Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient induced pluripotent stem cells. When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with a repurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3′ end maturation and telomere length. These findings pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-related diseases.

降低端粒酶活性的遗传损伤会抑制干细胞复制，并导致一系列不治之症，包括先天性角化病（DC）和肺纤维化（PF）。恢复全身干细胞端粒酶的方式尚不清楚。在这里，我们描述了小分子PAPD5抑制剂，它们在体外，干细胞模型和体内证明端粒的恢复。PAPD5是一种非典型的聚合酶，可寡聚腺苷酸化并使端粒酶RNA组分（TERC）不稳定。我们确定了BCH001，一种特定的PAPD5抑制剂，可在DC患者诱导的多能干细胞中恢复端粒酶活性和端粒长度。当人类血液干细胞经过工程改造以携带引起DC的PARN时将突变体异种移植到免疫缺陷小鼠中，用重新设计的PAPD5抑制剂，二氢喹啉嗪酮RG7834口服治疗，挽救TERC 3'端成熟和端粒长度。这些发现为开发系统性端粒疗法铺平了道路，以抵消DC，PF和其他可能与衰老相关的疾病中的干细胞衰竭。