Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy
Condition: Adrenomyeloneuropathy; X-linked Adrenoleukodystrophy
MeSH terms: Adrenoleukodystrophy
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Pioglitazone
Intervention type(s): Drug
Intervention MeSH terms: Pioglitazone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AMN; pioglitazone