Adrenoleukodystrophy future or investigational therapies: Difference between revisions
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==Overview== | ==Overview== | ||
Several other studies are being conducted on sobetirome, a thyroid hormone receptor agonist, and pioglitazone, a PPARγ agonist. Antioxidant therapy has also shown some persuasive results demanding a larger study whereas treatment with Gene therapy including Ex vivo lentiviral gene correction and in vivo adeno-associated virus 9 (AAV9) based gene therapy is being pursued. | |||
=Future or Investigational Therapies== | =Future or Investigational Therapies= | ||
===Metabolic modulators=== | |||
[[Lovastatin]] is an anti cholesterol drug that normalized plasma VLCFA in one study but showed no normalization to placebo in randomized double‐blind crossover trial. <ref name="EngelenOfman2010">{{cite journal|last1=Engelen|first1=Marc|last2=Ofman|first2=Rob|last3=Dijkgraaf|first3=Marcel G.W.|last4=Hijzen|first4=Michiel|last5=van der Wardt|first5=Lucinda A.|last6=van Geel|first6=Bjorn M.|last7=de Visser|first7=Marianne|last8=Wanders|first8=Ronald J.A.|last9=Poll-The|first9=Bwee Tien|last10=Kemp|first10=Stephan|title=Lovastatin in X-Linked Adrenoleukodystrophy|journal=New England Journal of Medicine|volume=362|issue=3|year=2010|pages=276–277|issn=0028-4793|doi=10.1056/NEJMc0907735}}</ref> | |||
Several other studies are being conducted on sobetirome, a thyroid hormone receptor agonist<ref name="HartleyKirkemo2017">{{cite journal|last1=Hartley|first1=Meredith D.|last2=Kirkemo|first2=Lisa L.|last3=Banerji|first3=Tapasree|last4=Scanlan|first4=Thomas S.|title=A Thyroid Hormone–Based Strategy for Correcting the Biochemical Abnormality in X-Linked Adrenoleukodystrophy|journal=Endocrinology|volume=158|issue=5|year=2017|pages=1328–1338|issn=0013-7227|doi=10.1210/en.2016-1842}}</ref>, and pioglitazone, a PPARγ agonist.<ref name="MoratóGalino2013">{{cite journal|last1=Morató|first1=Laia|last2=Galino|first2=Jorge|last3=Ruiz|first3=Montserrat|last4=Calingasan|first4=Noel Ylagan|last5=Starkov|first5=Anatoly A.|last6=Dumont|first6=Magali|last7=Naudí|first7=Alba|last8=Martínez|first8=Juan José|last9=Aubourg|first9=Patrick|last10=Portero-Otín|first10=Manuel|last11=Pamplona|first11=Reinald|last12=Galea|first12=Elena|last13=Beal|first13=M. Flint|last14=Ferrer|first14=Isidre|last15=Fourcade|first15=Stéphane|last16=Pujol|first16=Aurora|title=Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy|journal=Brain|volume=136|issue=8|year=2013|pages=2432–2443|issn=1460-2156|doi=10.1093/brain/awt143}}</ref> | |||
===Antioxidant therapy=== | |||
High-dose antioxidants have been seen in a limited open-label study with adolescents with AMN. Progress has been seen in a 6-minute walk test, which demands a larger study. <ref name="pmid31077039">{{cite journal| author=Casasnovas C, Ruiz M, Schlüter A, Naudí A, Fourcade S, Veciana M | display-authors=etal| title=Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study. | journal=Neurotherapeutics | year= 2019 | volume= 16 | issue= 4 | pages= 1167-1182 | pmid=31077039 | doi=10.1007/s13311-019-00735-2 | pmc=6985062 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31077039 }}</ref> | |||
N-Acetyl cysteine (NAC) adjunct therapy for individuals undergoing allogeneic HSCT has been shown to improve survival in patients with more advance neurological deficit.<ref name="MillerRothman2011">{{cite journal|last1=Miller|first1=Weston P.|last2=Rothman|first2=Steven M.|last3=Nascene|first3=David|last4=Kivisto|first4=Teresa|last5=DeFor|first5=Todd E.|last6=Ziegler|first6=Richard S.|last7=Eisengart|first7=Julie|last8=Leiser|first8=Kara|last9=Raymond|first9=Gerald|last10=Lund|first10=Troy C.|last11=Tolar|first11=Jakub|last12=Orchard|first12=Paul J.|title=Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report|journal=Blood|volume=118|issue=7|year=2011|pages=1971–1978|issn=0006-4971|doi=10.1182/blood-2011-01-329235}}</ref> | |||
===Gene therapy=== | |||
Ex vivo lentiviral gene Correction and in vivo adeno-associated virus 9 (AAV9)-based gene therapy is being pursued. The latter has shown to correct the metabolism of VLCFA in mice<ref name="GongMu2015">{{cite journal|last1=Gong|first1=Yi|last2=Mu|first2=Dakai|last3=Prabhakar|first3=Shilpa|last4=Moser|first4=Ann|last5=Musolino|first5=Patricia|last6=Ren|first6=JiaQian|last7=Breakefield|first7=Xandra O|last8=Maguire|first8=Casey A|last9=Eichler|first9=Florian S|title=Adenoassociated Virus Serotype 9-Mediated Gene Therapy for X-Linked Adrenoleukodystrophy|journal=Molecular Therapy|volume=23|issue=5|year=2015|pages=824–834|issn=15250016|doi=10.1038/mt.2015.6}}</ref>, although the former has also demonstrated positive effects in a study involving 17 ALD boys with early-stage brain disease who underwent Lenti-D ABCD1 gene therapy and confirmed that 15 of the patients survived the therapy. There was no treatment related death or graft versus host disease seen in them.<ref name="pmid19892975">{{cite journal| author=Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I | display-authors=etal| title=Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. | journal=Science | year= 2009 | volume= 326 | issue= 5954 | pages= 818-23 | pmid=19892975 | doi=10.1126/science.1171242 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19892975 }}</ref> | |||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
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Overview
Several other studies are being conducted on sobetirome, a thyroid hormone receptor agonist, and pioglitazone, a PPARγ agonist. Antioxidant therapy has also shown some persuasive results demanding a larger study whereas treatment with Gene therapy including Ex vivo lentiviral gene correction and in vivo adeno-associated virus 9 (AAV9) based gene therapy is being pursued.
