Gámez Alejandra, Sarkissian Christineh N, Wang Lin, Kim Woomi, Straub Mary, Patch Marianne G, Chen Lin, Striepeke Steve, Fitzpatrick Paul, Lemontt Jeffrey F, O'Neill Charles, Scriver Charles R, Stevens Raymond C
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Mol Ther. 2005 Jun;11(6):986-9. doi: 10.1016/j.ymthe.2005.02.013.
Phenylketonuria (PKU) is a metabolic disorder due primarily to mutations in the PAH gene that impair both phenylalanine hydroxylase activity and disposal of l-phenylalanine from the normal diet. Excess phenylalanine is toxic to cognitive development and a low-phenylalanine diet prevents mental retardation, but it is a difficult therapeutic option. Previous studies with recombinant phenylalanine ammonia-lyase, PAL, demonstrated pharmacologic and physiologic proofs of principle for PAL as an alternative therapy for PKU but its immunogenicity was problematic. From a series of formulations of linear and branched polyethylene glycols chemically conjugated to PAL, we have created a parenteral therapeutic agent for PKU treatment. All the pegylated molecules were fully characterized in vitro and the most promising formulations were then tested in vivo in the PKU mouse model. The linear 20-kDa PEG-PAL combination abolished in vivo immunogenicity after repeated challenge while retaining full catabolic activity against phenylalanine, suggesting potential as a novel PKU therapeutic.
苯丙酮尿症（PKU）是一种代谢紊乱疾病，主要由于PAH基因突变，该突变损害苯丙氨酸羟化酶活性以及从正常饮食中清除L-苯丙氨酸的能力。过量的苯丙氨酸对认知发育有毒性，低苯丙氨酸饮食可预防智力迟钝，但这是一种困难的治疗选择。先前对重组苯丙氨酸解氨酶（PAL）的研究证明了PAL作为PKU替代疗法的药理学和生理学原理证据，但其免疫原性存在问题。从一系列与PAL化学偶联的线性和支链聚乙二醇制剂中，我们制备了一种用于PKU治疗的肠胃外治疗剂。所有聚乙二醇化分子均在体外进行了全面表征，然后在PKU小鼠模型中对最有前景的制剂进行了体内测试。线性20 kDa聚乙二醇-PAL组合在反复攻击后消除了体内免疫原性，同时保留了对苯丙氨酸的完全分解代谢活性，表明其有作为新型PKU治疗药物的潜力。
