The FIGHT-RP1 Study

Retinitis Pigmentosa (RP) is a devastating eye disease and at present there are no known
treatment options that can alter the rate of vision loss. In a series of studies in animal
models, the effects of exposing cones in the periphery of the retina to a large excess of
oxygen results in progressive oxidative damage to cone photoreceptors and cone cell death.
Compared to control patients, those with RP showed significant reduction in the reduced to
oxidized glutathione ratio (GSH/GSSG) in aqueous humor and a significant increase in protein
carbonyl content. This demonstration of oxidative stress and oxidative damage in the eyes of
patients with RP, suggests that oxidative damage-induced cone cell death in animal models of
RP may translate to humans with RP and support the hypotheses that (1) potent antioxidants
will promote cone survival and function in patients with RP and (2) aqueous GSH/GSSG ratio
and carbonyl content on proteins provide useful biomarkers of disease activity in this
patient population. Orally administered N-Acetylcysteine (NAC) has been found to be a
particularly effective antioxidant that promotes prolonged cone survival and maintenance of
cone function in a mouse model of RP. There is good rationale to test the effect of NAC in
patients with RP. The first step is to do test different dosing regimens to identify the
lowest dose that is able restore aqueous GSH/GSSG ratio and reduce carbonyl adducts on
aqueous proteins.

In patients with Idiopathic Pulmonary Fibrosis, polymorphisms within the TOLLIP gene were
found to influence outcomes of NAC-treated patients. The product of the TOLLIP gene,
toll-interacting protein, is an inhibitory adaptor protein downstream of toll-like receptors,
mediators of innate and adaptive immunity. The identification of the influence of TOLLIP
polymorphisms on the effect of NAC in Idiopathic Pulmonary Fibrosis provides rationale for
collecting DNA and genotyping the same single nucleotide polymorphisms (SNPs) in the current
trial. In addition to this candidate gene genetic analysis, patient RNA will be collected and
banked for future transcriptome analysis. The rationale for this is to identify gene
expression changes that modify disease progression in RP. There is substantial variability in
rate of progression among patients with RP. A patient who loses all vision early in life can
have a sibling with the same mutation who maintains vision into advanced age. This suggests
that modifier genes can have a major impact on cone survival. This study will test the
hypothesis that the level of expression of gene products that contribute to the antioxidant
defense system may influence cone cell death and hence the rate of loss of visual field. It
is also possible that gene expression differences may contribute to differences in response
to NAC. For these reasons collecting RNA samples from patients will allow next generation
sequencing in the future to understand the transcriptome background on which the study
intervention has been performed.