A local joint research team said that they had discovered a potential therapy for adrenoleukodystrophy (ALD) -- also called the “Lorenzo’s oil disease” after a movie title -- through the gene scissor technique.
The team, led by Professor Cho Sung-rae of the Department of Rehabilitation Medicine at Severance Hospital and Professor Bae Sang-soo of the Department of Chemistry at Hanyang University, found it after correcting the mutated gene through gene scissors in cells derived from ALD patients and in animal models.
ALD is a genetic mutation in ABCD1, which is responsible for transporting fatty acids and is a hereditary rare and incurable disease in which very long-chain fatty acids abnormally accumulated in the nervous system and adrenal cortex and destroys the myelin surrounding the nerves. In severe cases, it can cause paralysis in the brain-spinal nerve system and makes it difficult for patients to walk.
To treat the symptoms, hospitals conventionally administered Lorenzo's oil, a combination of erucic acid and oleic acid, or bone marrow transplantation.
However, as the treatment did not cure the disease, there was an urgent need for a fundamental treatment, and various researchers have focused their attention on gene therapy.
The joint research team, too, applied gene-editing therapy using gene scissors to patient-derived cells and animal models for the first time to correct mutated genes in ALD patients.
Professor Bae's team used the homology-independent targeted insertion (HITI) method and the adenine base editing (ABE) method to insert the normal ABCD1 gene into the target site in cells collected from ALD patients succeeded in gene editing.
Gene editing is a method of correcting a mutated gene that causes disease by replacing a part of the DNA with errors with gene scissors, and ABE replaces one adenine base based on guide RNA.
Afterward, Professor Cho's team tried gene-editing therapy using adeno-associated virus vectors in an ALD animal model. As a result, the team confirmed that ABCD1 mRNA expression increased in the brain, spinal cord, liver, kidney, and adrenal glands while decreasing long-chain fatty acids in the blood.
"This is the first successful study of applying gene-editing therapy, a method of precisely inserting a normal gene into a target site, to cells and animal models derived from ALD," Professor Bae said.
Professor Cho said, “Through the results of this study, we confirmed the possibility of gene editing to treat not only ALD but also various intractable diseases caused by genetic mutations.”
Molecular Therapy has published the study in its latest issue.