ASP2905 / Astellas - LARVOL DELTA

Optimization of Exon-Skipping Riboswitches and Their Applications to Control Mammalian Cell Fate. (PubMed, ACS Synth Biol) - "In this study, we systematically optimized the design of a riboswitch that regulates exon skipping via an RNA aptamer that binds ASP2905...Furthermore, an optimized riboswitch was used to generate a mouse embryonic stem cell line that can be chemically induced to differentiate into myogenic cells by activating Myod1 expression and a human embryonic kidney cell line that can be induced to trigger apoptosis by activating BAX expression. The results demonstrate the tight chemical regulation of transgenes in mammalian cells to control their phenotype without exogenous protein factors."

Journal • BAX • MYOD1 • YOD1

Switchable and orthogonal gene expression control inside artificial cells by synthetic riboswitches. (PubMed, Chem Commun (Camb)) - "Here we report two novel synthetic riboswitches that respond to ASP2905 and theophylline and function in reconstituted cell-free protein synthesis (CFPS) system. We encapsulated the CFPS system as well as DNA-templated encoding reporter genes regulated by these orthogonal riboswitches inside liposomes, and achieved switchable and orthogonal control over gene expression by external stimulation with the cognate ligands."

Journal

A Novel Small Molecule-Aptamer Pair for Regulating Gene Expression In Vitro and In Vivo (ASGCT 2023) - "Existing systems (e.g., theophylline, tetracycline, guanine) require >0.1 mM of the trigger molecule to regulate gene expression, limiting their potential biomedical applications. The novel aptamer-ligand pair AC17-4/ASP2905 functions at low-micromolar concentrations in mammalian cell culture systems. In addition to riboswitches, our aptamer-ligand platform may be used to chemically regulate various RNA functions in mammalian cells."

Preclinical

Small-Molecule Aptamer for Regulating RNA Functions in Mammalian Cells and Animals. (PubMed, J Am Chem Soc) - "We conducted in vitro selection of RNA aptamers against a small molecule ASP7967 whose structure is closely related to ASP2905, a known inhibitor of potassium voltage-gated channel sub-family H member 3 (KCNH3)...An aptazyme-based riboswitch was successfully used to regulate human erythropoietin expression in mice injected with an adeno-associated virus (AAV8) vector using orally administered ASP7967. Furthermore, by combining aptazyme-based and exon-skipping riboswitch mechanisms, an ON/OFF ratio approaching 300 was achieved with a low basal expression level in cultured cells."

Journal • EPO

The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder. (PubMed, PLoS One) - "In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate."

Journal • Attention Deficit Hyperactivity Disorder • Biosimilar • Cardiovascular • CNS Disorders

ASP2905, a specific inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3 gene, is psychoactive in mice and rats. (PubMed, Behav Brain Res) - "ASP2905 inhibited hyperlocomotion induced by methamphetamine and by phencyclidine...The antipsychotic clozapine also reversed phencyclidine-induced prolonged immobility, while risperidone and haloperidol had no effect...In contrast, administration of clozapine did not ameliorate phencyclidine-induced prolongation of finding latency. Therefore, ASP2905 may alleviate the broad spectrum of symptoms of schizophrenia, including positive and negative symptoms and cognitive impairments, which is in contrast to currently available antipsychotics, which are generally only partially effective for ameliorating these symptoms."

Journal • Preclinical