杜氏肌营养不良
肌营养不良蛋白
遗传增强
内科学
肌营养不良
乌特罗芬
骨骼肌
医学
化学
生物
分子生物学
基因
生物化学
作者
Lilly East,Rachael A. Potter,John Snedeker,Alex Haile,Chris Wier,Louise R. Rodino‐Klapac
出处
期刊:Neurology
[Ovid Technologies (Wolters Kluwer)]
日期:2023-04-25
卷期号:100 (17_supplement_2)
标识
DOI:10.1212/wnl.0000000000203007
摘要
Objective:
To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between tissue vector genome exposure, biological efficacy and functional outcome in an animal model of Duchenne muscular dystrophy (DMD) (DMDmdx mice) following treatment with delandistrogene moxeparvovec (SRP-9001). Background:
Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. Design/Methods:
We evaluated vector biodistribution, expression, and clinical dose selection of delandistrogene moxeparvovec using a novel application of a PK and PD modeling approach applied to data collected from DMDmdx mice. We analyzed PK/PD relationships between dose, tissue vector genome exposure, SRP-9001 dystrophin protein expression (percent dystrophin positive fibers [PDPF] and western blot), and functional improvement (relative specific force from tibialis anterior and diaphragm). Results:
Linear kinetics with a dose-proportional increase in tissue drug exposure were demonstrated across the nearly 10-fold dose range (4.43×1013–4.01×1014 vg/kg), and in all tissues. The relationship between tissue vector exposure and PD endpoints (PDPF, motor function outcome) showed a saturable response across a wide range of vector exposures. The vector exposure at 1.33×1014 vg/kg (the clinical dose) approached the maximum treatment response. Relative specific force and PDPF were significantly correlated (P=4.43×10−6). However, the relationship appeared to be nonlinear, with increased PDPF expression approaching the maximal functional improvement. Relative specific force and western blot were not significantly correlated. Conclusions:
For the first time, biodistribution, biomarker and functional efficacy data were used to quantify and demonstrate PK/PD relationships for an adeno-associated virus (AAV)-based gene transfer therapy in a DMD animal model. The results continue to support the expected therapeutic benefit and clinical dose of delandistrogene moxeparvovec, an AAV-based gene transfer therapy. Disclosure: Mrs. East has received personal compensation for serving as an employee of Sarepta Therapeutics. Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Dr. Snedeker has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Snedeker has stock in Sarepta Therapeutics. Dr. Haile has nothing to disclose. Christopher Wier has received personal compensation for serving as an employee of Sarepta Therapeutics. Christopher Wier has stock in Sarepta Therapeutics. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.
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