ciliary neurotrophic factor (cntf) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RnA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of cntf treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod-and cone-specific gene expression. in addition, cntf triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RnA-seq data revealed the cntf responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous cntf on the retinal transcriptome landscape and illuminate likely cntf impacts in degenerating human retinas. Retinal degeneration (RD) is known as an irreversible, progressive neurologic disorder caused by genetic mutations and/or environmental or pathological damage to the retina. One therapeutic strategy to attenuate vision loss in disease conditions is treating the retina with neuroprotective agents that promote neuronal viability. Ciliary neurotrophic factor (CNTF) has been shown to be a potent neuroprotective agent for various types of retinal degenerations, including those caused by gene mutations, light-induced damage, and physical injury 1. Since CNTF enhances the survival of both photoreceptors and retinal ganglion cells, the two major cell classes damaged in retinal degenerative diseases, a CNTF-based therapy has been developed and tested in several clinical trials. To date, outcomes of the trials for retinitis pigmentosa, geographic atrophy, and achromatopsia have not demonstrated sufficient therapeutic benefits for human patients 2-5. However, CNTF therapy for macular telangiectasia type 2 has shown efficacy 6,7 , and a clinical trial for the second largest blinding disease glaucoma 8 is ongoing (https://clinicaltrials.gov/ct2/show/NCT01408472). To shed light on the molecular and cellular mechanisms of CNTF-mediated neuroprotection, we have delivered the same secreted recombinant CNTF used in human trials to a mouse model expressing the Rds/peripherin2 (Prph2) transgene with the P216L mutation 9. Pheripherin2 is a structural protein of the photoreceptor outer segment disc, and over 80 PRPH2 pathological mutations have been linked to RD, with...