Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy

TLDR

X‑linked adrenoleukodystrophy (ALD) is a hereditary demyelinating disorder typically treated with matched donor bone‑marrow transplantation. The study tested an alternative gene‑therapy approach in two young patients lacking matched donors. A lentiviral vector delivered a wild‑type ALD gene into patients’ hematopoietic stem cells ex vivo, which were then reinfused to generate myelin‑producing cells. Two years post‑infusion, the transferred gene remained expressed in blood cells, and both patients exhibited neurological improvement and disease‑progression delay comparable to bone‑marrow transplants.

Abstract

Slowing Brain Disease with Gene Therapy X-linked adrenoleukodystrophy (ALD), the hereditary brain demyelinating disorder that was featured in the movie “ Lorenzo's Oil ,” is typically treated by transplantation of bone marrow from matched donors. This treatment slows progression of the disease by introducing cells that differentiate into myelin-producing cells. Cartier et al. (p. 818 ; see Perspective by Naldini ) tested an alternative gene therapy–based approach in two young patients without matched donors. A lentiviral vector was used to introduce a wild-type copy of the ALD gene into the patients' hematopoietic stem cells ex vivo. The modified cells were then infused back into the patients. Expression of the transferred gene was still detectable in the patients' blood cells 2 years later, and both patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants.