Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia

Abstract

Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspects of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; IkbkapΔ20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477.

Development of a novel oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia

“…5A). As previously reported 59 , the FD mice at three months of age did not yet show a significant loss in RGC (Fig. 5B).…”

“…Mice were maintained in the same treatment regime for the entire trial duration and were sacrificed at 6 months of age for tissue collection. Our previous studies in the FD mouse show that by 6 months of age the disease phenotype is evident and quantifiable 56,59 . We started the treatment at birth to maximize the therapeutic value, and a preliminary study that assessed ELP1 expression in transgenic pups after PTC258 treatment showed that this compound can pass from dams to pups through lactation and increase the functional ELP1 protein amounts in the pups (Supplementary Fig.…”

“…They often become visually impaired or legally blind after their third decade of life 35,36 . Postnatal retinal degeneration was also recapitulated in different mouse models of FD 59,84 . Supporting the idea that starting the treatment at birth can be sufficient to prevent this aspect of the disease.…”

“…High-definition spectral-domain optical coherence tomography (SD-OCT) was used to measure the thickness of the RFNL and the ganglion cell-inner plexiform layer (GCIPL) in the superior, inferior, nasal, and temporal hemispheres of the mouse retina (Fig. 3A) 59 . At both ages, three and six months, we observed a significant reduction of the RNFL (Fig.…”

“…Our team identified the small molecule kinetin (6-furfurylaminopurine) as an orally active splicing modulator of ELP1 both in vitro and in vivo 57,58 . As part of the NIH Blueprint Neurotherapeutics Network, we have improved kinetin potency and efficacy and generated a more potent and efficacious ELP1 splicing modulator, BPN-15477 59,60 . More recently, our collaboration with PTC Therapeutics, Inc. led to the generation of a new class of highly potent SMCs, using BPN-15477 as a starting molecule, and to the identification of the novel compound PTC258.…”