Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?
Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?
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DOI：
10.1182/bloodadvances.2021004760
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发表时间：
2021-10-26
期刊：
影响因子：
7.5
通讯作者：
Arruda VR
中科院分区：
文献类型：
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作者：
Arruda VR
使用腺相关病毒（AAV）载体表达治疗水平的因子VIII（FVIII）的临床策略的前景是高度期望的。这最初是通过在患有重度血友病A的男性中进行的关于AAV 5-FVIII的临床研究的有希望的数据来预期的。然而，长期随访显示，从载体注射后1年开始至第5年，FVIII转基因水平持续下降，导致可持续性和持久性存在独特的疗效问题。早期研究的额外随访和正在进行的III期研究的结果可能会提供这种方法可行性的证据。在这里，潜在的潜在机制的FVIII水平下降，以及一些独特的早发性和迟发性结果的修订，进行了讨论。由于缺乏大型动物模型的长期临床前研究，无法得出FVIII水平下降是意外的结论。载体生产平台和剂量的组合，伴随着短期随访时FVIII超生理水平的异位表达，可能都有助于转基因水平的可持续性和持久性。值得注意的是，载体再给药以进一步改善FVIII水平在此时是不可行的。因此，需要一种一劳永逸的AAV策略来实现维持FVIII表达水平是有利地影响疾病表型的必要条件。
The prospect of a clinical strategy using an adeno-associated virus (AAV) vector for expression of therapeutic levels of factor VIII (FVIII) has been highly desirable. This was initially anticipated by promising data from clinical studies on AAV5-FVIII in men with severe hemophilia A. However, long-term follow-up showed a unique efficacy concern on the sustainability and durability derived from a continuous decline in the FVIII transgene levels starting 1 year after vector injection through year 5. Additional follow-up of early-phase studies and outcomes of an ongoing phase 3 study will likely provide evidence on the feasibility of this approach. Here, the potential underlying mechanisms of the FVIII declining levels, together with the revision of several unique early and late onset findings, are discussed. The lack of long-term preclinical studies in large animal models prevents the firm conclusion that FVIII levels decline was unexpected. It is possible that the combination of vector manufacturing platform and dose, accompanied with ectopic expression of supraphysiologic levels of FVIII at short-term follow-up, may all contribute to the sustainability and durability of the transgene levels. Notably, vector readministration to further improve the FVIII levels is not feasible at this time. Thus, the need of a one-and-done AAV strategy to achieve sustain FVIII levels of expression is sine qua non to impact favorably the disease phenotype.