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A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease.

ABSTRACT: Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1^+/- and Ccm3^+/- mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1^+/- and Ccm3^+/- transgenic mice were treated for 3 (Ccm3^+/-) or 4 months (Ccm1^+/-), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3^+/-Trp53^-/- lesions. Ccm1^+/-Msh2^-/- (n=68) and Ccm3^+/-Trp53^-/- (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.

SUBMITTER: McKerracher L

PROVIDER: S-EPMC7036327 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesRespiratory Syncytial Virus (RSV) is a leading cause of death and hospitalization among infants and young children. People with an immunocompromised status are also at risk for severe RSV infection. There is no specific treatment for RSV infection available. Ribavirin, an antiviral drug approved for severe lung infection by RSV, has shown limited clinical efficacies with severe side effects. Additionally, given the genetic variability of RSV genomes and seasonal change of different strains, a broad-spectrum antiviral drug is highly desirable. The RNA-dependent RNA polymerase (RdRp) domain is relatively conserved and indispensable for the replication of the virus genome and therefore serves as a potential therapeutic target. Previous attempts to identify an RdRp inhibitor have not been successful due to lack of potency or high enough blood exposure. DZ7487 is a novel orally available small molecule inhibitor specifically designed to target the RSV RdRp. Here we present our data showing that DZ7487 can potently inhibited all clinical viral isolates tested, with large safety margin predicted for human.MethodsHEp-2 cells were infected by RSV A and B. Antiviral activities were assessed by in vitro cytopathic effect assay (CPE) and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). DZ7487 antiviral effects in lower airway cells were evaluated in A549 and human small airway epithelial cells (SAEC) cells. DZ7487 induced RSV A2 escape mutations were selected through continuous culture with increasing DZ7487 concentrations in the culture medium. Resistant mutations were identified by next generation sequencing and confirmed by recombinant RSV CPE assays. RSV infection models in both BALB/c mice and cotton rats were used to evaluate DZ7487 in vivo antiviral effects.ResultsDZ7487 potently inhibited viral replication of all clinical isolates of both RSVA and B subtypes. In lower airway cells, DZ7487 showed superior efficacy than the nucleoside analog ALS-8112. Acquired resistant mutation was predominantly restricted at the RdRp domain resulting asparagine to threonine mutation (N363T) of the L protein. This finding is consistent with DZ7487's presumed binding mode. DZ7487 was well tolerated in animal models. Unlike fusion inhibitors, which can only prevent viral infection, DZ7487 potently inhibited RSV replication before and after RSV infection in vitro and in vivo.ConclusionsDZ7487 demonstrated potent anti-RSV replication effect both in vitro and in vivo assays. It has the desired drug-like physical properties to be an effective orally available anti-RSV replication drug with broad spectrum.

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A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease.

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