Millions of patients are burdened by AD, yet no new therapeutics have evolved to improve symptoms, let alone slow progression, despite two decades of intensive R&D. Approved older drugs marginally reduce cognitive symptoms, with limited response durability.

At CuraSen, we contend that these failures to treat complex brain diseases derive from well-intentioned, but misplaced focus on non-causal pathologic substrates, single genes, or single cell types.  All of these approaches have failed repeatedly in the large, heterogeneous AD population. 

Creating therapies for neurodegenerative disease demands appreciation of cerebral complexity, and pursuit of heterocellular approaches.  Such treatments should target the earliest vulnerabilities undermining patients’ brains, occurring decades before symptoms manifest.  With this ‘rethinking’ mindset, CuraSen targets restoring the pathway of earliest decline, the 'adrenergic system', and lost impact in higher brain areas, following deterioration of its cellular origins, called the locus coeruleus (LC): the ‘hypocenter’ of neurodegeneration, and earliest localization of neuronal loss and ’tangle’ pathology in AD.

Restoring adrenergic impact offers clinically precedented recovery of cognitive symptoms, via effects known to be supported by this pathway: improved attention, arousal, memory, executive function, mood.  Known adrenergic enhancing drugs are moderately efficacious in treating inattentiveness (ADHD) and depression, but indirectly mediated impact can be heightened in AD using direct acting agonists.   Shorter duration studies (1-3 months) can demonstrate symptom benefit and potentially lead to initial regulatory approval and patient relief, with longer term studies ultimately be needed to elucidate potential for slowing or stalling disease progression.

CuraSen’s unique approach restores LC impact using specific agonists for two of nine adrenergic receptors (β₂-, & α_1A-AR) identified within CuraSen to mediate cognitive signals and maintain brain health.  The first is targeted currently in two Ph2 studies in AD using two distinct agonists (CST-103 and CST-2032).  The second is the subject for this proposal, supporting preclinical and clinical advancement of a novel α_1A-AR agonist, CST-3056.