Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 1: 95 - 100

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.01.011

Review

Advances in the treatment of adrenoleukodystrophy

  • LIU Xiaoli ,
  • CAO Li
Expand
  • 1.Department of Neurology, Fengxian District Central Hospital Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201406, China
    2.Department of Neurology, Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
    3.Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai 200233, China
CAO Li, E-mail: caoli2000@yeah.net.

Received date: 2024-07-04

  Accepted date: 2024-08-22

  Online published: 2025-01-28

Supported by

National Natural Science Foundation of China(82371255);Shanghai Science and Technology Innovation Action Plan(23DZ2291500);Project of Shanghai Municipal Health Commission(2022LJ011);Project of Shanghai Fengxian District Science and Technology Commission(20231207);Scientific Research Fund Project of Shanghai Sixth people′s Hospital Medical Group;The Hundred Faculty Talent Pool Program at Shanghai University of Medicine & Health Sciences in 2023

Fold

Abstract

Adrenoleukodystrophy (ALD) is an X-linked, potentially fatal peroxisome disease, characterized by three main clinical phenotypes: adrenomyeloneuropathy (AMN), cerebral adrenoleukodystrophy (CALD), and primary adrenal insufficiency. The clinical phenotypes of ALD are unpredictable, with no genotype-phenotype correlation, and disease progression cannot be predicted based on very long chain fatty acid (VLCFA) levels in plasma. Additionally, the phenotypes can exhibit significant variability. Currently, no definitive treatment for this disease exists, and treatment options vary depending on the specific phenotypes. For AMN, only symptomatic supportive treatment is available. However, early CALD can be stabilized through allogeneic hematopoietic stem cell transplantation (allo-HSCT) and transgenic autologous hematopoietic stem cell transplantation (trans-ASCT), and primary adrenal insufficiency can be treated through hormone replacement therapy. Allo-HSCT and trans-ASCT can prevent the progression of early CALD, but cannot reverse the changes of AMN or halt the progression of adrenal insufficiency. Furthermore, they cannot prevent neurological dysfunction or death in terminal CALD. In recent years, multiple clinical trials of drugs targeting ALD have demonstrated therapeutic potential for ALD. Trans-ASCT and gene editing therapy have also made breakthroughs in animal models and clinical trials, providing alternative options for ALD patients ineligible for allo-HSCT treatment. This paper reviews the latest therapeutic research results of ALD and provides a basis for clinical practice.

Key words： adrenoleukodystrophy (ALD); cerebral adrenoleukodystrophy (CALD); adrenomyeloneuropathy (AMN); primary adrenal insufficiency; hematopoietic stem cell transplantation (HSCT)

Cite this article

LIU Xiaoli , CAO Li . Advances in the treatment of adrenoleukodystrophy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025 , 45(1) : 95 -100 . DOI: 10.3969/j.issn.1674-8115.2025.01.011

