability-Associated Ornithine Decarboxylase Variant, G84R

et al. 2022

View full text Add to dashboard Cite

Ornithine decarboxylase (ODC) is a rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are required for proliferation, and increased ODC activity is associated with cancer and neural over-proliferation. ODC levels and activity are therefore tightly regulated, including through the ODC-specific inhibitor, antizyme AZ1. Recently, ODC G84R has been reported as a partial loss-of-function variant that is associated with intellectual disability and seizures. However, G84 is distant from both the catalytic center and the ODC homodimerization interface. To understand how G84R modulates ODC activity, we have determined the crystal structure of ODC G84R in both the presence and the absence of the cofactor pyridoxal 5-phosphate. The structures show that the replacement of G84 by arginine leads to hydrogen bond formation of R84 with F420, the last residue of the ODC C-terminal helix, a structural element that is involved in the AZ1-mediated proteasomal degradation of ODC. In contrast, the catalytic center is essentially indistinguishable from that of wildtype ODC. We therefore reanalyzed the catalytic activity of ODC G84R and found that it is rescued when the protein is purified in the presence of a reducing agent to mimic the reducing environment of the cytoplasm. This suggests that R84 may exert its neurological effects not through reducing ODC catalytic activity but through misregulation of its AZ1-mediated proteasomal degradation.

show abstract

Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease

Cited by 19 publications

References 19 publications

Expanding the phenotype: Four new cases and hope for treatment in Bachmann‐Bupp syndrome

Expanding the phenotype: Four new cases and hope for treatment in Bachmann‐Bupp syndrome

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome: mechanism of action and therapeutic potential

Structure and Enzymatic Activity of an Intellectual Disability-Associated Ornithine Decarboxylase Variant, G84R

Contact Info

Product

Resources

About