Neuropediatrics 2019; 50(04): 211-218
DOI: 10.1055/s-0039-1685529
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Opening New Horizons in the Treatment of Childhood Onset Leukodystrophies

Stina Schiller
1   Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Germany
,
Marco Henneke
1   Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Germany
,
Jutta Gärtner
1   Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Germany
› Author Affiliations
Further Information

Publication History

16 August 2018

04 March 2019

Publication Date:
21 May 2019 (online)

Abstract

Leukodystrophies (LDs) predominantly affect the white matter of the central nervous system and its main component, the myelin. The majority of LDs manifests in infancy with progressive neurodegeneration. Main clinical signs are intellectual and motor function losses of already attained developmental skills. Classical LDs include lysosomal storage disorders like metachromatic leukodystrophy (MLD), peroxisomal disorders like X-linked adrenoleukodystrophy (X-ALD), disorders of mitochondrial dysfunction, and myelin protein defects like Pelizaeus-Merzbacher disease. So far, there are only single LD disorders with effective treatment options in an early stage of disease. The increasing number of patients diagnosed with LDs emphasizes the need for novel therapeutic options. Impressive advances in biotechnology have not only led to the continuous identification of new disease genes for so far unknown LDs but also led to new effective neuroprotective and disease-modifying therapeutic approaches. This review summarizes ongoing and novel innovative treatment options for LD patients and their challenges. It includes in vitro and in vivo approaches with focus on stem cell and gene therapies, intrathecal substrate or enzyme replacement, and genome editing.

