Our Science & Pipeline
A focus on complex selectivity
Histone deacetylases (HDACs) are a key class of proteins that are involved in chromatin remodeling and gene expression, and have been shown to regulate synaptogenesis and synaptic plasticity. There are 18 different HDAC enzymes in humans; several affect the expression of genes responsible for the creation and maintenance of synapses.
Inhibiting these HDACs activates a crucial switch that controls genes central to learning and memory. That makes HDAC inhibitors an attractive target for drug developers. But HDAC inhibitors are known to have dose limiting side effects and historically have not been used for long-term treatment of neurologic disorders.
At Rodin, we are designing compounds that selectively inhibit only specific HDAC complexes to drive increased neuronal gene expression while minimizing known class-based safety concerns.
Our initial focus is the HDAC-CoREST complex, which has been shown to be involved in repressing neuronal gene expression. Specific inhibition of the HDAC-CoREST complex reactivates neuronal gene expression, strengthens existing synapses and promotes the creation of new synapses, while minimizing dose-related side effects. This approach is further detailed in our recent publication.
Positive effects on synaptic integrity on multiple levels
Our lead compound, RDN-929, is a potent and selective inhibitor of the HDAC-CoREST complex, with a preclinical safety profile that should allow long-term dosing as a therapeutic for chronic neurologic diseases. Our data clearly demonstrate that RDN-929 show strong pro-synaptic pharmacological effects on multiple levels:
- Molecular: The synaptic protein, SV2A, which signals synaptic density, is increased in preclinical models following administration of our lead candidate, RDN-929
- Structural: Treatment with RDN-929 leads to significant, dose-dependent increases in the number of dendritic spines in multiple species
- Functional: Synapses are functionally strengthened in transgenic mice with neurodegenerative pathology after treatment with RDN-929; this significant improvement in long-term potentiation leads to long-lasting increases in synaptic efficacy and signal transmission –- the foundations of learning and memory
FTD-GRN (Frontotemporal dementia – Granulin)
Our second program focuses on FTD-GRN where we have shown that a different HDAC complex selective profile increases the levels of progranulin both in vitro and in vivo.