Editing Adrenoleukodystrophy (section)

==Treatments==

===Dietary therapy===
Initial attempts at dietary therapy in ALD involved restricting the intake of very-long chain fatty acids (VLCFA).  Dietary intake is not the only source for VLCFA in the body, as they are also synthesized endogenously.  This dietary restriction did not impact the levels of VLCFA in plasma and other body tissues.<ref name=bergerreview />  After the realization that endogenous synthesis was an important contribution to VLCFA in the body, efforts at dietary therapy shifted to inhibiting these synthetic pathways in the body.  The [[Augusto and Michaela Odone|parents]] of [[Lorenzo Odone]], a boy with ALD, spearheaded efforts to develop a dietary treatment to slow the progression of the disease.  They developed a mixture of unsaturated fatty acids ([[glyceryl trioleate|glycerol trioleate]] and glyceryl trierucate in a 4:1 ratio), known as [[Lorenzo's oil]] that inhibits elongation of saturated fatty acids in the body.<ref name=bergerreview /><ref name="transplantreview"/> Supplementation with Lorenzo's oil has been found to normalize the VLCFA concentrations in the body, although its effectiveness at treating the cerebral manifestations of the disease is still controversial and unproven.<ref name=oil>{{cite journal |last1=Moser |first1=Hugo W. |last2=Moser |first2=Ann B. |last3=Hollandsworth |first3=Kim |last4=Brereton |first4=N. Hong |last5=Raymond |first5=Gerald V. |s2cid=21333247 |title='Lorenzo's Oil' Therapy for X-linked Adrenoleukodystrophy: Rationale and Current Assessment of Efficacy |journal=Journal of Molecular Neuroscience |date=24 August 2007 |volume=33 |issue=1 |pages=105–113 |doi=10.1007/s12031-007-0041-4 |pmid=17901554 }}</ref>  Trials with Lorenzo's oil have shown that it does not stop the neurological degradation in symptomatic patients, nor does it improve adrenal function,<ref name=bergerreview /> but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction.<ref>{{cite journal |last1=Semmler |first1=Alexander |last2=Köhler |first2=Wolfgang |last3=Jung |first3=Hans H |last4=Weller |first4=Michael |last5=Linnebank |first5=Michael |title=Therapy of X-linked adrenoleukodystrophy |journal=Expert Review of Neurotherapeutics |date=9 January 2014 |volume=8 |issue=9 |pages=1367–1379 |doi=10.1586/14737175.8.9.1367 |pmid=18759549 |s2cid=207195153 |url=https://www.zora.uzh.ch/id/eprint/5565/2/Semmler_5565_X-ALD_TherapyV.pdf |access-date=4 January 2020 |archive-date=13 April 2021 |archive-url=https://web.archive.org/web/20210413092934/https://www.zora.uzh.ch/id/eprint/5565/2/Semmler_5565_X-ALD_TherapyV.pdf |url-status=live }}</ref>

'''Adrenomix®''':
In 2009, a second-generation mixture was created, adding to the glycerol trioleate (GTO) and trierucate [[glycerol]] (GTE), [[conjugated linoleic acid]] (CLA) a group of linoleic acid isomers capable of overcoming the [[Blood–brain barrier|blood-brain barrier]]. CLA, through the activation of peroxisome beta oxidation, increases the [[catabolism]] of pro-inflammatory molecules and ROS, acting as an anti-inflammatory and antioxidant. The use of CLA was initially considered in relation to the ability to inhibit [[fatty acid synthase]] together with a hypolipidic diet. A group of Italian researchers of the Bambino Gesù Pediatric Hospital in Rome showed that the administration of Adrenomix (GTO, GTE and CLA), in addition to decreasing levels of [[Very long chain fatty acid|VLCFA]] throughout the body, reduces neuro inflammation and improves somatosensory evoked potential, found unchanged or worsened with only administration of GTO and GTE.<ref>{{cite journal|title=A mixture of oleic, erucic and conjugated linoleic acids modulates cerebrospinal fluid inflammatory markers and improve somatosensorial evoked potential in X-linked adrenoleukodystrophy female carriers|year=2012 |pmid=22189598 |last1=Cappa |first1=M. |last2=Bizzarri |first2=C. |last3=Petroni |first3=A. |last4=Carta |first4=G. |last5=Cordeddu |first5=L. |last6=Valeriani |first6=M. |last7=Vollono |first7=C. |last8=De Pasquale |first8=L. |last9=Blasevich |first9=M. |last10=Banni |first10=S. |journal=Journal of Inherited Metabolic Disease |volume=35 |issue=5 |pages=899–907 |doi=10.1007/s10545-011-9432-3 |pmc=3432215 }}<!-- auto-translated by Module:CS1 translator --></ref>

