383 Preclinical safety and pharmacology of KB105, an HSV-based gene therapy vector for the treatment of autosomal recessive congenital ichthyosis (ARCI)

Abstract

ARCI, a heterogenous group of rare cornification diseases, is most commonly caused by mutations in Transglutaminase 1 (TGM1), an enzyme responsible for formation of the cornified envelope. Loss of TGM1 function results in an impaired epidermal barrier with dramatically increased trans-epidermal water loss often resulting in clinical dehydration; TGM1 deficiency also increases risk of skin malignancies. Current therapeutic options for treating ARCI provide limited symptomatic relief without addressing the underlying genetic defect, necessitating novel targeted therapeutics. We have developed KB105, a replication-defective HSV-1 gene therapy vector encoding human TGM1 for molecular correction of ARCI. Here we show that KB105 is both safe and effective for topical delivery of functional TGM1 in vivo. Preclinical evaluation was conducted in BALB/c mice since homozygous deletion of TGM1 is neonatal-lethal. Mouse skin was compromised using tape stripping or acetone to simulate ARCI-mediated barrier impairment. A dose-dependent increase in TGM1 expression was observed in mouse epidermis upon topical application of KB105 as early as 8 hours post-application, peaking around 48 hours post-application. Significantly, the exogenous TGM1 co-localized with its native substrate loricrin, which maintains cornified envelope integrity, indicating that KB105 successfully transduced the targeted epidermal layer. A fluorometric in situ assay employing a synthetic TGM1 substrate demonstrated increased transglutaminase activity in KB105-treated mouse skin, confirming functionality of the human transgene. In a repeat dose GLP toxicology study in the same species, KB105 was well tolerated and remained localized to the application site with no systemic exposure. Altogether, these data, along with robust in vitro efficacy data, support the use of KB105 as a topical gene therapy for the treatment of ARCI. Phase 1 clinical trials are anticipated to begin in the first half of 2019.