Goedeker Natalie L, Dharia Sachi D, Griffin Danielle A, Coy Jesantha, Truesdale Todd, Parikh Rajan, Whitehouse Kasen, Santra Sourav, Asher Damon R, Zaidman Craig M
Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8111, St. Louis, MO 63110, USA.
Sarepta Therapeutics, Inc., Cambridge, MA, USA.
Ther Adv Neurol Disord. 2023 Jan 24;16:17562864221149781. doi: 10.1177/17562864221149781. eCollection 2023.
Adeno-associated virus (AAV) vectors are a promising platform for transfer of transgenes designed to treat diseases. Pre-existing humoral immunity to these vectors can potentially impact the safety and efficacy of gene therapies. Consequently, individuals with pre-existing antibodies to the specific AAV serotypes used may be excluded from clinical trials and treatments. Recombinant AAV serotype rh74 (rAAVrh74), a vector originally isolated from rhesus monkeys and potentially less immunogenic than other serotypes isolated from humans (e.g. AAV2, AAV5, and AAV9), efficiently transduces muscle and is being investigated for use in gene therapy for Duchenne muscular dystrophy (DMD).
To evaluate prevalence of total binding antibodies (neutralizing and non-neutralizing) against rAAVrh74 in patients with DMD.
Eligible individuals ( = 107) were ⩾ 4 to < 18 years old with genetically confirmed DMD and were excluded from the study if they lived with a person who had known exposure to rAAVrh74 or other gene transfer therapy, or if they received prior treatment with gene transfer therapy. A single blood sample was obtained from each participant, and anti-rAAVrh74 total binding antibodies were measured by enzyme-linked immunosorbent assay. Total binding antibody level < 1:400 was defined as not elevated or seronegative. Primary endpoint was the percentage of subjects with elevated total antibody titers to rAAVrh74.
A large preponderance (86.1%) of patients with DMD in this data set was seronegative for anti-rAAVrh74 total binding antibodies. These patients would potentially meet the antibody status eligibility criterion for entry into rAAVrh74-based gene therapy clinical trials.
Measuring total binding antibodies is a more comprehensive approach to assess pre-existing immune response measuring neutralizing antibodies alone. The low seroprevalence of total binding antibodies against rAAVrh74 shown here supports the broad applicability of rAAVrh74-based gene transfer therapy for patients with DMD and potentially other neuromuscular diseases.
腺相关病毒（AAV）载体是用于传递旨在治疗疾病的转基因的一个有前景的平台。对这些载体预先存在的体液免疫可能会影响基因治疗的安全性和有效性。因此，对所使用的特定AAV血清型预先存在抗体的个体可能会被排除在临床试验和治疗之外。重组AAV血清型rh74（rAAVrh74）是一种最初从恒河猴中分离出来的载体，其免疫原性可能低于从人类分离出的其他血清型（如AAV2、AAV5和AAV9），能有效地转导肌肉，目前正在进行用于杜氏肌营养不良症（DMD）基因治疗的研究。
评估DMD患者中针对rAAVrh74的总结合抗体（中和及非中和抗体）的流行率。
符合条件的个体（n = 107）年龄在4至18岁之间，经基因确诊为DMD，如果他们与已知接触过rAAVrh74或其他基因转移疗法的人生活在一起，或者他们曾接受过基因转移疗法的治疗，则被排除在研究之外。从每个参与者采集一份血样，通过酶联免疫吸附测定法检测抗rAAVrh74总结合抗体。总结合抗体水平<1:400被定义为未升高或血清阴性。主要终点是抗rAAVrh74总抗体滴度升高的受试者百分比。
该数据集中大部分（86.1%）DMD患者抗rAAVrh74总结合抗体呈血清阴性。这些患者可能符合基于rAAVrh74的基因治疗临床试验的抗体状态合格标准。
测量总结合抗体是评估预先存在的免疫反应的一种比仅测量中和抗体更全面的方法。此处显示的针对rAAVrh74的总结合抗体的低血清流行率支持基于rAAVrh74的基因转移疗法对DMD患者以及可能的其他神经肌肉疾病的广泛适用性。
