提示: 手机请竖屏浏览!

造血干细胞基因疗法治疗大脑型肾上腺脑白质营养不良
Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy


Florian Eichler ... 妇产科和儿科 • 2017.10.26
相关阅读
• 输血依赖型β-地中海贫血患者的基因治疗 • 肾上腺脑白质营养不良的Lenti-D基因疗法

摘要


背景

在X连锁肾上腺脑白质营养不良(ALD)中,ABCD1基因突变导致ALD蛋白功能丧失。大脑型肾上腺脑白质营养不良的特征包括脱髓鞘和神经变性。疾病进展会导致神经功能丧失并死亡,而唯一能够阻止疾病进展的方法为同种异体造血干细胞移植。

 

方法

在一项单组、开放标签、2~3期安全性和疗效的研究中,我们纳入了罹患大脑型肾上腺脑白质营养不良的男童。在入组筛选时,患者需处于疾病早期,并且磁共振成像(MRI)检查显示有钆增强。该研究性治疗为向患者输注自体CD34+细胞;这些自体CD34+细胞转导了elivaldogene tavalentivec(Lenti-D)慢病毒载体。在此次中期分析中,我们对患者是否出现下列结局进行了评估:移植物抗宿主病、死亡、主要的功能残疾,以及神经功能的变化和MRI影像中病变范围的变化。主要终点是输入自体细胞后24个月时患者能够存活,并且无主要的功能残疾。

 

结果

共有17名男童接受了Lenti-D基因治疗。在中期分析时,中位随访时间为29.4个月(范围,21.6~42.0个月)。在细胞植入后,所有患者均有基因标记的细胞;在已知癌基因或克隆生长基因附近,我们未发现优先整合的证据。我们观察到,所有患者均可检测到ALD蛋白。未发现治疗相关的死亡或移植物抗宿主病;17例患者中有15例(88%)存活,没有主要的功能残疾,而且临床症状轻微。一例患者出现神经系统功能迅速恶化,死于疾病进展。另一例患者的MRI显示疾病进展,他退出本研究以接受同种异体干细胞移植,之后死于移植相关的并发症。

 

结论

本研究的早期结果提示,在患早期大脑型肾上腺脑白质营养不良的男童中,Lenti-D基因治疗可能是同种异体干细胞移植安全而有效的替代方法。我们还需要进一步随访,以充分评估疾病缓解的持续时间和长期安全性(由Bluebird Bio等资助;STARBEAM在ClinicalTrials.gov注册号为NCT01896102;在ClinicalTrialsRegister.eu注册号为2011-001953-10)。





作者信息

Florian Eichler, M.D., Christine Duncan, M.D., Patricia L. Musolino, M.D., Ph.D., Paul J. Orchard, M.D., Satiro De Oliveira, M.D., Adrian J. Thrasher, M.D., Myriam Armant, Ph.D., Colleen Dansereau, M.S.N., R.N., Troy C. Lund, M.D., Weston P. Miller, M.D., Gerald V. Raymond, M.D., Raman Sankar, M.D., Ami J. Shah, M.D., Caroline Sevin, M.D., Ph.D., H. Bobby Gaspar, M.D., Paul Gissen, M.D., Hernan Amartino, M.D., Drago Bratkovic, M.D., Nicholas J.C. Smith, M.D., Asif M. Paker, M.D., Esther Shamir, M.P.H., Tara O’Meara, B.S., David Davidson, M.D., Patrick Aubourg, M.D., and David A. Williams, M.D.
From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana–Farber and Boston Children’s Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children’s Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) — all in Massachusetts; University of Minnesota Children’s Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women’s and Children’s Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.). Address reprint requests to Dr. Williams at Boston Children’s Hospital, 300 Longwood Ave., Karp 08125.3, Boston, MA 02115, or at dawilliams@childrens.harvard.edu.

 

参考文献

1. Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997;120:1485-1508

2. Eichler FS, Ren JQ, Cossoy M, et al. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann Neurol 2008;63:729-742

3. Powers JM, Liu Y, Moser AB, Moser HW. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 1992;51:630-643

4. Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol 2007;6:687-692

5. Peters C, Charnas LR, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 2004;104:881-888

6. Polgreen LE, Chahla S, Miller W, et al. Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison’s disease improves survival and neurological outcomes. Eur J Pediatr 2011;170:1049-1054

7. Baumann M, Korenke GC, Weddige-Diedrichs A, et al. Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy. Eur J Pediatr 2003;162:6-14

8. Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis 2012;7:51-51

9. Shapiro E, Krivit W, Lockman L, et al. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 2000;356:713-718

10. Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 2011;118:1971-1978

11. Naldini L. Ex vivo gene transfer and correction for cell-based therapies. Nat Rev Genet 2011;12:301-315

12. Naldini L. Gene therapy returns to centre stage. Nature 2015;526:351-360

13. Williams DA, Thrasher AJ. Concise review: lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases. Stem Cells Transl Med 2014;3:636-642

14. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009;326:818-823

15. Moser HW, Loes DJ, Melhem ER, et al. X-linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality: a study involving 372 patients. Neuropediatrics 2000;31:227-239

16. Loes DJ, Hite S, Moser H, et al. Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 1994;15:1761-1766

17. Schmidt M, Schwarzwaelder K, Bartholomae C, et al. High-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR). Nat Methods 2007;4:1051-1057

18. Saute JA, Souza CF, Poswar FO, et al. Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome. Arq Neuropsiquiatr 2016;74:953-966

19. van Geel BM, Poll-The BT, Verrips A, Boelens JJ, Kemp S, Engelen M. Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study. J Inherit Metab Dis 2015;38:359-361

20. Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology 2003;61:369-374

21. Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999;45:100-110

22. Mitchell R, Nivison-Smith I, Anazodo A, et al. Outcomes of haematopoietic stem cell transplantation for inherited metabolic disorders: a report from the Australian and New Zealand Children’s Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry. Pediatr Transplant 2013;17:582-588

23. Beam D, Poe MD, Provenzale JM, et al. Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy. Biol Blood Marrow Transplant 2007;13:665-674

24. Amartino H, Eichler F, Duncan C, et al. Expanding our understanding of cerebral adrenoleukodystrophy and interim phase 2/3 results of an autologous hematopoietic stem cell gene therapy. In: Abstracts presented at the 13th International Congress of Inborn Errors of Metabolism — ICIEM 2017. J Inborn Errors Metab Screen 2017;5:1-413. abstract.

25. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008;118:3132-3142

26. Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest 2008;118:3143-3150

27. Stein S, Ott MG, Schultze-Strasser S, et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010;16:198-204

28. Avedillo Díez I, Zychlinski D, Coci EG, et al. Development of novel efficient SIN vectors with improved safety features for Wiskott-Aldrich syndrome stem cell based gene therapy. Mol Pharm 2011;8:1525-1537

29. Hacein-Bey-Abina S, Pai S-Y, Gaspar HB, et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 2014;371:1407-1417

30. Aiuti A, Biasco L, Scaramuzza S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 2013;341:1233151-1233151

31. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013;341:1233158-1233158

32. Hacein-Bey Abina S, Gaspar HB, Blondeau J, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA 2015;313:1550-1563

服务条款 | 隐私政策 | 联系我们