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Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy
Open accessAbstract
BACKGROUND: complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy. METHODS: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. RESULTS: A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up. CONCLUSIONS: At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).
Overview
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TL;DR
In boys with early-stage cerebral adrenoleukodystrophy and active MRI inflammation, elivaldogene autotemcel (eli-cel) lentiviral gene therapy preserved neurologic function and disability-free survival over a median follow-up of 6 years. However, insertional oncogenesis remains a risk, with one patient developing myelodysplastic syndrome at month 92.
Key findings
- At month 24, 29 of 32 patients (91%; 95% CI, 75 to 98) had no major functional disabilities, and overall survival was 94%.
- At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable in 30 of 32 patients (94%), and 26 of 32 patients (81%) had no major functional disabilities.
- Four of 32 patients (12%) had adverse events directly related to eli-cel; no graft-versus-host disease was observed.
- MDS with excess blasts developed in 1 patient at month 92 and was considered related to Lenti-D lentiviral vector; the patient underwent allogeneic HSCT and had no MDS at most recent follow-up.
Methods
- Phase 2–3, multicenter, open-label study of eli-cel in boys 17 years of age or younger with cerebral adrenoleukodystrophy confirmed by biochemical and genetic testing, early-stage cerebral disease with gadolinium enhancement on MRI, a neurologic function score of 0 or 1, and a Loes score of 0.5 to 9.
- A total of 32 patients received eli-cel; the primary efficacy end point was survival without any of six major functional disabilities at month 24, with secondary end points including overall survival and change in total neurologic function score.
- Statistical methods were primarily descriptive; the sample size was not determined by formal statistical methods, and confidence intervals were not adjusted for multiplicity.
Limitations
- The paper states that a limitation is the small number of patients included who had a high baseline Loes score, and that additional longer-term follow-up, including neuropsychiatric testing outcomes, is needed.
- Evident from the text: this was a single-arm, open-label study without a concurrent comparator, and the authors note that comparative inferences cannot be drawn from historical allogeneic HSCT data.
- Evident from the text: insertional oncogenesis is an ongoing risk, and longer-term follow-up is needed to determine whether efficacy is maintained.
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Claims the paper makes
29 Own result · 4 Check pending · 4 Not checked yet · 4 Own method · 4 Own interpretation · 1 No full text of the sources
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Serious infections occurred in 8 patients (25%).”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > SAFETY
plainn = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There did not appear to be a correlation between the vector copy number in the eli-cel and changes in the Loes score in the larger population with long-term follow-up described in the current study.”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At month 24, the neurologic function score was stable in 29 of 30 evaluable patients (97%; 95% CI, 83 to 100)”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > END POINTS
plainn = 30- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“28 of 30 evaluable patients (93%) had a neurologic function score of 0 or 1”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > END POINTS
plainn = 30- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“expression of transgene-derived protein in peripheral-blood leukocytes was observed in all patients”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > PHARMACODYNAMIC ASSESSMENTS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 18
- Probably not a substantial claim. 3
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Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The safety record of LVV, with one notable exception, 58 is excellent.”
From Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy (2025) · cites this paper as [58]
In the citing paper
“However, a significant number have developed a direct complication of the treatment due to insertional mutagenesis resulting in hematological malignancy.58”
From Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy (2025) · cites this paper as [58]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > DISCUSSION
“However, nonfatal MDS with excess blasts developed in one patient in the 24-month study.”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > END POINTS
“Myelodysplastic syndrome (MDS) developed in Patient 3 at month 92 while the patient was in the follow-up study”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > END POINTS
“At the most recent assessment in either the 24-month study or the long-term follow-up study (median follow-up, 6 years), stability of the neurologic function score was seen in 30 of 32 patients (94%)”
§ Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > PATIENTS AND TREATMENT
“a total of 32 patients 3 to 13 years of age (median, 6) received eli-cel; the median duration of follow-up as of February 1, 2023, was 60.2 months”
Citations
Cites
Moser, H. W., Mahmood, A., & Raymond, G. V. (2007) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0421 · Cited by 663
Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., Armant, M., Dansereau, C., Lund, T. C., Miller, W. P., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1700554 · Cited by 604
Self-citationEngelen, M., Kemp, S., de Visser, M., van Geel, B. M., Wanders, R. J., Aubourg, P., & Poll-The, B. (2012) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-7-51 · Cited by 562
Self-citationPeters, C., Charnas, L. R., Tan, Y., Ziegler, R. S., Shapiro, E. G., DeFor, T., Grewal, S. S., Orchard, P. J., Abel, S. L., Goldman, A. I., et al. (2004) · Blood · doi:10.1182/blood-2003-10-3402 · Cited by 374
Self-citationShapiro, E., Krivit, W., Lockman, L., Jambaqué, I., Peters, C., Cowan, M., Harris, R., Blanche, S., Bordigoni, P., Loes, D., et al. (2000) · The Lancet · doi:10.1016/s0140-6736(00)02629-5 · Cited by 329
Self-citationAdrenoleukodystrophy: a scoring method for brain MR observations.