'''[https://aldixylald.com/ Aldixyl®]''':
In 2016, based on studies developed in recent years in the field of adrenoleukodystrophy and adrenomyelouropathy, a mixture was developed that adds to GTO, GTE and CLA, a mixture of
powerful antioxidants at high dosages containing [[Lipoic acid|alpha lipoic acid]] (ALA), reduced L- glutathione and [[Vitamin E]] (α- tocopherol). Researchers at the IDIBELL- Hospital Duran i Reynals in Barcelona have shown that the early administration of a cocktail of powerful antioxidants, able to overcome the blood-brain barrier and thus carry out its activity at the [[Central nervous system|CNS]] level, prevents the [[oxidative stress]] typical of the disease, intervenes on the initial axonal dysfunctions and therefore on locomotor damage.<ref>{{cite journal|title=Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy|year=2011 |pmid=21786300 |last1=López-Erauskin |first1=J. |last2=Fourcade |first2=S. |last3=Galino |first3=J. |last4=Ruiz |first4=M. |last5=Schlüter |first5=A. |last6=Naudi |first6=A. |last7=Jove |first7=M. |last8=Portero-Otin |first8=M. |last9=Pamplona |first9=R. |last10=Ferrer |first10=I. |last11=Pujol |first11=A. |journal=Annals of Neurology |volume=70 |issue=1 |pages=84–92 |doi=10.1002/ana.22363 |pmc=3229843 }}<!-- auto-translated by Module:CS1 translator --></ref> This new mixture, unlike what happened with the administration of GTO and GTE alone, poorly accumulated at the level of the nervous system, enhances the anti-inflammatory activity and reduces the levels of VLCFA in the CNS by combining synergistically the activity of its components. In particular, CLA, in addition to overcoming the blood-brain barrier and regulating at the CNS level the metabolism of VLCFA is able to influence the catabolism of pro-inflammatory [[eicosanoid]]s and [[lipid peroxidation]] products.<ref>{{cite journal|title=Identification of metabolites from peroxisomal beta-oxidation of prostaglandins|year=1990 |pmid=2324649 |last1=Diczfalusy |first1=U. |last2=Alexson |first2=S. E. |journal=Journal of Lipid Research |volume=31 |issue=2 |pages=307–314 |doi=10.1016/S0022-2275(20)43216-X |doi-access=free }}<!-- auto-translated by Module:CS1 translator --></ref><ref>{{cite journal|title=Studies on the urinary excretion of thromboxane B2 in Zellweger patients and control subjects: evidence for a major role for peroxisomes in the beta-oxidative chain-shortening of thromboxane B2|year=1994 |pmid=8155738 |url=https://www.ncbi.nlm.nih.gov/pubmed/8155738 |last1=De Waart |first1=D. R. |last2=Koomen |first2=G. C. |last3=Wanders |first3=R. J. |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |volume=1226 |issue=1 |pages=44–48 |doi=10.1016/0925-4439(94)90057-4 }}<!-- auto-translated by Module:CS1 translator --></ref><ref>{{cite journal|title=Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of leukotrienes|year=2002 |pmid=12054595 |url=https://www.ncbi.nlm.nih.gov/pubmed/12054595 |last1=Ferdinandusse |first1=S. |last2=Meissner |first2=T. |last3=Wanders |first3=R. J. |last4=Mayatepek |first4=E. |journal=Biochemical and Biophysical Research Communications |volume=293 |issue=1 |pages=269–273 |doi=10.1016/S0006-291X(02)00214-0 }}<!-- auto-translated by Module:CS1 translator --></ref><ref>{{cite journal|title=12- and 15-hydroxyeicosatetraenoic acid are excreted in the urine of peroxisome-deficient patients: evidence for peroxisomal metabolism in vivo|year=1996 |pmid=8825400 |last1=Mayatepek |first1=E. |last2=Lehmann |first2=W. D. |journal=Pediatric Research |volume=39 |issue=1 |pages=146–149 |doi=10.1203/00006450-199601000-00022 |s2cid=20240456 |doi-access=free }}<!-- auto-translated by Module:CS1 translator --></ref><ref>{{cite journal|title=Impairment of 8-iso-PGF(2ALPHA) isoprostane metabolism by dietary conjugated linoleic acid (CLA)|year=2009 |pmid=19403295 |url=https://www.ncbi.nlm.nih.gov/pubmed/19403295 |last1=Iannone |first1=A. |last2=Petroni |first2=A. |last3=Murru |first3=E. |last4=Cordeddu |first4=L. |last5=Carta |first5=G. |last6=Melis |first6=M. P. |last7=Bergamini |first7=S. |last8=Casa |first8=L. D. |last9=Cappiello |first9=L. |last10=Carissimi |first10=R. |last11=O'Shea |first11=M. |last12=Bell |first12=D. |last13=De Santis |first13=E. |last14=Banni |first14=S. |journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids |volume=80 |issue=5–6 |pages=279–287 |doi=10.1016/j.plefa.2009.02.008 }}<!-- auto-translated by Module:CS1 translator --></ref> In this sense, the anti-inflammatory activity of ALA, reduced L-glutathione and Vitamin E is enhanced at the level of the whole body, and not only at the peripheral level as was the case in the past.<ref>{{cite journal|title=Neurophysiological abnormalities in adrenoleukodystrophy carriers. Evidence of different degrees of central nervous system involvement|year=1997 |pmid=9236627 |last1=Restuccia |first1=D. |last2=Di Lazzaro |first2=V. |last3=Valeriani |first3=M. |last4=Oliviero |first4=A. |last5=Le Pera |first5=D. |last6=Colosimo |first6=C. |last7=Burdi |first7=N. |last8=Cappa |first8=M. |last9=Bertini |first9=E. |last10=Di Biase |first10=A. |last11=Tonali |first11=P. |journal=Brain |volume=120 |issue=7 |pages=1139–1148 |doi=10.1093/brain/120.7.1139 |doi-access=free }}<!-- auto-translated by Module:CS1 translator --></ref>

