Inhibiting the HDAC6 enzyme with an experimental agent called SW-100 improved memory and lowered learning impairments in a mouse model of fragile X syndrome (FXS), a study has shown.
The study, “Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome,” was published in the journal ACS Chemical Neuroscience.
FXS is a genetic disease caused by mutations in the FMR1 gene, which disrupts the production of a functional FMRP protein. It is not fully clear how FMRP works, but it is believed to regulate the trafficking of RNA molecules and communication between nerve cells.
Therapies targeting one mediator of nerve cell communication associated with FMRP signals, called metabotropic glutamate receptors (mGluRs), have been proposed as a potential strategy to treat FXS. Despite positive preclinical results, the investigational compounds have failed to improve the outcome of human FXS patients in Phase 2 clinical trials.
Given the lack of an effective treatment for fragile X patients, other targets have been proposed for the development of new therapeutic strategies.
Results from a previous study revealed that treatment with valproic acid, an unspecific histone deacetylase (HDAC) inhibitor, could lessen the symptoms of attention deficit hyperactivity disorder in boys with FXS. However, the treatment could not improve the levels of FMRP protein.
Supported by these results and additional evidence of HDAC enzymes’ neuroprotective effect on other diseases, researchers evaluated the potential of inhibiting the HDAC6 enzyme for fragile X treatment. The team selected this particular enzyme due to its role in the regulation of genetic transcription (the first step of gene expression, which eventually leads to the production of proteins) and molecular trafficking.
Researchers developed a molecule with the ability to penetrate the brain-blood-barrier and subsequently, the brain. Called SW-100, this molecule can specifically inhibit the activity of the HDAC6 enzyme.
Experiments in a mouse model of fragile X syndrome, which shares several symptoms with those reported in FXS patients, showed that daily treatment with SW-100 could reverse impairment in coordinate spatial processing — processing metric distances — and in categorical spatial processing — which does not require computation of precise distances (e.g., above, below, touching, not touching).
In addition, SW-100 effectively improved memory and learning capacity in mice, as demonstrated by animals’ improved ability to recognize new objects and memorize temporal orders.
The team believes that these results provide “a strong rationale for pursuing HDAC6-based therapies” for the treatment fragile X.
“Further improvements in compound design will lead to drug candidates that can be tested in humans,” they concluded.