References

1 GUJRAL J, SETHURAM S. An update on the diagnosis and treatment of adrenoleukodystrophy[J]. Curr Opin Endocrinol Diabetes Obes, 2023, 30(1): 44-51.
2 HUFFNAGEL I C, LAHEJI F K, AZIZ-BOSE R, et al. The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration[J]. J Clin Endocrinol Metab, 2019, 104(1): 118-126.
3 CHEN Y, XU L P, ZHANG X H, et al. Haploidentical hematopoietic stem cell transplantation with busulfan, cyclophosphamide, and fludarabine conditioning for X-linked adrenal cerebral leukodystrophy[J]. Pediatr Transplant, 2024, 28(3): e14735.
4 LAUER A, SPERONI S L, CHOI M, et al. Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy[J]. Nat Commun, 2023, 14(1): 1900.
5 MILLER W P, ROTHMAN S M, NASCENE D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report[J]. Blood, 2011, 118(7): 1971-1978.
6 中华医学会儿科学分会血液学组, 中华医学会儿科学分会神经学组, 中华医学会儿科学分会内分泌遗传代谢学组, 等. 异基因造血干细胞移植治疗脑型肾上腺脑白质营养不良中国专家共识(2023)[J]. 中华儿科杂志, 2024, 62(4): 303-309.
  The Subspecialty Group of Hematology, the Society of Pediatrics, Chinese Medical Association, the Subspecialty Group of Neurology, the Society of Pediatrics, Chinese Medical Association, the Subspecialty Group of Endocrinology, Hereditary, and Metabolic Diseases, the Society of Pediatrics, Chinese Medical Association, et al. Chinese expert consensus on allogeneic hematopoietic stem cell transplantation for cerebral adrenoleukodystrophy (2023)][J]. Chinese Journal of Pediatrics, 2024, 62(4): 303-309.
7 YALCIN K, ?ELEN S S, DALOGLU H, et al. Allogeneic hematopoietic stem cell transplantation in patients with childhood cerebral adrenoleukodystrophy: a single-center experience “Better prognosis in earlier stage”[J]. Pediatr Transplant, 2021, 25(4): e14015.
8 BONKOWSKY J L, WILKES J. Time to transplant in X-linked adrenoleukodystrophy[J]. J Child Neurol, 2022, 37(5): 397-400.
9 PAGE K M, STENGER E O, CONNELLY J A, et al. Hematopoietic stem cell transplantation to treat leukodystrophies: clinical practice guidelines from the Hunter′s Hope Leukodystrophy Care Network[J]. Biol Blood Marrow Transplant, 2019, 25(12): e363-e374.
10 RAYMOND G V, AUBOURG P, PAKER A, et al. Survival and functional outcomes in boys with cerebral adrenoleukodystrophy with and without hematopoietic stem cell transplantation[J]. Biol Blood Marrow Transplant, 2019, 25(3): 538-548.
11 van GEEL B M, POLL-THE B T, VERRIPS A, et al. Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study[J]. J Inherit Metab Dis, 2015, 38(2): 359-361.
12 MATSUKAWA T, YAMAMOTO T, HONDA A, et al. Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy[J]. Brain Commun, 2020, 2(1): fcz048.
13 WALDHüTER N, K?HLER W, HEMMATI P G, et al. Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy[J]. J Inherit Metab Dis, 2019, 42(2): 313-324.
14 KüHL J S, SUAREZ F, GILLETT G T, et al. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy[J]. Brain, 2017, 140(4): 953-966.
15 CHIESA R, BOELENS J J, DUNCAN C N, et al. Variables affecting outcomes after allogeneic hematopoietic stem cell transplant for cerebral adrenoleukodystrophy[J]. Blood Adv, 2022, 6(5): 1512-1524.
16 GONG J, LIU Y Y, CHUNG T H, et al. Intracerebral lentiviral Abcd1 gene therapy in an early disease onset ALD mouse model[J]. Gene Ther, 2023, 30(1/2): 18-30.
17 CARTIER N, HACEIN-BEY-ABINA S, BARTHOLOMAE C C, et al. Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy[J]. Methods Enzymol, 2012, 507: 187-198.
18 CARTIER N, HACEIN-BEY-ABINA S, BARTHOLOMAE C C, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy[J]. Science, 2009, 326(5954): 818-823.
19 EICHLER F, DUNCAN C, MUSOLINO P L, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy[J]. N Engl J Med, 2017, 377(17): 1630-1638.
20 BOUGNèRES P, HACEIN-BEY-ABINA S, LABIK I, et al. Long-term follow-up of hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy[J]. Hum Gene Ther, 2021, 32(19/20): 1260-1269.
