The long road from lorenzo`s Oil: new perspectives on diet therapy

The long road from lorenzo’s Oil:
new perspectives on diet therapy
Professor Marina Melone/Doctor Clemente Dato
Second University of Naples, Italy
The start of the road
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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.

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.
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“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”.
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MOSER ET AL, 2005
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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.
“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]
in our Center...
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Second Department of Neurology of the Second
University of Naples, Italy.
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As of May 2016, 35 patients routinely followed for
diseases linked to ABCD1 mutations.
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Ten families.
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Adult female symptomatic carriers:
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Often misdiagnosed.
Spastic paraparesis, sensory and motor neuropathy, urinary
incontinence presenting later in life.
Patients with peculiar phenotypes:
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Mild clinical presentation, with rare cerebral and adrenal
involvement.
Adult males with adrenomyeloneuropathy:
●
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Late age of onset (37 +- 14.6 years, range 32-73 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?
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.
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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.
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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].
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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.
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[cappa et al, 2012]
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A preliminary study has been performed on five mildy
symptomatic or asymptomatic X-ALD women.
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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.
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Plasma levels of 26:0 and 26:0/22:0
ratio decreased in all patients.
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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).
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This results suggest that LO+CLA
may be helpful in adult,
symptomatic patients.
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A mixture with this composion, by
the
commercial
name
of
Adrenomix, has been used in Italy
since 2009.
Moratò et al, 2015
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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.
The phenotype of ABCD1deficient mice shows a
severe amount of spinal
chord degeneration, with
few signs of inflammation,
making them a model of
adrenomyeloneuropathy.

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.
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Notably, ABCD1-deficient mice
genetically engineered to also
overexpress SIRT1 do not show
axonal degeneration nor motor
deficits.
GALINO ET AL, 2011
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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
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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
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.
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“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.
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!