Dr. von Haunersches Kinderspital, University of Munich, German Center for Lung Research (DZL), Munich, Germany.
Research Unit Signaling and Translation, Helmholtz Zentrum München, Neuherberg, Germany.
Pediatr Pulmonol. 2024 Dec;59(12):3221-3227. doi: 10.1002/ppul.27178. Epub 2024 Jul 23.
Biallelic ATP-binding cassette subfamily A member 3 (ABCA3) variants can cause interstitial lung disease in children and adults, for which no proven treatments exist. Recent in vitro evidence suggested that cyclosporine A (CsA) could correct some ABCA3 variants, however for other variants this is unknown and no data in patients exist.
We retrieved the clinical data of two children aged 2 and 4 years carrying homozygous ABCA3 variants (G210C and Q1045R, respectively) and empiric CsA treatment from the Kids Lung Register database. In vitro experiments functionally characterized the two variants and explored the effects of CsA alone or combined with hydroxychloroquine (HCQ) in a human alveolar epithelial cell line (A549) derived from adenocarcinoma cells.
Six weeks following the introduction of CsA, both children required a reduced O flow supply, which then remained stable on CsA. Later, when CsA was discontinued, the clinical status of the children remained unchanged. Of note, the children simultaneously received prednisolone, azithromycin, and HCQ. In vitro, both ABCA3 variants demonstrated defective lysosomal colocalization and impaired ABCA3 vesicle size, with proteolytic cleavage impairment only in Q1045R. CsA alone corrected the trafficking impairment and ABCA3 vesicle size of both variants with a variant-specific effect on phosphatidylcholine recycling in G210C. CsA combined with HCQ were additive for improving trafficking of ABCA3 in G210C, but not in Q1045R.
CsA treatment might be helpful for certain patients with ABCA3 deficiency, however, currently strong clinical supporting evidence is lacking. Appropriate trials are necessary to overcome this unmet need.
双等位基因 ATP 结合盒亚家族 A 成员 3（ABCA3）变异可导致儿童和成人的间质性肺病，目前尚无有效的治疗方法。最近的体外证据表明环孢素 A（CsA）可纠正某些 ABCA3 变异，但对于其他变异，目前尚不清楚，也没有患者的数据。
我们从儿童肺登记数据库中检索了两名 2 岁和 4 岁携带纯合 ABCA3 变异（分别为 G210C 和 Q1045R）的儿童的临床数据，并进行了环孢素 A 的经验性治疗。体外实验对两种变异进行了功能表征，并在来源于腺癌细胞的人肺泡上皮细胞系（A549）中探索了环孢素 A 单独或联合羟氯喹（HCQ）的作用。
在引入环孢素 A 6 周后，两名儿童均需要减少氧气流量供应，此后在环孢素 A 治疗下保持稳定。后来，当停止使用环孢素 A 时，儿童的临床状况保持不变。值得注意的是，儿童同时接受了泼尼松龙、阿奇霉素和 HCQ 的治疗。体外研究表明，两种 ABCA3 变异均存在溶酶体共定位缺陷和 ABCA3 囊泡大小受损，只有 Q1045R 存在蛋白水解切割受损。环孢素 A 单独纠正了两种变异的转运缺陷和 ABCA3 囊泡大小，对 G210C 的磷脂酰胆碱循环具有变异特异性影响。环孢素 A 联合 HCQ 可改善 G210C 中 ABCA3 的转运，但对 Q1045R 无影响。
环孢素 A 治疗可能对某些 ABCA3 缺乏症患者有帮助，但目前缺乏强有力的临床支持证据。需要进行适当的试验来满足这一未满足的需求。
