title: Developing therapeutic approaches for metachromatic leukodystrophy.
abstract: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood-brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.
authors: McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors: Shilpa A
authors: SA
authors: Patil
authors: Gustavo H B
authors: GH
authors: Maegawa
mesh_terms: D000483:Alleles; D001812:Blood-Brain Barrier; D002553:Cerebroside-Sulfatase / Q000235:genetics; D004793:Enzyme Reactivators; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000628:therapy*
chemical_list: D004793:Enzyme Reactivators; D002553:Cerebroside-Sulfatase
keywords: arylsulfatase A; enzyme enhancement therapy; enzyme replacement therapy; gene therapy; metachromatic leukodystrophy; small molecules
references: Mol Genet Metab. 2009 Aug;97(4):284-91
references: 19447653
references: Brain Res. 2006 Jun 13;1094(1):13-23
references: 16729983
references: Hum Genet. 1997 Dec;101(2):135-40
references: 9402957
references: J Cell Biol. 1999 Mar 22;144(6):1271-84
references: 10087269
references: J Biol Chem. 1989 Jun 5;264(16):9283-8
references: 2470753
references: J Biol Chem. 2003 Aug 8;278(32):29496-501
references: 12756243
references: J Inherit Metab Dis. 1995;18(2):157-8
references: 7564234
references: Ann Neurol. 1993 Aug;34(2):212-8
references: 8101704
references: Birth Defects Orig Artic Ser. 1971 Feb;7(1):103-12
references: 5173355
references: Digestion. 1992;51(2):121-4
references: 1499874
references: Clin Chem. 1996 Feb;42(2):232-8
references: 8595716
references: Neurobiol Dis. 2009 Nov;36(2):242-51
references: 19632328
references: Science. 1965 Dec 17;150(3703):1613-4
references: 5866661
references: Mol Genet Metab. 2011 Dec;104(4):566-73
references: 21982629
references: Cell. 1996 Jul 26;86(2):209-19
references: 8706126
references: Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21486-91
references: 23236186
references: Brain Res. 1987 Apr 28;410(1):89-96
references: 3107757
references: J Clin Invest. 2006 Nov;116(11):3070-82
references: 17080200
references: Hoppe Seylers Z Physiol Chem. 1964;339(1):260-76
references: 5829234
references: Pediatr Neurol. 2003 Nov;29(5):391-403
references: 14684234
references: Expert Rev Neurother. 2010 Sep;10(9):1449-66
references: 20819015
references: J Neuropathol Exp Neurol. 1962 Oct;21:534-54
references: 13999412
references: Pediatr Radiol. 1998 Sep;28(9):706-8
references: 9732500
references: Clin Neuropathol. 1987 Sep-Oct;6(5):224-30
references: 2826059
references: Acta Paediatr Jpn. 1993 Oct;35(5):404-8
references: 8256624
references: Biol Blood Marrow Transplant. 2013 Apr;19(4):616-24
references: 23348427
references: Hum Genet. 1991 Jan;86(3):251-5
references: 1671769
references: Mol Biotechnol. 2010 Jun;45(2):180-6
references: 20151227
references: FEBS J. 2005 Mar;272(5):1179-88
references: 15720392
references: Hum Mutat. 1999;14(3):240-8
references: 10477432
references: J Biol Chem. 2009 Aug 28;284(35):23502-16
references: 19578116
references: J Ultrasound Med. 1996 Dec;15(12):821-5
references: 8947856
references: Metab Brain Dis. 2008 Dec;23(4):469-84
references: 18797988
references: Cell Biol Toxicol. 2010 Feb;26(1):43-55
references: 19904619
references: Cell. 2003 May 16;113(4):435-44
references: 12757705
references: Expert Opin Emerg Drugs. 2010 Sep;15(3):495-507
references: 20557271
references: Cell. 2008 Sep 5;134(5):769-81
references: 18775310
references: Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):966-71
references: 23277556
references: J Clin Gastroenterol. 1995;21 Suppl 1:S98-103
references: 8774999
references: J Inherit Metab Dis. 2009 Apr;32(2):181-9
references: 19130290