21 LUIS A. The old and the new: prospects for non-integrating lentiviral vector technology[J]. Viruses, 2020, 12(10): 1103.
22 National Library of Medicine. A clinical study to assess the efficacy and safety of gene therapy for the treatment of cerebral adrenoleukodystrophy (CALD)[EB/OL]. [2022-10-11]. https://clinicaltrials.gov/ct2/show/study/NCT03852498.
23 GONG Y, MU D, PRABHAKAR S, et al. Adenoassociated virus serotype 9-mediated gene therapy for X-linked adrenoleukodystrophy[J]. Mol Ther, 2015, 23(5): 824-834.
24 HONG S A, SEO J H, WI S, et al. In vivo gene editing via homology-independent targeted integration for adrenoleukodystrophy treatment[J]. Mol Ther, 2022, 30(1): 119-129.
25 GOPALAPPA R, LEE M, KIM G, et al. In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model[J]. Mol Ther, 2024, 32(7): 2190-2206.
26 ENGELEN M, VAN BALLEGOIJ W J C, MALLACK E J, et al. International recommendations for the diagnosis and management of patients with adrenoleukodystrophy: a consensus-based approach[J]. Neurology, 2022, 99(21): 940-951.
27 GOODISON W, BARON F, SEARY C, et al. Functional electrical stimulation to aid walking in patients with adrenomyeloneuropathy: a case study and observational series[J]. JIMD Rep, 2022, 63(1): 11-18.
28 GONG Y, BERENSON A, LAHEJI F, et al. Intrathecal adeno-associated viral vector-mediated gene delivery for adrenomyeloneuropathy[J]. Hum Gene Ther, 2019, 30(5): 544-555.
29 CAPPA M, TODISCO T, BIZZARRI C. X-linked adrenoleukodystrophy and primary adrenal insufficiency[J]. Front Endocrinol, 2023, 14: 1309053.
30 PETRYK A, POLGREEN L E, CHAHLA S, et al. No evidence for the reversal of adrenal failure after hematopoietic cell transplantation in X-linked adrenoleukodystrophy[J]. Bone Marrow Transplant, 2012, 47(10): 1377-1378.
31 BORNSTEIN S R, ALLOLIO B, ARLT W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline[J]. J Clin Endocrinol Metab, 2016, 101(2): 364-389.
32 ESPOSITO D, PASQUALI D, JOHANNSSON G. Primary adrenal insufficiency: managing mineralocorticoid replacement therapy[J]. J Clin Endocrinol Metab, 2018, 103(2): 376-387.
33 MOSER H W, RAYMOND G V, LU S E, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo′s oil[J]. Arch Neurol, 2005, 62(7): 1073-1080.
34 SINGH I, KHAN M, KEY L, et al. Lovastatin for X-linked adrenoleukodystrophy[J]. N Engl J Med, 1998, 339(10): 702-703.
35 ENGELEN M, OFMAN R, DIJKGRAAF M G W, et al. Lovastatin in X-linked adrenoleukodystrophy[J]. N Engl J Med, 2010, 362(3): 276-277.
36 PAI G S, KHAN M, BARBOSA E, et al. Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients[J]. Mol Genet Metab, 2000, 69(4): 312-322.
37 MONTERNIER P A, SINGH J, PARASAR P, et al. Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy[J]. J Inherit Metab Dis, 2022, 45(4): 832-847.
38 RODRíGUEZ-PASCAU L, VILALTA A, CERRADA M, et al. The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy[J]. Sci Transl Med, 2021, 13(596): eabc0555.
39 K?HLER W, ENGELEN M, EICHLER F, et al. Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2?3 trial[J]. Lancet Neurol, 2023, 22(2): 127-136.
40 GOLSE M, WEINHOFER I, BLANCO B, et al. Leriglitazone halts disease progression in adult patients with early cerebral adrenoleukodystrophy[J]. Brain, 2024, 147(10): 3344-3351.
41 SCH?LS L. Leriglitazone: frustration and hope in adrenoleukodystrophy[J]. Lancet Neurol, 2023, 22(2): 103-105.
42 MONTERNIER P A, PARASAR P, THEUREY P, et al. Beneficial effects of the direct AMP-kinase activator PXL770 in in vitro and in vivo models of X-linked adrenoleukodystrophy[J]. J Pharmacol Exp Ther, 2022, 382(2): 208-222.
43 Business Wire. Poxel announces PXL770 awarded FDA fast track designation for X-linked adrenoleukodystrophy[EB/OL]. (2022-04-11)[2024-11-19]. https://www.businesswire.com/news/home/2022041 1005632/en/Poxel-Announces-PXL770-Awarded-FDA-Fast-Track-Designation-for-X-linked-Adrenoleukodystrophy.
Options
Outlines

/

〈 〉