Future or Investigational Therapies
Metabolic modulators
Lovastatin is an anti cholesterol drug that normalized plasma VLCFA in one study but showed no normalization to placebo in randomized double‐blind crossover trial. [1]
Several other studies are being conducted on sobetirome, a thyroid hormone receptor agonist[2], and pioglitazone, a PPARγ agonist.[3]
Antioxidant therapy
High-dose antioxidants have been seen in a limited open-label study with adolescents with AMN. Progress has been seen in a 6-minute walk test, which demands a larger study. [4]
N-Acetyl cysteine (NAC) adjunct therapy for individuals undergoing allogeneic HSCT has been shown to improve survival in patients with more advance neurological deficit.[5]
Gene therapy
Ex vivo lentiviral gene Correction and in vivo adeno-associated virus 9 (AAV9)-based gene therapy is being pursued. The latter has shown to correct the metabolism of VLCFA in mice[6], although the former has also demonstrated positive effects in a study involving 17 ALD boys with early-stage brain disease who underwent Lenti-D ABCD1 gene therapy and confirmed that 15 of the patients survived the therapy. There was no treatment related death or graft versus host disease seen in them.[7]
References
- ↑ Engelen, Marc; Ofman, Rob; Dijkgraaf, Marcel G.W.; Hijzen, Michiel; van der Wardt, Lucinda A.; van Geel, Bjorn M.; de Visser, Marianne; Wanders, Ronald J.A.; Poll-The, Bwee Tien; Kemp, Stephan (2010). "Lovastatin in X-Linked Adrenoleukodystrophy". New England Journal of Medicine. 362 (3): 276–277. doi:10.1056/NEJMc0907735. ISSN 0028-4793.
- ↑ Hartley, Meredith D.; Kirkemo, Lisa L.; Banerji, Tapasree; Scanlan, Thomas S. (2017). "A Thyroid Hormone–Based Strategy for Correcting the Biochemical Abnormality in X-Linked Adrenoleukodystrophy". Endocrinology. 158 (5): 1328–1338. doi:10.1210/en.2016-1842. ISSN 0013-7227.
- ↑ Morató, Laia; Galino, Jorge; Ruiz, Montserrat; Calingasan, Noel Ylagan; Starkov, Anatoly A.; Dumont, Magali; Naudí, Alba; Martínez, Juan José; Aubourg, Patrick; Portero-Otín, Manuel; Pamplona, Reinald; Galea, Elena; Beal, M. Flint; Ferrer, Isidre; Fourcade, Stéphane; Pujol, Aurora (2013). "Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy". Brain. 136 (8): 2432–2443. doi:10.1093/brain/awt143. ISSN 1460-2156.
- ↑ Casasnovas C, Ruiz M, Schlüter A, Naudí A, Fourcade S, Veciana M; et al. (2019). "Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study". Neurotherapeutics. 16 (4): 1167–1182. doi:10.1007/s13311-019-00735-2. PMC 6985062 Check
|pmc=value (help). PMID 31077039. - ↑ Miller, Weston P.; Rothman, Steven M.; Nascene, David; Kivisto, Teresa; DeFor, Todd E.; Ziegler, Richard S.; Eisengart, Julie; Leiser, Kara; Raymond, Gerald; Lund, Troy C.; Tolar, Jakub; Orchard, Paul J. (2011). "Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report". Blood. 118 (7): 1971–1978. doi:10.1182/blood-2011-01-329235. ISSN 0006-4971.
- ↑ Gong, Yi; Mu, Dakai; Prabhakar, Shilpa; Moser, Ann; Musolino, Patricia; Ren, JiaQian; Breakefield, Xandra O; Maguire, Casey A; Eichler, Florian S (2015). "Adenoassociated Virus Serotype 9-Mediated Gene Therapy for X-Linked Adrenoleukodystrophy". Molecular Therapy. 23 (5): 824–834. doi:10.1038/mt.2015.6. ISSN 1525-0016.
- ↑ Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I; et al. (2009). "Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy". Science. 326 (5954): 818–23. doi:10.1126/science.1171242. PMID 19892975.