 
  • References

  • 1 Kevelam SH, Steenweg ME, Srivastava S. , et al. Update on leukodystrophies: a historical perspective and adapted definition. Neuropediatrics 2016; 47 (06) 349-354
  • 2 Piguet F, Sondhi D, Piraud M. , et al. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther 2012; 23 (08) 903-914
  • 3 van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 2017; 134 (03) 351-382
  • 4 Vanderver A, Simons C, Helman G. , et al; Leukodystrophy Study Group. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79 (06) 1031-1037
  • 5 Kristjánsdóttir R, Uvebrant P, Rosengren L. Glial fibrillary acidic protein and neurofilament in children with cerebral white matter abnormalities. Neuropediatrics 2001; 32 (06) 307-312
  • 6 Shah DK, Ponnusamy V, Evanson J. , et al. Raised plasma neurofilament light protein levels are associated with abnormal MRI outcomes in newborns undergoing therapeutic hypothermia. Front Neurol 2018; 9: 86
  • 7 Boesen MS, Jensen PEH, Magyari M. , et al. Increased cerebrospinal fluid chitinase 3-like 1 and neurofilament light chain in pediatric acquired demyelinating syndromes. Mult Scler Relat Disord 2018; 24: 175-183
  • 8 Neufeld EF. Enzyme replacement therapy - a brief history. In: Mehta A, Beck M, Sunder-Plassmann G. , eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 10
  • 9 Ries M. Enzyme replacement therapy and beyond-in memoriam Roscoe O. Brady, M.D. (1923-2016). J Inherit Metab Dis 2017; 40 (03) 343-356
  • 10 Dali CSC, Riethmueller J, Giugliani R. , et al. Intrathecal delivery of recombinant human arylsulfatase A in children with late-infantile metachromatic leukodystrophy. Mol Genet Metab 2016; 117: 14-124
  • 11 Boelens JJ, van Hasselt PM. Neurodevelopmental outcome after hematopoietic cell transplantation in inborn errors of metabolism: current considerations and future perspectives. Neuropediatrics 2016; 47 (05) 285-292
  • 12 Bredius RG, Laan LA, Lankester AC. , et al. Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression. Bone Marrow Transplant 2007; 39 (05) 309-310
  • 13 Martin HR, Poe MD, Provenzale JM, Kurtzberg J, Mendizabal A, Escolar ML. Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. Biol Blood Marrow Transplant 2013; 19 (04) 616-624
  • 14 Penati R, Fumagalli F, Calbi V, Bernardo ME, Aiuti A. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccharidosis I. J Inherit Metab Dis 2017; 40 (04) 543-554
  • 15 Zerah M, Piguet F, Colle MA. , et al. Intracerebral gene therapy using AAVrh.10-hARSA recombinant vector to treat patients with early-onset forms of metachromatic leukodystrophy: preclinical feasibility and safety assessments in nonhuman primates. Hum Gene Ther Clin Dev 2015; 26 (02) 113-124
  • 16 Sessa M, Lorioli L, Fumagalli F. , et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 2016; 388 (10043): 476-487
  • 17 Eichler F, Duncan C, Musolino PL. , et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 2017; 377 (17) 1630-1638
  • 18 Biffi A, Montini E, Lorioli L. , et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013; 341 (6148): 1233158
  • 19 Cartier N, Aubourg P. Hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy in X-linked adrenoleukodystrophy. Brain Pathol 2010; 20 (04) 857-862
  • 20 Steinfeld R, Grapp M, Kraetzner R. , et al. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 2009; 85 (03) 354-363
  • 21 Huppke P, Weissbach S, Church JA. , et al. Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. Nat Commun 2017; 8 (01) 818
  • 22 Cesani M, Lorioli L, Grossi S. , et al. Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum Mutat 2016; 37 (01) 16-27
  • 23 Patil SA, Maegawa GH. Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des Devel Ther 2013; 7: 729-745
  • 24 Gomez-Ospina N. Arylsulfatase A deficiency. In: Adam MP, Ardinger HH, Pagon RA. , et al. eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; ; 1993-2019 2006. May 30 [updated 2017 Dec 14]
  • 25 Berger J, Löschl B, Bernheimer H. , et al. Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. Am J Med Genet 1997; 69 (03) 335-340
  • 26 Gieselmann V, Krägeloh-Mann I. Metachromatic leukodystrophy--an update. Neuropediatrics 2010; 41 (01) 1-6
  • 27 Groeschel S, Kühl JS, Bley AE. , et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol 2016; 73 (09) 1133-1140
  • 28 Helman G, Van Haren K, Bonkowsky JL. , et al; GLIA Consortium. Disease specific therapies in leukodystrophies and leukoencephalopathies. Mol Genet Metab 2015; 114 (04) 527-536
  • 29 Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis 2017; 2 (1-2): 1-71
  • 30 Spiegel R, Bach G, Sury V. , et al. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab 2005; 84 (02) 160-166
  • 31 Pavuluri P, Vadakedath S, Gundu R, Uppulety S, Kandi V. Krabbe disease: report of a rare lipid storage and neurodegenerative disorder. Cureus 2017; 9 (01) e949
  • 32 Sharp ME, Laule C, Nantel S. , et al. Stem cell transplantation for adult-onset Krabbe disease: report of a case. JIMD Rep 2013; 10: 57-59
  • 33 Duffner PK, Caviness Jr VS, Erbe RW. , et al. The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York. Genet Med 2009; 11 (06) 450-454
  • 34 Escolar ML, Poe MD, Provenzale JM. , et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 2005; 352 (20) 2069-2081
  • 35 Kwon JM, Matern D, Kurtzberg J. , et al. Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease. Orphanet J Rare Dis 2018; 13 (01) 30
  • 36 Conzelmann E, Sandhoff K. Partial enzyme deficiencies: residual activities and the development of neurological disorders. Dev Neurosci 1983- 1984; 6 (01) 58-71
  • 37 Torii T, Miyamoto Y, Yamauchi J, Tanoue A. Pelizaeus-Merzbacher disease: cellular pathogenesis and pharmacologic therapy. Pediatr Int 2014; 56 (05) 659-666
  • 38 Nevin ZS, Factor DC, Karl RT. , et al. Modeling the mutational and phenotypic landscapes of Pelizaeus-Merzbacher disease with human iPSC-derived oligodendrocytes. Am J Hum Genet 2017; 100 (04) 617-634