===Transplant===
While dietary therapy has been shown to be effective to normalize the very-long chain fatty acid concentrations in the plasma of individuals with ALD, [[Hematopoietic stem cell transplantation#Allogeneic|allogeneic hematopoietic stem cell transplants]] is the only treatment that can stop [[demyelination]] that is the hallmark of the cerebral forms of the disease.<ref name=transplantreview>{{cite journal |last1=Cartier |first1=Nathalie |last2=Aubourg |first2=Patrick |title=Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in X-Linked Adrenoleukodystrophy |journal=Brain Pathology |date=27 October 2009 |volume=20 |issue=4 |pages=857–862 |doi=10.1111/j.1750-3639.2010.00394.x |pmid=20626747 |s2cid=24182017 |pmc=8094635 }}</ref>  In order to be effective, the transplant must be done at an early stage of the disease; if the demyelination has progressed, transplant can worsen the outcome, and increase the rate of decline.  While transplants have been shown to be effective at halting the demyelination process in those presenting with the childhood cerebral form of ALD, follow-up of these patients has shown that it does not improve adrenal function.<ref name=adrenalfunction>{{cite journal |last1=Petryk |first1=A |last2=Polgreen |first2=L E |last3=Chahla |first3=S |last4=Miller |first4=W |last5=Orchard |first5=P J |title=No evidence for the reversal of adrenal failure after hematopoietic cell transplantation in X-linked adrenoleukodystrophy |journal=Bone Marrow Transplantation |date=5 March 2012 |volume=47 |issue=10 |pages=1377–1378 |doi=10.1038/bmt.2012.33 |pmid=22388279 |pmc=4547590 }}</ref>

