Assessing the potential of DZIP1L gene in autosomal recessive polycystic kidney disease gene therapy

I read with interest the recent review by Lu et al. (Gene therapy for pediatric genetic kidney diseases. Pediatr Discov. 2023; 1(1):e16) and congratulate the authors for their comprehensive review.1 The authors stated that PKHD1 is currently the only known disease-causing gene for autosomal recessive polycystic kidney disease (ARPKD). However, while PKHD1 is the primary gene implicated in ARPKD, it has been shown that DZIP1L is the second gene involved in the disease pathogenesis and is associated with a moderate form of ARPKD.2-4 The role of DZIP1L in ARPKD is also widely discussed in the review referenced by the authors to support their claim.5 Moreover, while it is a rarer cause of the disease, the DZIP1L gene has several advantages over PKHD1 in the development of gene therapy for ARPKD. In 2017, Lu et al. sequenced 743 patients presenting with suspected ARPKD or sporadic PKD. This investigation unveiled DZIP1L mutations as the causative factor underlying an ARPKD-like phenotype in 7 patients from 4 consanguineous families.2 The study also demonstrated that the DZIP1L protein localized to centrioles and the basal bodies of primary cilia, and ciliary trafficking of polycystin-1 and polycystin-2 was impaired in DZIP1L-mutant cells.2, 3 Concordantly, Hertz et al. recently reported 4 ARPKD patients with DZIP1L mutations from 3 consanguineous families.4 Given the extensive length of PKHD1, with its product named fibrocystin consisting of 4074 amino acids, it is not possible to package the cDNA of the gene into a single, or even dual, adeno-associated virus (AAV) vector, which is the most commonly used vector for in vivo gene delivery for inherited diseases.6 Moreover, PKHD1-associated ARPKD is often accompanied by congenital hepatic fibrosis, necessitating that any gene therapy developed for the disease would also target the biliary epithelium.3 Therefore, exceeding the packaging capacity of AAV vectors and the challenges of efficiently targeting both the liver and kidneys may hinder the progress of genomic medicines in treating PKHD1-associated ARPKD. Although being a rarer cause of the disease, the smaller size of the DZIP1L gene and its protein consisting of 767 amino acids offer a remarkable advantage for gene therapy applications by overcoming the AAV packaging limitations faced by PKHD1. Furthermore, liver involvement in the form of hepatosplenomegaly was reported for only one of the 11 patients with DZIP1L mutations, and the patients with truncating mutations showed no apparent hepatic complications.2, 4 While it is required to characterize more patients with diverse DZIP1L mutation profiles to establish phenotypic characteristics of DZIP1L-associated ARPKD, the available data suggest that liver involvement in DZIP1L-associated ARPKD might be less frequent and milder than PKHD1-associated ARPKD. Therefore, it might be sufficient for patients with DZIP1L mutations to target the kidneys using local delivery routes, such as retrograde ureteral or renal vein injection, which may enable more efficient and specific gene delivery to the kidneys.7, 8 The potential for gene therapy in DZIP1L-associated ARPKD will become more evident as new cohorts of patients with DZIP1L mutations are reported and the phenotypic features of the disease are characterized in more detail. Further research is warranted to fully assess the therapeutic potential of DZIP1L-based gene therapy strategies and advance the development of genomic medicines for ARPKD. The author declares no competing interests. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.