Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (ALD) is an X-linked recessive metabolic storage disease caused by mutations in the ABCD1 gene that inhibit the production of adrenoleukodystrophy protein (ALDP). ALDP functions to transport very long-chain fatty acids (VLCFAs) to be metabolized by β- oxidation in peroxisomes. ABCD1 deficiency prevents the VLCFAs from being metabolized, resulting in the accumulation of toxic levels of VLCFAs throughout the body. It is believed that the accumulation of VLCFAs leads to the breakdown of myelin in the white matter of the central nervous system and the adrenal cortex, leading to neurological symptoms. There are several types of ALD, but the three major types are the childhood cerebral form, adrenomyelopathy, and adrenal insufficiency (Addison’s Disease). ALD mostly affects young boys, however some forms of the disease affect men later in life. Female carriers of ALD are often asymptomatic but may have mild symptoms due to heightened levels of VLCFAs.

Childhood cerebral ALD is the most severe form of the disease. Symptoms typically occur early in childhood and are often misdiagnosed as ADHD or behavioral issues before more severe neurological symptoms such as vision and hearing loss, loss of coordination, and seizures present. Childhood cerebral ALD typically leads to a vegetative state or death within 2-10 years.

A Sheep Model of ALD

In mouse models of ALD, the demyelenation experienced by human patients does not occur. Our lab plans to use CRISPR technology to create a sheep model of this disease and to create an AAV gene therapy treatment that could be translated to human patients in the future.