Clinical Pharmacology Considerations on Recombinant Adeno-Associated Virus-Based Gene Therapy

被引：17

作者：

Sun, Kefeng ^{[1
,3
]}

Liao, Michael Z. Z. ^{[2
]}

机构：

[1] Takeda Dev Ctr Amer, Cambridge, MA USA

[2] Genentech Inc, Clin Pharmacol, South San Francisco, CA USA

[3] Takeda Dev Ctr Amer Inc, 125 BinneySt, Cambridge, MA 02142 USA

来源：

JOURNAL OF CLINICAL PHARMACOLOGY | 2022年 / 62卷

关键词：

adeno-associated virus (AAV); biodistribution; dose-exposure-response; durability; gene therapy; immune response; pharmacokinetics; pharmacodynamics (PK; PD); T-CELL RESPONSES; FACTOR-IX; SUCCESSFUL TRANSDUCTION; NONCLINICAL SAFETY; FOLLOW-UP; ER STRESS; HEMOPHILIA; AAV; VECTOR; EXPRESSION;

D O I：

10.1002/jcph.2141

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Recombinant adeno-associated virus (AAV) is currently the most widely used platform for in vivo gene therapy. Clinical pharmacology is a central field for AAV gene therapy, represented by the pillars of pharmacokinetics, pharmacodynamics/efficacy, and safety. In this review, we provide a comprehensive summary of clinical pharmacology considerations for recombinant AAV. The main topics covered are biodistribution and shedding, dose-exposure-response relationship, safety, immune and stress response, and clinical dose selection strategies. We highlight how the cumulative knowledge of AAV gene therapy could help with guiding clinical trial design and assessing and mitigating risks, as well as planning and executing pharmacokinetic/pharmacodynamic /safety data analyses. In addition, we discuss the major gaps and areas of growth in clinical pharmacology understanding of recombinant AAV. These include the mechanisms of the durability of treatment response and variability in biodistribution, transduction, and immunogenicity, as well as a potential influence on AAV's safety and efficacy profiles by drug product characteristics and patient intrinsic/extrinsic factors.

引用

页码：S79 / S94

页数：16

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