Validation of direct AMP kinase (AMPK) activation for treatment of X-linked Adrenoleukodystrophy

Document Type

Conference Proceeding

Publication Date


Publication Title

J Neurol Sci


Background and aims: X-linked Adrenoleukodystrophy (ALD and adrenomyeloneuropathy - AMN) is a neurologic peroxisomal disorder, caused by ABCD1-gene mutations, leading to Very Long Chain Fatty Acid (VLCFA; C26:0) accumulation, AMPK downregulation, inflammation, mitochondrial impairment and demyelination. We investigated PXL770, a clinical-stage new direct AMPK activator, in AMN/ALD models.

Methods: AMN/ALD patient-derived fibroblasts/lymphocytes and ABCD1-KO mouse glial cells were exposed to PXL770 for 7 days. Phospho-AMPK was measured by Western-blot, VLCFA content by LC-MS, selected gene expression by RT-qPCR and oxygen consumption with a Seahorse Analyzer. PXL770 (oral 75 mg/kg, BID, 12 weeks) was administered to ABCD1-KO mice. VLCFA content was measured by LC-MS, sciatic nerve axonal morphology by electronic microscopy, and locomotor function by beam balance test.

Results: In AMN fibroblasts PXL770 reduced C26:0 levels (−90%, p = 0.0001), increased compensatory ABCD2 mRNA levels (9-fold), and improved mitochondrial function by increasing basal and ATP-linked respiration (14% and 112%, respectively) and decreasing proton leak (−25%). Similar profile was achieved in ALD fibroblasts, ALD/AMN lymphocytes and ABCD1-KO mice glial cells. In ALD lymphocytes, PXL770 decreased mRNAs encoding pro-inflammatory proteins including NF-κB, iNOS and CCR3 (2.9-fold, 8.2-fold, 5.9-fold, respectively). In ABCD1-KO mice treated with PXL770, C26:0 levels were decreased in the spinal cord by 29% (greater VLCFA decrease was also observed in brain/plasma). Sciatic nerve axons showed less myelin invaginations (−61%) and neurologic function was improved compared to untreated mice.

Conclusions: We established preclinical validation for the potential utility of direct AMPK activators as a treatment for X-ALD, supporting further development of PXL770 for this debilitating neurometabolic disease.



First Page