McPherson, W. K. | Search bioRxiv

bioRxiv2024

Truncated Complement Factor H Y402 Gene Therapy Cures C3 Glomerulonephritis

Patients with both age-related macular degeneration (AMD) and C3 glomerulonephritis (C3G) are challenged by the absence of effective therapies to reverse and eliminate their disease burden. Capitalizing on complement dysregulation as both a significant risk factor for AMD and the known pathophysiology of C3G, we investigated the potential for adeno-associated virus (AAV) delivery of complement factor H (CFH) to rescue C3G in a Cfh-/- mouse model of C3G. While past efforts to treat C3G using exogenous human CFH resulted in limited success before immune rejection led to a foreign protein response, our findings demonstrate the capacity for long-term AAV-mediated delivery of truncated CFH (tCFH) to restore inhibition of the alternative pathway of complement and ultimately reverse C3G without immune rejection. Comparing results from the administration of several tCFH vectors also revealed significant differences in their relative efficiency and efficacy. These discoveries pave the way for subsequent development of AAV-mediated tCFH replacement therapy for patients with C3G, while simultaneously demonstrating proof of concept for a parallel AAV-mediated tCFH gene augmentation therapy for patients with AMD.

pathology↗

bioRxiv2022

Dietary sugar and protein exert opposing effects on key larval growth and metabolic regulators, the Drosophila insulin-like peptides Dilp2 and Dilp6.

Nutrient intake drives secretion of insulin and insulin-like peptides that stimulate glucose uptake, nutrient storage, protein synthesis and cell growth. The Drosophila genome encodes seven insulin-like peptides (Dilps) that bind to a single known insulin receptor to drive growth and nutrient storage. Whether Dilps respond uniformly to changes in dietary nutrients is unknown. Here we characterized the endocrine response to starvation and dietary sugar and protein in mid-third instar Drosophila larvae, measuring circulating Dilp2, derived from insulin-producing cells in the brain, and Dilp6, produced by the fat body. Starvation led to a 90% reduction in circulating Dilp2 without affecting circulating Dilp6 levels. Dietary protein, but not sugar, restored hemolymph Dilp2 from starved levels, while elevated and imbalanced ratios of sugar to protein led to modest reductions in circulating Dilp2. In contrast, hemolymph Dilp6 was increased by a sugar-only diet. Surprisingly, dietary protein strongly reduced circulating Dilp6 levels. Dietary sugar drives glycogen and triglyceride storage, and levels of these stored nutrients positively correlate with Dilp6. Protein in the diet promotes whole-animal growth, which correlates strongly with circulating Dilp2. Our data show that Dilp2 and Dilp6 secretion are regulated in opposite ways by distinct dietary nutrients. These findings raise the question of how the single known insulin receptor integrates divergent signals from distinct Dilps to control growth and metabolism.

physiology↗