Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy

Source: Eichler F, Duncan CN, Musolino PL, et al. Lentiviral gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2024;391(14):1302-1312; doi: 10.1056/NEJMoa2400442.Investigators from multiple institutions conducted an open-label trial with long-term follow-up in children with cerebral adrenoleukodystrophy who were treated with gene therapy. Cerebral adrenoleukodystrophy is an X-linked disease caused by variants in the ABCD1 gene, resulting in loss of cognition and neurologic function and early death. Participants in the current study were boys with cerebral adrenoleukodystrophy and early stage cerebral disease (based on gadolinium enhancement on MRI). Study patients received elivaldogene autotemcel (eli-cell) gene therapy, consisting of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1-complementary DNA. Eli-cell was infused in the participants after they were conditioned with busulfan and cyclophosphamide. The primary outcome was survival at month 24 without any of 6 major functional disabilities: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement. Secondary outcomes included survival at 24 months. Following the 24-month trial, long-term follow-up for these outcomes continued. Adverse events also were monitored throughout the study period.A total of 32 boys, median age 6 years, received eli-cell gene therapy between October 2013 and April 2019. Median duration of follow-up in study participants was 60.2 months. At month 24, 29 (91%) were alive and had none of the major functional disabilities. One patient had major functional disabilities and died prior to month 24. Two patients were withdrawn to undergo allogeneic stem cell transplantation; 1 of these subsequently died before month 24. Thus, overall survival at month 24 was 94% (30 of 32). The 29 study participants remaining in the study at month 24 were entered into the follow-up phase of the study, but 1 boy was lost to follow-up at month 54. During the follow-up phase, 1 patient developed cortical blindness. At the time of last follow-up, 26 of the original 32 study participants (81%) were alive and free of major functional disabilities. Overall, 22 (69%) patients had a serious adverse event. Eight had serious adverse events related to the conditioning regimen prior to eli-cell infusion. During the follow-up phase, 5 children had new onset seizures, and 3 had worsening of neurologic function. One patient developed myelodysplastic syndrome with excess blasts at month 92, necessitating an allogeneic stem-cell transplantation.The authors conclude the eli-cell gene therapy was associated with long-term survival without major functional disabilities in most patients, but insertional oncogenesis is an ongoing risk.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Cerebral adrenoleukodystrophy (cALD) due to X-linked ABCD1 gene mutations leads to a deficiency in the ALD protein, with the lethal buildup of very-long-chain fatty acids in tissue and plasma causing inflammation, demyelination, and progressive destruction of white matter.1 It is the most severe type of X-linked ALD, affecting one-third of affected boys under 12 years of age, who die within 5 to 10 years if left untreated.1 Although allogeneic hematopoietic stem cell transplant (HSCT) from donor cells expressing ALD protein is the standard of care, only 20% have a matched donor, with an overall survival of 77.8% and major-disability-free survival of 63.2% at 4 years.2Early HSCT gene therapy trials for hemoglobinopathies, immunodeficiencies, and metabolic neurologic disorders using certain retroviral vectors has resulted in activation or dysregulation of nearby oncogenes and subsequent hematologic cancers.3 In contrast, lentiviral and altered retroviral vectors, without long terminal repeat sequences, tended to integrate in introns away from transcription sites and thus were considered safe for future trials. (See AAP Grand Rounds. 2022;47[4]:45;4 2022;47[2]:22;5 and 2019;42[1]:8.6) In a systematic review of long-term follow-ups of other lentiviral vectors transducing autologous HSC in 250 patients, there were no cases of hematologic cancers linked to insertional genotoxicity.7Approximately 15 years ago, the Lenti-D lentiviral vector used in this current trial was made with an internal MNDU3 promoter-enhancer to make ALD in cerebral macrophages, microglia, and HSCs. MNDU3 includes the U3 segment of the myeloproliferative sarcoma virus long terminal repeat with the negative control region deleted and the DL587 endogenous retrovirus primer binding site substituted.3 A separate eli-cell, autologous Lenti-D clinical trial of 35 cALD patients used busulfan-fludarabine as the preparative regimen (compared to busulfan-cyclophosphamide in the current trial), and all had mobilized HSCs with G-CSF and plerixafor (compared to 11 of 32 subjects in the current trial). Over 116 person-years of follow-up (compared to 222 person-years in the current trial), 6 (17%) patients developed a hematologic cancer.3Autologous lentiviral gene therapy for those with early cerebral ALD who lack a suitable HSCT donor appears to extend lives by preserving neurologic function yet increases the risk for hematologic cancer.