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Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy
Florian Eichler1, Christine N Duncan1, Patricia L Musolino1
1From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.) and Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School (C.N.D., D.A.W.), Boston, Bluebird Bio, Somerville (G.F.D., L.D., A.C.D., H.L.T.), and McNeil Pediatrics Consultancy, Sudbury (E.M.) - all in Massachusetts; the Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota (T.C.L., A.O.G., P.J.O.), and Midwest Radiology (D.J.L.) - both in Minneapolis; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (S.D.O., R.S., S.A.H.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., P.G.); INSERM, Université Paris-Saclay, Hôpital Kremlin-Bicêtre (P.A.), the Reference Center for Leukodystrophies, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay (C.S.), and Robert-Debre Hospital, GHU Nord-Université de Paris (J.-H.D.) - all in Paris; the Departments of Pediatric Oncology/Hematology/Hemostaseology (J.-S.K.) and Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases (U.P.), University Hospital Leipzig, Leipzig, Germany; Instituto Neurogenia and Hospital Universitario Austral - both in Buenos Aires (H.A.); Women's and Children's Health Network and the University of Adelaide - both in Adelaide, SA, Australia (N.S.); ITACI/Instituto da Criança-Hospital das Clínicas da Universidade de São Paulo, Sao Paulo (J.F.F.); and Shape Therapeutics, Seattle (A.C.D.).
Gene therapy with elivaldogene autotemcel (eli-cel) shows promising long-term results for cerebral adrenoleukodystrophy, preserving neurologic function and survival in most patients. Ongoing monitoring is crucial due to potential risks of insertional oncogenesis.
Area of Science:
- Neurology
- Genetics
- Hematology
Background:
- Cerebral adrenoleukodystrophy (CALD) is a severe X-linked neurodegenerative disorder.
- It leads to white-matter disease, neurological decline, and premature death.
- Current treatments are limited, highlighting the need for effective therapies.
Purpose of the Study:
- To evaluate the efficacy and safety of elivaldogene autotemcel (eli-cel) gene therapy.
- To assess eli-cel in boys with early-stage CALD and active inflammation on MRI.
- To determine key endpoints including survival and functional disability at 24 months.
Main Methods:
- A Phase 2-3 study involving 32 patients with early-stage CALD.
- Patients received eli-cel, a gene therapy using autologous CD34+ cells with a lentiviral vector.
- Efficacy endpoints included survival without major functional disabilities and neurologic function scores.
Main Results:
- At 24 months, 91% of patients completed the study; none had major functional disabilities, and 94% had overall survival.
- At a median 6-year follow-up, 81% of patients remained free of major functional disabilities.
- Neurologic function remained stable in 94% of patients; 4 adverse events were directly linked to eli-cel, including one case of myelodysplastic syndrome.
Conclusions:
- Elivaldogene autotemcel gene therapy demonstrates significant long-term efficacy in preserving function for CALD patients.
- The therapy offers a potential treatment option for early-stage CALD, improving survival and functional outcomes.
- Insertional oncogenesis remains a potential risk associated with lentiviral vector integration, requiring continued monitoring.
