Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia

Abstract

Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.

Capturing the biology of disease severity in a PSC-based model of familial dysautonomia

“…Conditional knockout mouse models suggest that phenotype severity is a direct result of ikap levels 28,29 . To determine the role of IKBKAP expression on disease severity in human FD patient samples, we first looked at the effect on IKBKAP splicing.…”

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

“…The FD mutation leads to reduced DRG size and number [13,18–20,62]. We first utilized CKO Tyrp2 FD mice to analyze how the loss of IKBKAP disrupts DRG development and survival.…”

“…The conditional knockout of IKBKAP using a Cre expression system under control of the Wnt-1 promoter resulted in mice that died a few days after birth [20,44]. Recently a combined heterozygote model in which one IKBKAP allele is knocked-in with the FD mutation and the second is knocked-out resulted in a mouse that recapitulates many phenotypic features of FD and recreates the same tissue-specific mis-splicing defect seen in FD patients [62]. As IKAP depletion occurs early in embryogenesis in these mice, the roles of IKAP in DRG development and early differentiation cannot be separated from its role in neurodegeneration.…”

Familial Dysautonomia: Mechanisms and Models

“…The introduction of the human IKBKAP FD transgene attenuated the severe FD phenotype observed in the Ikbkap Δ 20/flox mouse, while still recapitulating FD major features and recreating the same tissue-specific missplicing defect seen in FD patients (Morini et al , 2016). With the availability of mouse models that faithfully recapitulate major features of FD, several questions regarding FD disease process as well as testing of novel therapeutic strategies can now be addressed in vivo .…”