references: Pediatr Surg Int. 1997 Jul;12(5-6):424-5
references: 9244117
references: J Biol Chem. 2002 Mar 15;277(11):9455-61
references: 11777924
references: N Engl J Med. 1991 Jan 3;324(1):18-22
references: 1670590
references: Nature. 2013 Feb 21;494(7437):323-7
references: 23389440
references: Am J Hum Genet. 1991 Dec;49(6):1340-50
references: 1684088
references: PLoS One. 2013 Apr 19;8(4):e61418
references: 23620750
references: Neurobiol Dis. 2005 Feb;18(1):83-8
references: 15649698
references: Mol Ther. 2009 Apr;17(4):600-6
references: 19174759
references: J Biol Chem. 1994 Mar 18;269(11):8362-5
references: 8132559
references: J Cent Nerv Syst Dis. 2012 Apr 26;4:73-9
references: 23650469
references: Trends Cell Biol. 2011 Oct;21(10):585-93
references: 21763137
references: Mol Cells. 2013 Apr;35(4):291-7
references: 23515578
references: J Neurochem. 1990 Nov;55(5):1585-91
references: 1976756
references: Lancet Neurol. 2007 Sep;6(9):765-72
references: 17689147
references: J Inherit Metab Dis. 1994;17(4):500-9
references: 7967499
references: Expert Opin Biol Ther. 2005 Jan;5(1):55-65
references: 15709909
references: Trends Neurosci. 1998 Mar;21(3):126-30
references: 9530920
references: Anal Biochem. 2013 Mar 1;434(1):15-25
references: 23138179
references: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8
references: 16864780
references: Glia. 2011 Jul;59(7):1009-21
references: 21491498
references: Science. 2008 Feb 15;319(5865):916-9
references: 18276881
references: Bone Marrow Transplant. 1998 Dec;22(11):1119-22
references: 9877277
references: Bone Marrow Transplant. 2007 Mar;39(5):309-10
references: 17237829
references: Hum Mol Genet. 2012 Jun 1;21(11):2599-609
references: 22388935
references: Hum Genomics. 2009 Dec;4(2):69-72
references: 20038494
references: Genes Dev. 2008 Oct 1;22(19):2645-50
references: 18832069
references: J Neurosci. 2009 May 20;29(20):6663-76
references: 19458236
references: Gene Ther. 2002 Jan;9(1):53-63
references: 11850723
references: Mol Genet Metab. 2009 Sep-Oct;98(1-2):215-24
references: 19595619
references: J Clin Invest. 2004 Apr;113(8):1118-29
references: 15085191
references: Acta Neuropathol. 2004 Oct;108(4):261-71
references: 15322834
references: J Neurosci. 2007 Aug 22;27(34):9009-21
references: 17715338
references: Mol Genet Metab. 2012 Jan;105(1):56-63
references: 22078456
references: Brain Res. 1989 Mar 20;482(2):347-50
references: 2706492
references: Keio J Med. 1992 Sep;41(3):161-7
references: 1434311
references: PLoS One. 2011;6(12):e29504
references: 22216298
references: Trends Endocrinol Metab. 2004 Jul;15(5):222-8
references: 15223052
references: Cell. 2007 Nov 16;131(4):809-21
references: 18022373
references: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4506-11
references: 17360554
references: Dev Neurosci. 2008;30(5):340-57
references: 18667806
references: PLoS Biol. 2008 Feb;6(2):e26
references: 18254660
references: Acta Paediatr. 2007 Apr;96(455):26-32
references: 17391436
references: Biochem J. 1994 Jan 1;297 ( Pt 1):123-30
references: 7506530
references: Semin Hematol. 2010 Jan;47(1):70-8
references: 20109614
references: Gene Ther. 2006 Dec;13(24):1686-95
references: 16871228
references: NeuroRx. 2005 Jan;2(1):3-14
references: 15717053
references: J Biol Chem. 2010 Apr 2;285(14):10902-10
references: 20110363
references: J Biol Chem. 2007 Mar 23;282(12):9150-61
references: 17237499
references: Acta Paediatr. 2008 Apr;97(457):15-21
references: 18339182
references: Curr Biol. 2001 Aug 21;11(16):1283-7
references: 11525744
references: J Biol Chem. 2010 Jul 2;285(27):20423-7
references: 20430897
references: Am J Med Genet. 1997 Mar 31;69(3):335-40
references: 9096767
