Genetic Therapies for Autosomal Dominant Polycystic Kidney Disease

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Project Summary/Abstract Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disease with a prevalence of approximately one in one thousand live births. ADPKD is a progressive disease in which patients develop fluid-filled cysts in their kidneys throughout their lifetimes, gradually lose kidney function, and which can end in kidney failure. ADPKD can be caused by mutations in either the PKD1 gene (encoding polycystin-1 or PC-1) or the PKD2 gene (encoding polycystin-2 or PC-2). PKD1 mutations account for approximately 78% of ADPKD cases. Mutations in PKD2 account for most of the remaining cases. The severity of the cysts that develop in the kidneys of an ADPKD patient increases over the lifetime of the patient. While younger patients may experience no symptoms and perhaps not realize they are genetically susceptible to ADPKD, older patients develop decreased renal function characterized by an increase in total kidney volume (TKV) and decreased glomerular filtration rate (GFR), which can culminate in end-stage renal disease (ESRD). There is currently no cure or long-term treatment for ADPKD. Homozygosity for loss of function PKD1 mutations or PKD2 mutations is embryonic lethal. Patients who are heterozygous for mutations in either PKD gene generally develop ADPKD. Because of this, ADPKD is a potential candidate for treatment by gene therapy. While the disease was defined as autosomal dominant, recent studies indicate that ADPKD pathogenesis may be caused by haploinsufficiency of either polycystin-1 or -2. It may therefore be possible to treat ADPKD by restoring polycystin gene dosage to a wild type level. In recessive genetic diseases, portions of proteins may be mutated or lost making the wild-type protein immunogenic in patients. In theory, this will not be a problem for ADPKD due to the fact that the patient's immune system is tolerized to normal polycystin proteins that are provided throughout life by the undamaged copies of PKD1 and PKD2 genes. The current project proposal will attempt to restore PKD1 expression to wild type levels by delivering cDNA of the gene using helper-dependent adenovirus (HD-Ad) vectors and by delivering smaller transcriptional activators using adeno-associated virus (AAV) and lentiviral (LV) vectors.