===Gene therapy===
For patients where an appropriate match for a transplant cannot be found, there have been investigations into the use of [[gene therapy]].  Appropriate [[Vectors in Gene Therapy|vectors]] are selected and modified to express [[wild type]] ''ABCD1'', which is then transplanted into the patients using a similar procedure as for a bone marrow or stem cell transplant.<ref name="transplantreview"/>  Gene therapy has only been tried on a small number of patients, mainly in [[France]].  These patients were only considered for gene therapy after there was no [[Human leukocyte antigen|HLA match]] for a traditional transplant.  In two reported cases, the gene therapy was successful, with a resolution of the demyelination process up to two years after the procedure.  Although the gene therapy was successful in resolving the neurological symptoms, plasma VLCFA levels remained elevated.<ref name="transplantreview"/>

[[Elivaldogene autotemcel]] is pending authorization by the European Commission {{as of|May 2021|lc=yes}}. While this treatment is effective with 90% of patients being free of major functional disabilities after treatment, it costs $3.0 million per treatment and it comes with several adverse effects including mucositis and alopecia.<ref>{{Cite web |last=Liu |first=Angus |date=September 19, 2022 |title=A $3M gene therapy: Bluebird bio breaks its own pricing record with FDA approval of Skysona |url=https://www.fiercepharma.com/pharma/3m-gene-therapy-bluebird-breaks-own-record-fda-approval-skysona |access-date=November 1, 2023 |website=Fierce Pharma}}</ref><ref name="Skysona: Pending EC decision">{{cite web | title=Skysona: Pending EC decision | website=[[European Medicines Agency]] (EMA) | date=21 May 2021 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/skysona | access-date=1 June 2021 | archive-date=2 June 2021 | archive-url=https://web.archive.org/web/20210602214431/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/skysona | url-status=live }}</ref><ref>{{cite press release | title=Bluebird Bio Receives Positive CHMP Opinion for Skysona (elivaldogene autotemcel, Lenti-D) Gene Therapy for Patients Less Than 18 Years of Age with Early Cerebral Adrenoleukodystrophy (CALD) | publisher=Bluebird Bio | via=Business Wire | date=21 May 2021 | url=https://www.businesswire.com/news/home/20210521005242/en/bluebird-bio-Receives-Positive-CHMP-Opinion-for-SKYSONA%E2%84%A2-elivaldogene-autotemcel-Lenti-D%E2%84%A2-Gene-Therapy-for-Patients-Less-Than-18-Years-of-Age-with-Early-Cerebral-Adrenoleukodystrophy-CALD | access-date=1 June 2021 | archive-date=2 June 2021 | archive-url=https://web.archive.org/web/20210602215413/https://www.businesswire.com/news/home/20210521005242/en/bluebird-bio-Receives-Positive-CHMP-Opinion-for-SKYSONA%E2%84%A2-elivaldogene-autotemcel-Lenti-D%E2%84%A2-Gene-Therapy-for-Patients-Less-Than-18-Years-of-Age-with-Early-Cerebral-Adrenoleukodystrophy-CALD | url-status=live }}</ref><ref name="SPS">{{cite web | title=Elivaldogene autotemcel | website=SPS - Specialist Pharmacy Service | date=28 May 2021 | url=https://www.sps.nhs.uk/medicines/elivaldogene-autotemcel/ | access-date=1 June 2021 | archive-date=2 June 2021 | archive-url=https://web.archive.org/web/20210602214726/https://www.sps.nhs.uk/medicines/elivaldogene-autotemcel/ | url-status=live }}</ref> There are also reports of hematologic cancer development in patients receiving this gene therapy, including myelodysplastic syndrome and acute myeloid leukemia.<ref>N Engl J Med 2024;391:1287-1301, DOI: 10.1056/NEJMoa2405541</ref>