references: J Neurochem. 1966 Nov;13(11):1037-45
references: 5924656
references: N Engl J Med. 1990 Jan 4;322(1):28-32
references: 1967188
references: Hum Genet. 1989 Apr;82(1):45-8
references: 2565866
references: Neurobiol Dis. 2004 Jul;16(2):396-406
references: 15193296
references: Trans Am Neurol Assoc. 1964;89:147-50
references: 5828490
references: J Lipid Res. 1988 Nov;29(11):1475-9
references: 3241123
references: Hum Genet. 1992 Mar;88(5):513-23
references: 1348043
references: Bone Marrow Transplant. 1996 Jun;17(6):1003-8
references: 8807106
references: J Neurosci Res. 2009 Nov 15;87(15):3259-66
references: 19021296
references: Nat Rev Mol Cell Biol. 2009 Sep;10(9):623-35
references: 19672277
references: J Neurosci. 2006 Mar 22;26(12):3109-19
references: 16554462
references: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13280-5
references: 8917582
references: Nat Med. 2008 Nov;14(11):1247-55
references: 18953351
references: Hum Mutat. 1993;2(4):261-7
references: 8104633
references: Nat Rev Mol Cell Biol. 2003 Mar;4(3):202-12
references: 12612639
references: Lancet. 1999 Sep 11;354(9182):901-5
references: 10489949
references: Genomics. 1996 Jul 1;35(1):215-22
references: 8661123
references: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3557-62
references: 14990803
references: Nat Med. 2001 Dec;7(12):1356-61
references: 11726978
references: Neuropediatrics. 2010 Feb;41(1):1-6
references: 20571983
references: Bone Marrow Transplant. 2008 Oct;42 Suppl 2:S2-6
references: 18978739
references: J Biol Chem. 1986 Jun 25;261(18):8263-9
references: 3087971
references: Biochem Biophys Res Commun. 1989 Mar 15;159(2):605-11
references: 2539117
references: Ann Neurol. 2004 Nov;56(5):642-9
references: 15505823
references: J Neurosci. 2008 Sep 24;28(39):9741-54
references: 18815260
references: BMC Neurosci. 2011 Mar 02;12:22
references: 21366909
references: J Comb Chem. 1999 Jan;1(1):55-68
references: 10746014
references: Curr Biol. 1998 Jul 16;8(15):R512-3
references: 9705943
references: J Biotechnol. 2005 May 25;117(3):243-51
references: 15862354
references: Eur J Pediatr. 1993 May;152(5):450-1
references: 8319717
references: Hum Gene Ther. 2007 Sep;18(9):821-36
references: 17845130
references: Hum Genet. 1991 May;87(1):87-8
references: 1674719
references: JAMA. 1999 Jan 20;281(3):249-54
references: 9918480
references: Biol Chem. 2008 Jan;389(1):1-11
references: 18095864
references: FEBS J. 2010 Aug;277(16):3404-14
references: 20646068
references: PLoS One. 2011;6(6):e20218
references: 21695197
references: Arch Pathol Lab Med. 1977 May;101(5):255-9
references: 576797
references: Science. 1997 Apr 18;276(5311):428-31
references: 9103204
references: Bone Marrow Transplant. 2003 Feb;31(4):229-39
references: 12621457
references: J Mol Biol. 2001 Jan 12;305(2):269-77
references: 11124905
references: Lancet. 2012 Jan 28;379(9813):335-41
references: 22133539
references: Curr Opin Neurol. 1999 Apr;12(2):167-76
references: 10226749
references: Mol Genet Metab. 2012 Nov;107(3):490-5
references: 23041259
references: Acta Paediatr. 2008 Apr;97(457):88-93
references: 18339196
references: Biochemistry. 1998 Mar 17;37(11):3654-64
references: 9521684
references: PLoS One. 2008 May 28;3(5):e2296
references: 18509511
references: J Biol Chem. 2009 Nov 27;284(48):33549-60
references: 19801672
references: J Neurol Sci. 2007 Apr 15;255(1-2):7-16
references: 17341424
references: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14821-6
references: 8962139
references: Glycoconj J. 2004;21(1-2):59-62
references: 15467400
references: Hum Mol Genet. 2008 Jan 1;17(1):119-29
references: 17913701
references: Nat Med. 2010 Nov;16(11):1205-9
references: 21052074