  • 39 Clayton BLL, Popko B. Endoplasmic reticulum stress and the unfolded protein response in disorders of myelinating glia. Brain Res 2016; 1648 (Pt B): 594-602
  • 40 Inoue K. Cellular pathology of Pelizaeus-Merzbacher disease involving chaperones associated with endoplasmic reticulum stress. Front Mol Biosci 2017; 4: 7
  • 41 Wishnew J, Page K, Wood S. , et al. Umbilical cord blood transplantation to treat Pelizaeus-Merzbacher disease in 2 young boys. Pediatrics 2014; 134 (05) e1451-e1457
  • 42 Osorio MJ, Rowitch DH, Tesar P, Wernig M, Windrem MS, Goldman SA. Concise review: stem cell-based treatment of Pelizaeus-Merzbacher disease. Stem Cells 2017; 35 (02) 311-315
  • 43 Gupta N, Henry RG, Strober J. , et al. Neural stem cell engraftment and myelination in the human brain. Sci Transl Med 2012; 4 (155) 155ra137
  • 44 Saher G, Rudolphi F, Corthals K. , et al. Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet. Nat Med 2012; 18 (07) 1130-1135
  • 45 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 (07) 1971-1978
  • 46 Roscoe RB, Elliott C, Zarros A, Baillie GS. Non-genetic therapeutic approaches to Canavan disease. J Neurol Sci 2016; 366: 116-124
  • 47 Mendes MI, Smith DE, Pop A. , et al. Clinically distinct phenotypes of Canavan disease correlate with residual aspartoacylase enzyme activity. Hum Mutat 2017; 38 (05) 524-531
  • 48 Wong LJ. Mitochondrial syndromes with leukoencephalopathies. Semin Neurol 2012; 32 (01) 55-61
  • 49 Cao J, Wu H, Li Z. Recent perspectives of pediatric mitochondrial diseases. Exp Ther Med 2018; 15 (01) 13-18
  • 50 Nightingale H, Pfeffer G, Bargiela D, Horvath R, Chinnery PF. Emerging therapies for mitochondrial disorders. Brain 2016; 139 (Pt 6): 1633-1648
  • 51 Livingston JH, Crow YJ. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières syndrome and beyond. Neuropediatrics 2016; 47 (06) 355-360
  • 52 Rice G, Patrick T, Parmar R. , et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet 2007; 81 (04) 713-725
  • 53 Crow YJ, Vanderver A, Orcesi S, Kuijpers TW, Rice GI. Therapies in Aicardi-Goutières syndrome. Clin Exp Immunol 2014; 175 (01) 1-8
  • 54 Mort M, Ivanov D, Cooper DN, Chuzhanova NA. A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 2008; 29 (08) 1037-1047
  • 55 McDonald CM, Campbell C, Torricelli RE. , et al; Clinical Evaluator Training Group; ACT DMD Study Group. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390 (10101): 1489-1498
  • 56 Keeling KM. Nonsense suppression as an approach to treat lysosomal storage diseases. Diseases 2016; 4 (04) 4
  • 57 Gómez-Grau M, Garrido E, Cozar M. , et al. Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases. PLoS One 2015; 10 (08) e0135873
  • 58 Min YL, Bassel-Duby R, Olson EN. CRISPR correction of Duchenne muscular dystrophy. Annu Rev Med 2018 ;•••: Doi: 10.1146/annurev-med-081117-010451
  • 59 Shimizu-Motohashi Y, Miyatake S, Komaki H, Takeda S, Aoki Y. Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: from discovery to clinical trials. Am J Transl Res 2016; 8 (06) 2471-2489
  • 60 Siva K, Covello G, Denti MA. Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases. Nucleic Acid Ther 2014; 24 (01) 69-86
  • 61 Regis S, Corsolini F, Grossi S, Tappino B, Cooper DN, Filocamo M. Restoration of the normal splicing pattern of the PLP1 gene by means of an antisense oligonucleotide directed against an exonic mutation. PLoS One 2013; 8 (09) e73633
  • 62 Tantzer S, Sperle K, Kenaley K, Taube J, Hobson GM. Morpholino antisense oligomers as a potential therapeutic option for the correction of alternative splicing in PMD, SPG2, and HEMS. Mol Ther Nucleic Acids 2018; 12: 420-432
  • 63 Hagemann TL, Powers B, Mazur C. , et al. Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease. Ann Neurol 2018; 83 (01) 27-39
  • 64 Zizioli D, Guarienti M, Tobia C. , et al. Molecular cloning and knockdown of galactocerebrosidase in zebrafish: new insights into the pathogenesis of Krabbe's disease. Biochim Biophys Acta 2014; 1842 (04) 665-675
  • 65 Galloway DA, Moore CS. miRNAs as emerging regulators of oligodendrocyte development and differentiation. Front Cell Dev Biol 2016; 4: 59
  • 66 Wen MM. Getting miRNA therapeutics into the target cells for neurodegenerative diseases: a mini-review. Front Mol Neurosci 2016; 9: 129
  • 67 Haussecker D, Kay MA. RNA interference. Drugging RNAi. Science 2015; 347 (6226): 1069-1070
  • 68 Arakawa T, Ejima D, Kita Y, Tsumoto K. Small molecule pharmacological chaperones: from thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta 2006; 1764 (11) 1677-1687
  • 69 Muntau AC, Leandro J, Staudigl M, Mayer F, Gersting SW. Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators. J Inherit Metab Dis 2014; 37 (04) 505-523
  • 70 Graziano AC, Pannuzzo G, Avola R, Cardile V. Chaperones as potential therapeutics for Krabbe disease. J Neurosci Res 2016; 94 (11) 1220-1230
  • 71 Grapp M, Wrede A, Schweizer M. , et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun 2013; 4: 2123
  • 72 Ingato D, Lee JU, Sim SJ, Kwon YJ. Good things come in small packages: Overcoming challenges to harness extracellular vesicles for therapeutic delivery. J Control Release 2016; 241: 174-185
  • 73 Rufino-Ramos D, Albuquerque PR, Carmona V, Perfeito R, Nobre RJ, Pereira de Almeida L. Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases. J Control Release 2017; 262: 247-258
  • 74 Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev 2016; 106 (Pt A): 148-156
  • 75 Fazio N, Ungaro A, Spada F. , et al. The role of multimodal treatment in patients with advanced lung neuroendocrine tumors. J Thorac Dis 2017; 9 (Suppl. 15) S1501-S1510
  • 76 Lee SU, Cho KH. Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination. Radiat Oncol J 2017; 35 (03) 189-197