=== Drugs ===
The anti-diabetic medication [[pioglitazone]] was shown in a mouse model of ALD to be effective at treating the metabolic effects of ALD, including metabolic failure and increased [[oxidative stress]]. Pioglitazone was also shown to prevent axonal degeneration and increase mitochondria levels, as well as stop the progression of locomotor decline in ALD model mice.<ref>{{Cite journal |last=Morató |first=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 |date=August 2013 |title=Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy |url=https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awt143 |journal=Brain |language=en |volume=136 |issue=8 |pages=2432–2443 |doi=10.1093/brain/awt143 |issn=1460-2156 |pmc=4550111 |pmid=23794606}}</ref> Subsequently, the drug leriglitazone has been developed by Minoryx Therapeutics as a more [[Blood–brain barrier|brain penetrant]] metabolite of pioglitazone.<ref>{{Cite journal |last=Rodríguez-Pascau |first=Laura |last2=Vilalta |first2=Anna |last3=Cerrada |first3=Marc |last4=Traver |first4=Estefania |last5=Forss-Petter |first5=Sonja |last6=Weinhofer |first6=Isabelle |last7=Bauer |first7=Jan |last8=Kemp |first8=Stephan |last9=Pina |first9=Guillem |last10=Pascual |first10=Sílvia |last11=Meya |first11=Uwe |last12=Musolino |first12=Patricia L. |last13=Berger |first13=Johannes |last14=Martinell |first14=Marc |last15=Pizcueta |first15=Pilar |date=2021-06-02 |title=The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy |url=https://www.science.org/doi/10.1126/scitranslmed.abc0555 |journal=Science Translational Medicine |language=en |volume=13 |issue=596 |doi=10.1126/scitranslmed.abc0555 |issn=1946-6234}}</ref> Currently, leriglitazone is in [[Phases of clinical research|phase 2/3 clinical trials]] for adult and childhood cALD in the USA and the EU, and has completed a clinical trial for AMN.<ref>{{Cite journal |last=Köhler |first=Wolfgang |last2=Engelen |first2=Marc |last3=Eichler |first3=Florian |last4=Lachmann |first4=Robin |last5=Fatemi |first5=Ali |last6=Sampson |first6=Jacinda |last7=Salsano |first7=Ettore |last8=Gamez |first8=Josep |last9=Molnar |first9=Maria Judit |last10=Pascual |first10=Sílvia |last11=Rovira |first11=Maria |last12=Vilà |first12=Anna |last13=Pina |first13=Guillem |last14=Martín-Ugarte |first14=Itziar |last15=Mantilla |first15=Adriana |date=2023-02-01 |title=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 |url=https://linkinghub.elsevier.com/retrieve/pii/S1474442222004951 |journal=The Lancet Neurology |language=English |volume=22 |issue=2 |pages=127–136 |doi=10.1016/S1474-4422(22)00495-1 |issn=1474-4422 |pmc=11847323 |pmid=36681445}}</ref>

===Adrenal insufficiency===
Treatment of the adrenal insufficiency that can accompany any of the common male phenotypes of ALD does not resolve any of the neurological symptoms.  Hormone replacement is standard for ALD patients demonstrating adrenal insufficiency.<ref name=peroxleuk>{{cite journal |last1=Poll-The |first1=Bwee |last2=Engelen |first2=Marc |title=Peroxisomal Leukoencephalopathy |journal=Seminars in Neurology |date=15 March 2012 |volume=32 |issue=1 |pages=042–050 |doi=10.1055/s-0032-1306385 |pmid=22422205 |s2cid=39152217 }}</ref>  Adrenal insufficiency does not resolve with successful transplant; most patients still require hormone replacement.<ref name=adrenalfunction />