Developing AAV-based gene therapy for adrenoleukodystrophy (X-ALD)

Abstract

Background & Aim Adrenoleukodystrophy (X-ALD) is an X-linked disease. ALD is caused by mutations of the gene encoding ATP-Binding cassette subfamily D member 1 (ABCD1), a peroxisomal transmembrane protein. Dysfunctional ABCD1 protein results in excessive accumulation of very long chain fatty acid (VLCFA) in neural system and leads to demyelination and neural death. Currently, no effective treatments are available to cure X-ALD except BMT at very early stage of disease. Gene therapy using virus as a vehicle is an efficient method to transfer a target gene to human cells. Adeno-associated virus (AAV)-based gene therapy is of high interest for current research. The mechanism of AAV gene transfer does not cause any insertions of target gene into the human genome, which highly enhance the safety of the therapy. There are different serotypes of AAV, each targets different cell types. Therefore, AAV would be a promising vector to cure different diseases in the future. Methods, Results & Conclusion Here in this project, AAV vector with functional ABCD1 gene is constructed and its effectiveness is being tested in vitro for treating X-ALD. Meanwhile, a new animal model – ABCD1 gene mutated rabbit is used to mimic condition of X-ALD patients. Compared to the same age wild type rabbits, the diseased model shows a 5-10 folds increase in plasma VLCFA level before the treatment, and magnetic resonance imaging (MRI) scan is performed to determine demyelination inside the CNS. After AAV injection, rabbits' blood VLCFA level is monitored regularly, MRI scan and brain tissue sectioning are examined to determine the effectiveness of the AAV-based gene therapy targeting X-ALD.