250. A Phase 2/3 Study of the Efficacy and Safety of Ex Vivo Gene Therapy with Lenti-D TM Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy
Authors: Florian S. Eichler, Christine Duncan, Hernan Amartino, Razina Aziz-Bose, André Baruchel, Colleen Dansereau, Jean-Hugues Dalle, H. Bobby Gaspar, Paul Gissen, Donald B. Kohn, Jerome Larghero, Troy C. Lund, Weston P. Miller, Patricia L. Musolino, Tara O'Meara, Paul J. Orchard, Asif M. Paker, Ami J. Shah, Esther Shamir, Gerald V. Raymond, Raman Sankar, Nicholas J.C. Smith, Adrian J. Thrasher, Patrick Aubourg, David A. Williams
Journal: Molecular Therapy (2016)

Cerebral X-linked adrenoleukodystrophy (CALD) is a severe brain demyelinating disease caused by a deficiency in ALD protein (ALDP), an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. Brain lesion progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We used gene transfer with a third-generation SIN-lentivirus vector with MND as an internal promoter expressing the ABCD1 gene (Lenti-D vector) to transduce autologous hematopoietic stem cells (HSCs) in 17 patients with CALD and gadolinium enhancement on brain MRI lacking HLA antigen-matched sibling donors (ages 4-13y; mean, 5.8y). At enrollment, Neurological Function Score (NFS) was 0 in all subjects and median Loes Score was 2 (1-8). Cells were transduced under GMP conditions at an academic site or a central contract manufacturing site and the drug product frozen, certified for release and transported to study sites for infusion. 6.0-20.4X10e6 CD34+ cells/kg of drug product were infused after myeloablative conditioning with busulfan and cyclophosphamide. Vector copy number (VCN) in infused cells was 0.5 to 2.5. As of 10/1/15, 6 subjects had 12-23m follow up, 8 had 6-12m, and 3 had <6m. All patients engrafted with gene marked cells. Time to absolute neutrophil count (ANC)>500/µl was 19-38d (without G-CSF; N=4) and 10-19d (with G-CSF started day +5; N=13). Time to platelet counts >20,000/µl without platelet transfusions was 14-54 days. Median VCN in DP and peripheral blood leukocytes (PBL) and proportions of PBLs and CD14+ myeloid cells expressing ALDP as detected by flow cytometric analysis are below. Integration site analysis shows polyclonal reconstitution in all subjects, with no indication of vector mediated clonal skewing to date. Neurologic outcomes (NFS and major functional disabilities [MFD]) were assessed at each study visit. MRI results (Loes Score and gadolinium enhancement) were periodically reviewed centrally. MRI data were available on 8 subjects with ≥6m follow up. All 8 had resolution of gadolinium enhancement on brain MRI. Median change in Loes Score was 1 (0-6), and no patient demonstrated progression of NFS. Two SAEs were assessed possibly related to Lenti-D drug product (DP), BK virus cystitis and tachycardia. To date, the safety profile of Lenti-D DP appears consistent with myeloablative conditioning. These early results demonstrate feasibility of centralized manufacturing for a HSC gene therapy trial and short-term safety and efficacy of gene therapy in CALD. Assessment of long-term outcomes and safety continues. Tabled 1Median (IQR) VCN and ALDP expression over timeVCN% PBLs expressing ALDP% CD14+ expresing ALDPPretreatmentDP:1.0 (0.6, 1.6), N=170.9 (0.5, 1.5), N=171.0 (0.7, 1.6), N=116 monthsPBL:0.5 (0.3, 1.0), N=1313.5 (9.3, 20.1), N=1226.4 (14.0, 36.0), N=1012 monthsPBL:0.7 (0.4, 0.8), N=922.9 (18.8, 29.5), N=532.5 (22.3, 45.2), N=6 Open table in a new tab