Recent data published in The New England Journal of Medicine show that among 67 children with a rare neurological disorder who received gene therapy from Bluebird Bio, seven developed blood cancer. The gene therapy, Skysona, is designed to treat cerebral adrenoleukodystrophy (CALD) in children. The latest data indicate that since June 2022, four additional cancer cases have been identified, and one patient unfortunately passed away due to complications from cancer treatment.

Skysona aims to slow the progression of CALD by inserting the ABCD1 gene into CD34+ hematopoietic stem cells using a lentiviral vector (Lenti-D), enabling these cells to produce functional ALDP protein, which is essential for breaking down very long-chain fatty acids.

Scientists believe that these adverse events are related to insertional mutations caused by the Lenti-D vector. The integration of this vector may activate proto-oncogenes near the insertion sites, such as MECOM and PRDM16, which are closely associated with cancer development. Additionally, mutations in genes such as KRAS, NRAS, and WT1 have been observed in some patients, further increasing the risk of cancer.

Previous studies have shown that both γ-retroviral and lentiviral vectors pose relatively low risks for insertional carcinogenesis. However, this clinical trial has demonstrated that the Lenti-D vector may lead to clonal dominance and cancer, particularly when insertions occur near certain oncogenes. This finding underscores the importance of minimizing risks in the design of lentiviral vectors, such as avoiding enhancer elements that may lead to gene overexpression or using gene-targeting technologies.

Due to the potential dangers of random mutations, leading scientist Dr. Patrick Hsu has commented that the use of inherently random techniques should be approached with caution in clinical settings. Indeed, these events remind us that while advancing new therapies, we must also carefully consider their potential long-term risks.

With continuous advances in gene-editing technologies, new techniques such as base editing, prime editing, and large-fragment insertion technologies like eePASSIGE offer more targeted approaches. The delivery of RNP complexes (Cas9 protein + gRNA) or mRNA + gRNA can achieve high editing efficiency while avoiding the insertion of foreign genes. This raises the question: could these more efficient and safer editing methods be used in gene therapy? In terms of delivery vehicles, lipid nanoparticles (LNPs) have recently achieved significant breakthroughs in delivering siRNA and therapeutic mRNA, with well-established manufacturing processes. Could LNPs be considered a key delivery vector for future gene therapy development?

Currently, researchers and healthcare professionals are closely monitoring patients who have received Skysona, and it is possible that more cases will emerge. Despite the adverse events, gene therapy remains a promising approach for rare genetic diseases, with a future focus on ensuring the safety and efficacy of these therapies.

Reference: Duncan CN, Bledsoe JR, Grzywacz B, et al. Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2024 Oct 10;391(14):1287-1301. doi: 10.1056/NEJMoa2405541.