Adrenoleukodystrophy (ALD) is a rare, fatal genetic disorder that affects the brain, adrenal cortex, and testes of male patients. It is an X-linked disease, meaning that the gene that causes ALD is carried on the X chromosome (Migeon et al., 1981). Since males only have one X chromosome, they bear the full force of the disease. The most severe form of this disease, the childhood cerebral form, only affects young boys. After developing normally for 3-10, about 35% of boys with this disease will present with impaired motor function, and their health rapidly degrades until their death (Cartier et al., 2009). The biochemical reasons behind this are only partially understood.
In cells, there are vesicles (sac-like structures) called peroxisomes that degrade unwanted cellular materials. Peroxisomes degrade very long chain fatty acids (VLCFA) in a process called β-oxidation that produces energy for the cell. In ALD, however, this process is impaired (Weber et al., 2014). In order for VLCFA to enter the peroxisome, they must be taken in by a transport protein called ABCD1 (also called ALDP). Since the ABCD1 gene codes for the ABCD1 protein, mutations in the ABCD1 gene will lead to a non-functional protein. Since ABCD1 is not functional in ALD, VLCFA are not brought into the peroxisome to be broken down, and they accumulate in the cell (Mosser et al., 1993). This can be seen in Figure 1. VLCFA accumulation causes an inflammatory response that destroys neurons. Neurons have a myelin sheath, which is crucial for neurons to function. The inflammatory response triggered by VLCFA accumulation degrades this myelin, causing neural death (Schlüter et al., 2012).
There are several treatments that have been proposed and have shown promise. The first one ever demonstrated was called Lorenzo’s Oil. This, however, was only shown to be effective in ALD patients who have not shown any symptoms. It also does not cure the disease, but only postpones the progression of the disease (Moser HW et al., 2005). The only cure that has been demonstrated is bone marrow transplantation. Bone marrow cells give rise to microglia, which cause the inflammatory response in the brains of ALD patients. By replacing these cells, the myelin of neurons will remain intact and affected persons will not suffer the symptoms of this disease (Cartier et al., 2009).
Bone marrow transplants are done by killing all of a person’s normal bone marrow cells and giving them someone else’s bone marrow stem cells. These stem cells will give rise to all of the normal blood cells, including microglia. The difficulty with this is that every person expresses certain markers on the surface of their cells. Transplant patients have to find someone whose bone marrow cells express markers similar enough to their own so that their body does not think that it is foreign material that needs to be destroyed, leading to transplant rejection. Because of this, many people do not find the match that they need (Cartier et al., 2009). More recently, a therapy has been developed that puts a twist on transplantation. A group of scientists have taken a person’s own bone marrow stem cells and corrected them with gene therapy (Figure 2). They did this by using viral vectors, which means that they made a virus that contained the gene for ABCD1. They then made this virus infect the bone marrow stem cells that they took from the ALD patient. The corrected stem cells were then transplanted back into the patient now that they and the cells they give rise to will express ABCD1 (Cartier et al., 2009). This cures ALD and circumvents the issue of transplant rejection.