Prevalence, Awareness, and Treatment of Elevated LDL Cholesterol in US Adults, 1999-2020.

PURPOSE: The photoreceptor outer segment is a highly specialized ciliary structure essential for phototransduction, rendering photoreceptors especially vulnerable to ciliary dysfunction. WDR34, a key component of the retrograde intraflagellar transport machinery, has been implicated in rod-cone dystrophy. However, the pathogenic mechanisms linking WDR34 deficiency to photoreceptor degeneration remain elusive. In this study we aim to investigate the in vivo function of Wdr34 in the photoreceptor cells using conditional knockout allele of Wdr34.

METHODS

We generated retina-specific Wdr34 knockout mice using rod-specific and cone-specific drivers to investigate the in vivo roles of WDR34 in photoreceptor maintenance.

RESULTS

Wdr34 deficiency in rod photoreceptors resulted in progressive rod cell degeneration accompanied by a marked decline in scotopic electroretinography (ERG) responses. Similarly, cone-specific Wdr34 ablation led to impaired photopic ERG responses and subsequent cone photoreceptor death. Transcriptomic profiling of Wdr34-deficient retinas revealed broad differential gene expression changes, with significant enrichment in axonemal integrity and microtubule-based transport. Notably, subretinal delivery of an adeno-associated virus vector expressing WDR34 significantly preserved rod photoreceptor structure and function, underscoring the therapeutic potential of WDR34 gene supplementation.

CONCLUSIONS

Our findings establish WDR34 as a critical factor for photoreceptor survival and function, emphasizing its role in the pathogenesis of WDR34-associated retinal degeneration. Moreover, this study demonstrates that WDR34-targeted gene therapy can effectively delay photoreceptor loss, highlighting a promising treatment strategy for patients with WDR34-related retinal disease.