Selecting the right therapeutic target for kidney disease.

Kidney disease is a complex disease with several different etiologies and underlying associated pathophysiology. This is reflected by the lack of effective treatment therapies in chronic kidney disease (CKD) that stop disease progression. However, novel strategies, recent scientific breakthroughs, and technological advances have revealed new possibilities for finding novel disease drivers in CKD. This review describes some of the latest advances in the field and brings them together in a more holistic framework as applied to identification and validation of disease drivers in CKD. It uses high-resolution 'patient-centric' omics data sets, advanced in silico tools (systems biology, connectivity mapping, and machine learning) and 'state-of-the-art' experimental systems (complex 3D systems in vitro, CRISPR gene editing, and various model biological systems in vivo). Application of such a framework is expected to increase the likelihood of successful identification of novel drug candidates based on strong human target validation and a better scientific understanding of underlying mechanisms.

Rapid Production of Human VEGF-A following Intradermal Injection of Modified VEGF-A mRNA Demonstrated by Cutaneous Microdialysis in the Rabbit and Pig In Vivo.

Chemically modified mRNA is a novel, highly efficient, biocompatible modality for therapeutic protein expression that may overcome the challenges and safety concerns with current gene therapy strategies. We explored the efficiency of intradermally injected modified VEGF-A165 mRNA (VEGF-A mRNA) formulated in a biocompatible citrate/saline buffer to locally produce human VEGF-A165 protein. Rabbits (n=4) and minipigs (n=3) were implanted with subcutaneous microdialysis probes close to the injection sites and interstitial-fluid samples and skin biopsies were analysed for production of VEGF-A protein over time for up to 8 hours. Three to 4 hours after the intradermal injection of VEGF-A mRNA, detectable levels of human VEGF-A protein were seen in the microdialysis eluates in both species. In the pig, the VEGF-A concentrations increased dose-dependently reaching a maximum 6 hours after dosing (62.7±28.4, 357.6±240.6, and 746.3±210.2 pg/mL following injection of 24, 120, and 600 µg VEGF-A mRNA, respectively). Likewise, in tissue biopsies harvested at study end (8 hours after VEGF-A mRNA injection), the content of VEGF-A protein increased dose-dependently. In contrast, VEGF-A protein was not detected in eluates originating from sites injected with citrate/saline vehicle. It is concluded that intradermal injection of VEGF-A mRNA is associated with a rapid and local production of VEGF-A protein. Considering the pro-angiogenic effect of VEGF-A, VEGF-A mRNA may hold promise for regenerative treatment of patients with diabetic wounds and ischemic cardiovascular disease.