X-linked Adrenoleukodystrophy Clinical Trial
Official title:
Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy: a Phase II, Single-arm, Multicentric Clinical Trial
X-linked adrenoleukodystrophy is a rare, demyelinating and neurodegenerative disorder, due to
loss of function of a fatty acid transporter, the peroxisomal ABCD1 protein. Its more
frequent phenotype, the adrenomyeloneuropathy in adults, is characterized by axonal
degeneration in spinal cord, spastic paraparesis and a disabling peripheral neuropathy.
Actually, there is no efficient treatment for the disease. The work of the researchers in the
last twelve years dissecting the physiopathological basis of the disorder has uncovered an
involvement of the early oxidative stress in the neurodegenerative cascade and mitocondrial
depletion. In a preclinical trial they have observed that pioglitazone, a PPARγ/PGC-1α axis
metabolic activator with immunomodulatory, anti-inflammatory and antioxidant response
regulator properties, efficiently reverse the clinical symptoms and the axonal degeneration
in the mouse model for the disease and normalize stress and mitochondrial depletion
biomarkers.
The researchers will test the effectiveness of the drug in terms of motor function and
correction of oxidative damage markers in proteins and DNA and inflammation markers in an
open trial. Fifteen-twenty patients will be included and clinically explored and assessed in
the HU of Bellvitge and the HU of Donostia using clinical scales for spasticity, evoked
potentials, electroneurinograms and cranial RMN. The information will be collected in a data
base that will be of great value to improve the present attention and the future follow-up of
the patients and to facilitate their inclusion in therapeutic randomized, double blind,
against placebo, multicentric and international clinical trials.
Proof of concept for this trial is provided by the results of biochemical, neuropathological
and motor effects of pioglitazone in two mouse models of AMN. Pioglitazone was given orally
(9 mg/kg/day) for two months in both models.
The Abcd1‐null mouse model already shows at 3,5 months biochemical signs oxidative stress
that increase with time and are then associated with energy homeostasis alterations, although
first clinical signs of AMN—i.e. axonopathy and locomotor impairment—appear at 20 months. In
these mice, there are mitochondrial anomalies, decreased levels of PGC‐1α which is a master
regulator of mitochondrial biogenesis, and decreased levels and activity of SIRT1α, which
activates PGC‐1α.
The Abcd1‐null mouse can be considered as a "AMN‐like" model, because of the absence of
demyelinating lesions in brain and spinal cord, the presence of non‐inflammatory
''dying‐back'' axonopathy in peripheral nerves and spinal cord and its late‐onset motor
deficits that all are hallmarks of AMN in X‐ALD patients. This model was used to assess the
efficacy of pioglitazone on several biochemical markers in the spinal cord of Abcd1‐null mice
(N=12), using comparisons with placebo-¬treated Abcd1‐null mice (N=12) or wild‐type mice
(N=12).
In Abcd1‐null mice treated with pioglitazone at 10,5 months of age and studied at 12 months
(1,5 months following the beginning of the ongoing treatment), mitochondrial anomalies were
corrected to the level of wild type control mice. Indeed, mitochondrial DNA and protein
(including PGC‐1α, NRF1 and TFAM) levels were corrected; as well as mitochondrial metabolism,
as assessed by pyruvate kinase activity, ATP and NAD+ concentrations. Pioglitazone had no
effect on SIRT1 expression (mRNA and protein levels). However, pioglitazone significantly
lowered the carbonylation of SIRT1 protein, which presumably accounts for the observed rescue
of SIRT1 activity.
In these mice treated with pioglitazone, oxidative lesions in the spinal cord were reversed.
Studied oxidative stress biomarkers included markers of oxidative lesions to proteins (GSA,
AASA), lipids (MDAL) and carbohydrates (CEL). Additionally, the activity and concentration
level of antioxidant enzymes GPX1, which were increased in untreated Abcd1‐null mice, but not
SOD2, was normalized to the level of wild type mice.
The second mouse model is the double knockouts (DKO) in which both Abcd1 and Abcd2
transporters are inactivated. The Abcd1‐/Abcd2‐/‐DKO exhibits greater VLCFA accumulation in
spinal cord (Pujol et al., 2004), higher levels of oxidative damage to proteins, and a more
severe AMN-¬like pathology, with earlier onset of motor impairment than the single Abcd1‐null
mouse (12 months in the DKO compared to 20 months in Abcd1‐null mice). Efficacy of
pioglitazone at the motor and neuropathologic levels was studied in 17 Abcd1‐/Abcd2‐/‐mice
comparing them with placebo‐treated Abcd1‐/Abcd2-/-mice (N=17) and wild‐type mice (N=25).
In Abcd1‐/Abcd2‐/‐mice treated with pioglitazone at 13 months of age and studied at 15 or 17
months (treatment duration of 2 to 4 months), axonal degeneration was prevented, as shown by
the normalization to the control level of number of APP or synaptophysin positive axons.
Also, pioglitazone arrested the progression of locomotor deficits in these mice, as assessed
by the treadmill test and the bar‐cross test. Indeed, the locomotor performances of
pioglitazone DKO after four months of treatment mice reached the performances of the
controls.
Overall, these studies show the efficacy of treatment with pioglitazone in "AMN‐like mice
"and provide a strong rationale for conducting a preliminary open clinical trial with
pioglitazone in AMN patients.
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