Preclinical proof-of-concept for this approach using 1) human sCFH delivered systemically using an adeno associated virus (AAV) in a mouse model of atypical hemolytic uremic syndrome (aHUS) and 2) a mouse version of sCFH delivered using an AAV in mouse models of C3 glomerulopathy and aHUS each demonstrated recovery from complement dysregulation, reduced organ damage, and improved survival. Restoring CFH function using sCFH protein could restore normal complement regulation and reduce retinal injury that manifests as progressive GA. Song has extensive experience researching complement-mediated inflammatory, autoimmune, and thrombotic vasculopathy disorders. The construct was co-invented by Wenchao Song, Ph.D., Professor of Pharmacology at the Perelman School of Medicine at the University of Pennsylvania. SCFH is an engineered and optimized version of CFH that can fit into AAV vectors with robust expression and full functionality confirmed in human cells in vitro, and in multiple preclinical animal models and species in vivo. ![]() Mutations in the gene encoding CFH are among the strongest genetic risk factors for AMD including GA, with approximately 75% of patients carrying a high-risk variant of CFH with reduced complement inhibitory function, leading to complement pathway hyperactivity. Dysregulation of the complement system can lead to autoimmune and inflammatory diseases, including GA. 4D-175 is designed to achieve continuous expression of sCFH in the retina from a single injection in order to inhibit the inflammatory complement pathway in patients with GA without requiring repeated injections.Ĭomplement Factor H (CFH) is a master regulator of the complement system, functioning as a natural inhibitor of the alternative complement pathway. Thus, a treatment that achieves consistent expression of a therapeutic could lead to more optimal clinical outcomes. Challenges in adhering to monthly or every-other-month treatment for wet AMD can lead to suboptimal clinical outcomes, suggesting the same may be encountered in the treatment of GA. Similar treatment regimens with anti-VEGF agents for neovascular (wet) AMD have proven difficult to maintain. in February 2023 and is administered by intravitreal (IVT) injection once every 25 to 60 days. The first treatment for GA, complement inhibitor pegcetacoplan injection, was approved in the U.S. According to published estimates, there are over one million individuals with GA in the U.S. Geographic atrophy is a highly prevalent disease with a significant unmet medical need. The transgene encoding sCFH, a shortened and optimized form of a natural inhibitor of the inflammatory complement pathway invented at the University of Pennsylvania, will be combined with 4DMT’s proprietary retinotropic R100 vector to engineer the product candidate 4D-175 for treatment of GA secondary to AMD. ![]() Continues expansion of the proprietary R100 retinotropic vector-based large-market ophthalmology portfolio beyond 4D-150 for wet AMD and diabetic macular edema (DME)ĮMERYVILLE, Calif., Ap(GLOBE NEWSWIRE) - 4D Molecular Therapeutics (Nasdaq: FDMT, “4DMT”), a clinical-stage biotherapeutics company harnessing the power of directed evolution for genetic medicines targeting large-market diseases, today announced that it acquired the rights and know-how for short-form human complement factor H (sCFH) from Aevitas Therapeutics, Inc. ![]() CFH variants with reduced complement inhibitory function are a well-validated genetic risk factor for GA secondary to age-related macular degeneration (AMD), with approximately 75% of AMD patients carrying a high-risk variant of CFH utilizing a precision medicine approach, this population represents a potential target population for 4D-175.Announces sCFH as payload for 4D-175 lead product candidate for geographic atrophy (GA) sCFH extensively characterized in 3 genetic mouse models and in non-human primates (NHP).technology invented at University of Pennsylvania 4DMT acquires all world-wide rights to short-form human complement factor H (sCFH) from Aevitas Therapeutics, Inc.
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