Abstract
Purpose :
In humans, neurofibromatosis type 1 (NF-1) associated with global heterozygous loss of one NF-1 allele is associated with many debilitating signs and symptoms, including optic pathway gliomas and vision loss. A large animal genetic model of NF-1 would greatly aid translational research into therapeutics. Here we investigate retinal and visual pathway structural and functional measures in a porcine model of NF-1 deficiency.
Methods :
A total of 16 Ossabaw pigs (12 NF-1 heterozygote and 4 age-matched wild type littermates) (Recombinetics, Inc.) underwent fundus photography, intraocular pressure (IOP) measurement, visually evoked potential (VEP) measurement, and magnetic resonance imaging (MRI) of the optic nerve, chiasm and brain. Retinas were immunostained, imaged and quantified for retinal ganglion cell (RGC) -specific marker RBPMS. Results were tabulated using descriptive statistics and differences described using unpaired T-test statistics.
Results :
All NF-1-heterozygote pigs evidenced cafe au lait spots (Figure 1A), confirming genotype penetrance. The mean ages of NF-1- heterozygote and wild type littermates were 11.63 ± 0.35 and 11.71 ± 0.43 months, respectively. The mean weights of NF-1-deficient and wild type littermates were 71.77 ± 1.86 and 76.88 ± 2.13 kg, respectively. MRI showed no gliomas detected on optic nerve, chiasm or brain (Figure 1B). IOP was elevated 42% in the NF-1 group compared to the control group (17.83 mmHg vs 12.54 mmHg, respectively; P=0.0416; Figure 1C). Mean VEP amplitude was 32% higher in the NF-1 group compared to controls (P=0.0921; Figure 2A). All fundus images appeared normal and showed no anatomic differences (Figure 2B). RGC counts in the higher density visual steak showed no differences between genotypes, but the surrounding retina of the NF-1-heterozygote group showed 24% fewer RGCs than in controls (P=0.0003; Figure 2C).
Conclusions :
NF-1-heterozygote pigs show cafe au lait spots, slightly higher IOP, no gliomas, no loss of VEP, and no optic nerve head changes, but a 24% decrease in peripheral RGCs. Future work should assess whether this represents failure to differentiate these RGCs during early development, or a neurodegenerative loss over time. These data suggest that NF-1 heterozygosity in a porcine model may confer advantages for further study of this model, aiding in translational research for this disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.