Eflornithine repurposed to treat rare genetic syndrome

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By Marilynn Larkin

NEW YORK (Reuters Health) - Eflornithine, an FDA-approved drug to treat hirsutism that is being studied in several cancer clinical trials, effectively treated a child with a new genetic syndrome, yielding improvements in neurological symptoms and brain architecture.

Drs. Andre Bachmann and Caleb Bupp of Michigan State University in Grand Rapids, for whom the condition is now named (Bachmann-Bupp syndrome), say their strategy of using an approved single patient investigational repurposed drug treatment is a rapid approach that could be used to treat other rare diseases.

The newly identified genetic syndrome is the result of a mutation in the ODC1 gene. "ODC1 acts in the polyamine pathway in the body, and there are many other genes in that pathway," they told Reuters Health by email. "Only one other disease from this pathway was known before (Snyder-Robinson Syndrome), but there are at least three more polyamine pathway genes since our original discovery that are connected to patients with similar neurodevelopmental disorders."

"We think there are more to be found," they said, "and we are also hopeful that there may be some similarities for treatment since all these genes work in the same metabolic pathway in the body."

As reported in eLife, the affected patient was a three-year old girl with global developmental delay and alopecia universalis due to a nonsense variant that caused premature abrogation of 14-aa residues in the C-terminus of the ODC protein, leading to enhanced function.

The patient's red blood cells showed enhanced ODC activity and elevated putrescine levels compared to healthy controls. Four additional patients with similar mutations and phenotypic features of this syndrome have since been reported and at least four more cases have been identified, but not yet reported (https://bit.ly/3wVRQfA).

From previous studies and metabolic profile, eflornithine (technically known as difluoromethylornithine, or DFMO) was identified as potentially beneficial with therapy, leading to FDA approval for the single-patient study. Dosing was based on past experience in children with neuroblastoma also treated with this drug.

Treatment normalized the girl's polyamine levels without disrupting other pathways. She demonstrated "remarkable" improvement in both neurological symptoms and cortical architecture, according to the authors.

Her BMI increased during treatment from the 25th to the 90th percentile primarily due to an increase in muscle bulk.

Prior to therapy, she couldn't stand, sit, or "cruise," and her fine motor skills were limited. Her gain in muscle strength enabled her to hold up her head without support, and after four months of therapy, she was able to sit unsupported and maintain posture with a physical therapist providing resistance, use a walker, and feed herself with a spoon.

Further, repeat MRI done at the end of the nine-month treatment trial showed normalization of the cerebral white matter and resolution of follicular cysts.

Drs. Bachmann and Bupp said, "We will develop in vivo models to study dosing but also to better understand if early administration after birth can prevent symptoms and how long drug should be given (e.g., are there any reversible effects once drug is discontinued)."

Dr. Matthew Might, Director, Hugh Kaul Precision Medicine Institute at the University of Alabama at Birmingham commented in an email to Reuters Health, "I applaud the researchers for being willing to engage in the difficult task of validating the efficacy of a proposed therapy when there is only one patient."

"While there is no large randomized clinical trial here (which might have been impossible with a community so small), they were able to identify markers of efficacy that are highly compelling even within one patient," he said. "The hair growth before and after is particularly striking."

"Recruiting additional patients to a larger and more formal study with pre-defined endpoints would be a reasonable next step," he added.

"I think the take-home message here is that repurposing is increasingly a viable path toward treatment in ultra-rare disorders, and that it is possible to do thoughtful and compelling science with n=1 trials," Dr. Might concluded.

SOURCE: https://bit.ly/3rppDwx eLife, online July 20, 2021.

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