(1994) · PubMed Central · Cited by 321
Self-citationMiller, W. P., Rothman, S. M., Nascene, D., Kivisto, T., DeFor, T. E., Ziegler, R. S., Eisengart, J., Leiser, K., Raymond, G., Lund, T. C., et al. (2011) · Blood · doi:10.1182/blood-2011-01-329235 · Cited by 290
Self-citationMoser, H. W., Loes, D. J., Melhem, E. R., Raymond, G. V., Bezman, L., Cox, C. S., & Lu, S.-E. (2000) · Neuropediatrics · doi:10.1055/s-2000-9236 · Cited by 210
Self-citationMahmood, A., Raymond, G. V., Dubey, P., Peters, C., & Moser, H. W. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70177-1 · Cited by 193
Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?
Eichler, F. S., Ren, J., Cossoy, M., Rietsch, A. M., Nagpal, S., Moser, A. B., Frosch, M. P., & Ransohoff, R. M. (2008) · Annals of Neurology · doi:10.1002/ana.21391 · Cited by 178
Self-citation
Research works printed but not linked: 2
- Raymond GV, Moser AB, Fatemi A. X-Linked adrenoleukodystrophy. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews. Seattle: University of Washington, 1993 (http://www.ncbi.nlm.nih.gov/books/NBK1315/).
- Williams DA, Bledsoe JR, Duncan CN, et al. Myelodysplastic syndromes after eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD). Mol Ther 2022;30:Suppl 1:6-6. abstract.
Cited by
Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy
Duncan, C. N., Bledsoe, J. R., Grzywacz, B., Beckman, A., Bonner, M., Eichler, F. S., Kühl, J.-S., Harris, M. H., Slauson, S., Colvin, R. A., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2405541 · Cited by 164
Self-citationOttaviano, G., & Qasim, W. (2025) · Leukemia · doi:10.1038/s41375-025-02585-8 · Cited by 46
CRISPR-dependent base editing as a therapeutic strategy for rare monogenic disorders
Cabré-Romans, J.-J., & Cuella-Martin, R. (2025) · Frontiers in Genome Editing · doi:10.3389/fgeed.2025.1553590 · Cited by 34
Clinical hematopoietic stem cell-based gene therapy
John, T. D., & Czechowicz, A. D. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.029 · Cited by 30
Recent Advances in mRNA-LNP Delivery Systems for Extrahepatic Organs: A Review
Bai, Y., Cui, L., Liu, T., Wang, Z., Cao, H., He, S., Qiu, J., Li, Y., Zhou, Y., Shi, J., et al. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5c00385 · Cited by 25
Metadata
- Authors
- Eichler, F., Duncan, C. N., Musolino, P. L., Lund, T. C., Gupta, A. O., De Oliveira, S., Thrasher, A. J., Aubourg, P., Kühl, J.-S., Loes, D. J., Amartino, H., Smith, N., Folloni Fernandes, J., Sevin, C., Sankar, R., Hussain, S. A., Gissen, P., Dalle, J.-H., Platzbecker, U., Downey, G. F., McNeil, E., Demopoulos, L., Dietz, A. C., Thakar, H. L., Orchard, P. J., & Williams, D. A.
- Affiliations
- University of Minnesota (US)
- From 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 Pari...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2024-10-10
- Volume
- 391
- Issue
- 14
- Pages
- 1302-1312
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC12465018
- OpenAlex
- W4403262143
- Semantic Scholar
- 9bd2879b2dea452f82ce86cd5f7f1b658ac44a75
- Cited by
- 107
- References
- 24
- Citations by year
- 2026: 50 · 2025: 50 · 2024: 7
- FWCI
- 20.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Bluebird Bio
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- cerebral adrenoleukodystrophy, lentiviral gene therapy, insertional oncogenesis, myelodysplastic syndrome, neurological function, functional disability, long-term safety
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adolescent, Adrenoleukodystrophy, Brain, Child, Child, Preschool, Follow-Up Studies, Genetic Vectors, Humans, Magnetic Resonance Imaging, Male, Myelodysplastic Syndromes, Genetic Therapy, Lentivirus, Treatment Outcome, Hematopoietic Stem Cell Transplantation
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