AAV vector-mediated gene therapy for cystinuria type B

About This Grant

PROJECT SUMMARY Urinary stone disease (urolithiasis) is a prevalent and global health issue, affecting approximately 9% of the U.S. population and over 10% in many developed countries. Due to lifestyle changes and global warming, the prevalence of urolithiasis has been increasing. Cystinuria, characterized by an abnormal elevation of cystine concentration in the urine, is the most common monogenic cause of urolithiasis and significantly contributes to the disease burden, accounting for approximately 10% of pediatric cases and affecting 1 in 7,000 births worldwide. This condition is caused by biallelic loss-of-function mutations in the SLC3A1 gene (type A) or the SLC7A9 gene (type B), which encode the two components of the b(0,+)-type amino acid transporter, rBAT and b0,+AT, respectively. This transporter is expressed exclusively in proximal tubes of the kidney and responsible for cystine and dibasic amino acid reabsorption from urine. Due to the poor solubility of cystine at high urinary concentrations, patients with cystinuria suffer from recurrent formation of cystine caliculi in the urinary tract starting in childhood or adolescence, which leads to progressive kidney damage and significant reductions in quality of life. Current conversative treatments including hyperhydration, urinary alkalization, dietary restrictions, and pharmacological treatments, have limited efficacy and are often poorly tolerated due to side effects. As a result, patients require repeated surgical interventions for stone removal, which also has the risk of progressive impairment of renal functions . Therefore, there is an urgent and unmet need for innovative therapies that address the root cause of cystinuria and offer a potentially cure. To make breakthroughs in this field, this grant proposal aims to develop clinically applicable novel AAV vector-mediated gene therapy for cystinuria, with a focus on cystinuria type B (CysB) as the prototype for the therapy. The proposal builds upon data from preliminary studies conducted in mice and non-human primates (NHPs), demonstrating the feasibility of AAV vector-mediated gene therapy for CysB, and sets the following three specific aims to achieve the goal. We will seek to discover AAV capsids that outperform the current benchmark capsid in PT transduction via RP delivery, while evading neutralizing antibodies (NAbs) and minimizing off-target transduction (Aim 1). We will optimize therapeutic payloads for AAV RP injection-mediated gene replacement therapy for CysB using a CysB mouse model (Aim 2). We will evaluate dose-response, biodistribution, and safety of optimized therapeutic AAV vector in NHPs to facilitate future clinical translation of AAV vector-mediated CysB gene therapy (Aim 3). Successful outcomes will provide a transformative therapy for CysB by targeting its root cause and eliminating the need for burdensome conservative measures, medications with side effects, and repeated surgical interventions. In addition, this work will have the potential to revolutionize treatment not only for other types of cystinuria but also for other kidney diseases affecting renal tubules, regardless of whether they have genetic or non-genetic etiologies.