Novel PDE4 Inhibitor Improves Symptoms of Autism Disorder Fragile X Syndrome in Animal Model Interview with:

Dr. Mark E. Gurney, PhD MBA

Dr. Gurney

Dr. Mark E. Gurney, PhD MBA
Chairman & CEO, Tetra Discovery Partners Inc. What is the background for this study? What are the main findings?

Response: Fragile X is a genetic condition. Affected patients display a range of behavioral and other symptoms, including seizures, sleep disorders, anxiety, irritability, hyperactivity, autism, mild-to-severe cognitive impairment and intellectual disability.

BPN14770 is a novel therapeutic agent that selectively inhibits phosphodiesterase-4D (PDE4D). Inhibition of PDE4 has been validated as a treatment strategy by many research groups in the Fragile X field, but non-selective PDE4 inhibitors have been associated with significant GI side-effects that have limited those drugs’ use. As a selective inhibitor, such side-effects were not seen for BPN14770 in a Phase 1 clinical trial in healthy young and elderly adults.

In the current study, daily treatment of Fragile X knock-out (FXS) mice with BPN14770 showed a reduction in hyperarousal, improved social interactions and natural behaviors, and changes in nerve structure in the prefrontal cortex of the brain, the portion of that brain associated with cognition. Moreover, the drug’s benefit persisted for two weeks after all drug was cleared from the mice. At the same time, the behavior of normal mice treated with the drug remained unchanged. Examination of neurons from the prefrontal cortex of the treated FXS mice showed an improvement in dendritic spine morphology. What should clinicians and patients take away from your report?

Response: BPN14770 has shown potential as a treatment for Fragile X, the most common inherited cause of autism, in the standard mouse model of the disease. It improved multiple aspects of the behavioral disorder.

This research suggests that BPN14770 may be useful in the treatment of Fragile X, and potentially other conditions on the autism spectrum. A Phase 2 clinical trial of BPN14770 in Fragile X is planned for the first half of 2018. What recommendations do you have for future research as a result of this study?

Response:  One of the earliest biochemical changes identified in patients with Fragile X was a decrease in the amount of cAMP produced in tissues. BPN14770, through inhibition of PDE4D, has been shown to increase cAMP in normal mice. This benefit of BPN14770 needs to be explored in the mouse Fragile X model and potentially provides a translational biomarker for BPN14770 therapeutic benefit in Fragile X patients. Is there anything else you would like to add?

Response:  Tetra Discovery Partners is also planning to initiate a Phase 2 clinical study of BPN14770 as a potential treatment to aid memory and cognition in Alzheimer’s disease patients during 2018. Thank you for your contribution to the community.


Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D)

Mark E. Gurney, Patricia Cogram, Robert M Deacon, Christopher Rex & Michael Tranfaglia

Scientific Reports 7, Article number: 14653(2017)

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.


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Last Updated on November 7, 2017 by Marie Benz MD FAAD