The long road from lorenzo s Oil: new perspectives on diet therapy. Professor Marina Melone/Doctor Clemente Dato Second University of Naples, Italy
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1 The long road from lorenzo s Oil: new perspectives on diet therapy Professor Marina Melone/Doctor Clemente Dato Second University of Naples, Italy
2 The start of the road Lorenzo s Oil was autonomously developed in 1986 by Michela and Augusto Odone, in order to treat their son Lorenzo. Lorenzo was affected by X-ALD. Glyceryl triolate Glyceryl trierucate Lorenzo s Oil is a 4:1 mixture of glyceryl trioleate and glyceryl trierucate (GTO e GTE). GTO and GTE competitively inhibit the elongase that produces VLCFA, normalizing VLCFA levels in X-ALD and AMN patients.
3 89 asymptomatic patients with normal brain MRI (mean age 4,7 years) showed two-fold or greater reduction in the risk of developing the childhood cerebral form of X-ALD. In this single-arm study, hexacosanoic acid reduction by Lorenzo s oil was associated with reduced risk of developing MRI abnormalities. We recommend Lorenzo s oil therapy in asymptomatic boys with X-linked adrenoleukodystophy who have normal brain MRI results. MOSER ET AL, 2005 Beyond the Odones experience and Moser s final study on asymptomatic children, the story of Lorenzo s oil has been fraught, especially in regard to other patients population in the family of ABCD1 disorders.
4 It was a breathtaking scientific achievement spearheaded by two laypeople. [ ] Yet Lorenzo s story tells us as much about the limitations of medical research as it does about its triumphs [Lerner, 2009]
5 in our Center... Second Department of Neurology of the Second University of Naples, Italy. As of May 2016, 35 patients routinely followed for diseases linked to ABCD1 mutations. Ten families.
6 Adult female symptomatic carriers: Often misdiagnosed. Spastic paraparesis, sensory and motor neuropathy, urinary incontinence presenting later in life. Patients with peculiar phenotypes: Mild clinical presentation, with rare cerebral and adrenal involvement. Adult males with adrenomyeloneuropathy: Late age of onset ( years, range years) A 54-year-old man with AMN who, in the last 2 years, developed a severe frontal syndrome. A 62-year-old man, genetically diagnosed, currently asymptomatic.. What do we offer to these patients?
7 Current challenges We know that Lorenzo s Oil is able to decrease plasma VLCFA level. However, plasma VLCFA level is not an accurate marker or predictor of clinical state and other processes need to be considered. Inflammation plays an important pathogenetic role Immunoreactivity may stems from accumulation of C:26 in the cell membrane; Oxidative stress, due to inflammation and peroxisomal beta-oxidation products. The decrease of peroxisomal beta-oxidation may also lead to a decreased catabolism of proinflammatory eicosanoids and lipid peroxidation products. So, if we can reliably induce peroxisomal function, we may be able to suppress inflammation and oxidative stress, too.
8 A team of specialists from Rome, Milan and Cagliari, has hypothesized that conjugated lipoleic acid (CLA, family of isomers of lipoleic acids) may induce peroxisomal betaoxidation and allow eruric acid to pass the blood brain barrier[cappa et al, 2012]. CLA is high affinity ligand of the peroxisome-activated receptor (PPAR) alpha, a transcriptor factor for the genes involved in peroximal beta oxidation, and thereby able to induce key enzymes for this process. [cappa et al, 2012] A preliminary study has been performed on five mildy symptomatic or asymptomatic X-ALD women. They were treated with a mixture of LO (40g/day) and CLA (5 g/day) for two months; during this period, blood and CSF samples were collected for fatty acids composition, and Sensory Evoked Potential Testing was performed.
9 Plasma levels of 26:0 and 26:0/22:0 ratio decreased in all patients. Platelet count was not affected. IL6 levels in CSF decreased in three patients and remained stable in two. In SEP testing, P40 and N37 latency decreased in all patients (note: this change is not present in pure LO treatment Restuccia et al, 1999). This results suggest that LO+CLA may be helpful in adult, symptomatic patients. A mixture with this composion, by the commercial name of Adrenomix, has been used in Italy since 2009.
10 Moratò et al, 2015 Sirtuin1 (SIRT1) is a deacetylase that activates PGC 1-alpha and promotes mitocondrial biogenesis. SIRT1 is dysregulated in X-ALD patients and animal models, probably as a response to ROS formation. This could, however, be part of a vicious circle. Oxidative Stress Sirt1 DYSREGULATION DECREASE IN MITOCONDRIAL NUMBER AND FUNCTION Notably, SIRT1 transcription is induced by the phenol Resveratrol (RSV). This has also been confirmed in fibrobasts from X-ALD patients.
11 The phenotype of ABCD1deficient mice shows a severe amount of spinal chord degeneration, with few signs of inflammation, making them a model of adrenomyeloneuropathy.
12 ABCD1-deficient mice treated with reseveratrol, show a decrease in C:26:0 dependant ROS generation; it prevents cell death and normalizes ATP levels. ABCD1-deficient mice treated with reseveratrol show results comparable to ABCD1-deficient mice also engineered to overexpress SIRT1. Notably, ABCD1-deficient mice genetically engineered to also overexpress SIRT1 do not show axonal degeneration nor motor deficits.
13 GALINO ET AL, 2011 Treating ABCD1-deficient mice with an association of nacetyl-cystein and alpha-lipoic acid prevents protein oxidation, preserves NADH, NADPH, ATP and GSH levels. petrillo et al, 2013 A significant decrease of total and reduced glutathione was found in lymphocytes of 14 adult patients with X-ALD, associated to high levels of all oxidized glutathione forms. Glutathione
14 López-Erauskin et al, 2011 The administration of a combination of alpha-lipoic acid, glutathion and alphatocopherol (vitamin E) prevents and arrests progression of locomotor deficits in Abcd1-deficient and Abcd2-deficient mice. Our data strongly suggest that an early and carefully tailored antioxidant intervention using the cocktail described could be a plausible therapeutic option for AMN patients, who do not suffer from severe neuroinflammatory demyelination. A mixture with this composition will be commercialized soon in Italy by the name of Aldixyl.
15 It has been a long, winding road: many steps have been taken, but we still have a great journey ahead of us. Thank you for your attention!
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