Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is a rare genetic neurodevelopmental disorder characterised by moderate to severe mental retardation. In FXS several cognitive processes are affected, including short-term memory, visual memory and visual-spatial relationships. Patients also present a number of neurological symptoms: hyperactivity, anxiety, attention deficit and epileptic seizures. Severely affected males, may acquire only rudimentary language skills and more than 50% have autism spectrum disorder. Other characteristics of the disease are large testicles (macroorchidism), and distinct facial features, including long face, large ears, prominent jaw, hypermobility of finger joints, flat feet and hypotonia.
FXS is caused by an expansion of a CGG repeat sequence in the promoter region of the FMR1 gene, which is located on chromosome X and encodes the fragile X mental retardation 1 protein (FMRP). Expansion of the CGG repeat beyond 200 repeats leads to methylation and full or partial silencing of the gene FMR1 (depending on the degree of methylation). FMRP is a translational modulator of synaptic proteins and participates in the nucleocytoplasmic shuttling of mRNA, mRNA transport at the synapse and dendritic mRNA localization. Thus, in FXS, neurons exhibit abnormal dendritic spines associated with altered forms of synaptic plasticity. The abundance of proteins at the synapse is altered in the absence of FMRP and consequently several molecular pathways are dysregulated in FXS neurons. FMRP is highly expressed in all brain regions in both neurons and glial cells and as a translational regulator, it acts both as a repressor and as an enhancer of translation.
In FXS, supportive behavioural treatment and some medications addressing symptoms are available. However, specific therapeutic options that target the underlying disorder or treat intellectual disability in FXS are not yet available. Several preclinical and clinical trials of a number of potential disease-targeting strategies have proven unsuccessful, and thus, approved therapies for FXS are not yet available.
Decreased levels of cyclic AMP (cAMP) have been consistently found altered in patients and FXS animal models. Interestingly, in mouse and Drosophila FXS models, cAMP is decreased in the brain and pharmacological manipulations that restore cAMP levels, reversed behavioural deficits. cAMP is synthesised by the activity of adenylate cyclase and is degraded by phosphodiesterase (PDE) activity. PDE4 is the most abundant cAMP-specific PDE in the brain of flies and mammals, and pharmacologic inhibition of PDE4 in the fly, rescues memory as structural brain defects in the FXS Drosophila model.
BNP14770, is a selective inhibitor of PDE4D and its use in a mouse model of FXS, ameliorates multiple behavioural phenotypes, including hyperactivity and social interaction. Behavioural improvement seems to be associated with changes in the structure of dendritic spines in specific neurons. The effects of BNP14770 have been found long lasting and promising in preclinical studies, therefore clinical trials have begun on patients.
With the support of FRAXA research Foundation, Dr. Elizabeth Berry-Kravis at Rush University Medical Center in Chicago-USA and Tetra Therapeutics, have performed an exploratory, phase 2, randomized study that aimed at determining whether BPN14770 could improve cognitive functions and behavioural outcomes in patients with FXS (see reference below). The study included 30 adult male patients (age 18-41 years) with FXS that received a 25 mg dose of either BPN14770 or placebo twice daily during a 24-weeks period.
The primary outcome measures of the study, were safety and tolerability. In this regard, the dose utilized of BPN14770 was well tolerated and no significant adverse effects were reported. A significant improvement in language and daily functioning, were found using direct, computer-based assessment of cognitive performance, indicating significant cognitive improvement. Based on the results, the planning process has begun for a large phase 3 trial of this drug on Fragile X.
Berry-Kravis EM, Harnett MD, Reines SA, Reese MA, Ethridge LE, Outterson AH, Michalak C, Furman J, Gurney ME. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nat Med. 2021 May;27(5):862-870. doi: 10.1038/s41591-021-01321-w.