Dietary therapy that limited the intake of VLCFA was not successful because most of these fatty acids were created endogenously (Kemp et al., 2005). A new therapy, Lorenzo’s Oil, was introduced that was shown to halt progression of the disease by lowering the C26:0 concentrations in tissues (Moser et al., 2005). It does this through mixed inhibition of the endogenous elongation enzymes that create VLCFA with oleic acid (C18:1) and erucic acid (C22:1). The monounsaturated fatty acids become monounsaturated VLCFA by ELOVL1, which were thought to be harmless (Sassa et al., 2014). The highly publicized Lorenzo’s Oil, however, did not provide the cure that researchers had thought it would. This is because Lorenzo’s Oil only works if the boys are asymptomatic or have very small MRI abnormalities. Thus, early diagnosis is essential for this treatment to work. The long-term effectiveness of this treatment remains to be seen because there have not been many studies that are based on long-term follow ups.
Since this inhibition creates monounsaturated VLCFA, it is necessary to know what effects these may have on the cell. The toxicity of unsaturated-VLCFA was demonstrated in Fourcade et al. (2008) as the mono- and poly-unsaturated fatty acids generated more ROS. This is most likely because the double bond in the long hydrocarbon chain makes them more susceptible to radical generation (Baarine et al., 2012). Thus, it does not seem likely that the long-term effectiveness of Lorenzo’s Oil will prove to be great because it generates VLCFA that are likely to cause oxidative damage, even while normalizing the C26:0 levels in cells.
Bone Marrow Transplant
The only cure that has proven to be effective is hematopoietic cell transplant (HCT). The reasoning behind the first attempts at bone marrow transplant in X-ALD patients was based on roughly equal proportions of evidence and guesswork. There is a great deal of lymphocyte infiltration into X-ALD brains so typical immunosuppressive treatments were attempted, but they were unsuccessful (Aubourg et al., 1990). Thus, the idea that bone marrow transplant could offer treatment was proposed because it might correct some of the cells in the inflammatory pathway. Since microglial cells were shown to be derived from marrow cells (Cartier et al., 2009), this gave more credence to this therapy because the corrected hematopoietic cells could give rise to corrected microglia. This could arrest the inflammatory pathway (Aubourg et al., 1990). The success of bone marrow transplants has spurred research into the mechanism for its therapeutic effects. The initial assumptions that replacing microglia could ameliorate the disease seem to have been correct. Microglia that express ABCD1 are able to metabolize VLCFA, and thus, they do not promote inflammation. For more information see “Inflammation Response is Triggered by Microglia.”
Although it was attempted several times in the 1980’s, the first successful treatment of X-ALD using bone marrow transplantation was published in 1990 (Aubourg et al., 1990). Since this operation came with many risks, only one patient was used in this study. The authors believed that the disease had progressed too far in the other patients for the operation to be successful so they chose a patient who exhibited only mild symptoms. Immediately follow the transplant, the patient’s condition worsened, but after eighteen months, the progression not only halted, but the lesions disappeared (Aubourg et al., 1990). The reason behind the delayed benefit most likely has to do with the time that it takes for the wildtype-hematopoietic cells to repopulate the brain with functional microglia (Cartier et al., 2009).
This method for treating CALD became more popular, and a 2000 study in Lancet confirmed the beneficial effects of bone marrow transplant (Shapiro et al., 2000). After following up with 12 transplant patients, the inflammatory demyelination was arrested in all of them. There was marked improvement in one and complete reversal of brain lesions in two patients (Shapiro et al., 2000). This offered a great deal of hope for the treatment of CALD.
The effectiveness of bone marrow transplants is limited by the fact that it can only be done on patients who have mild to no symptoms. Since the demyelination happens so rapidly, there is a short window in which this can be done. To circumvent the issue of having to find a match from the bone marrow registry, a group of researchers designed a gene therapy method. Cartier et al. (2009) treated two X-ALD boys who were at the beginning stages of inflammatory demyelination. They took CD34+ (hematopoietic) cells from the two patients and used a lentiviral vector to transduce the ABCD1 gene into these cells. The vectors were derived from replication deficient HIV-1 because these are able to evade the cell’s natural anti-retroviral mechanisms such as adenosine deaminase (Cartier et al., 2009). The corrected hematopoietic cells gave rise to CD14+ (monocytes), CD3+ (T cells), and CD19+ (B cells) that expressed ABCD1 (Figure 1)
They were able to confirm that the genes had been inserted and that this insertion was not likely to cause significant harm (i.e. inserting into a tumor suppressor gene). The patients’ marrow was ablated using radiation, and the corrected CD34+ cells were put back into the patients. They showed similar results to the donor-HCT patients as their conditions worsened for a little over a year before the demyelination was halted (Cartier et al., 2009). While this procedure had been performed in mice, they did not know what a sufficient number of corrected cells would be needed so as to get similar benefits. Donor hematopoietic cells had an 80% engraftment rate, which means that about 80% of the microglia were derived from the donor cells. In this study, however, they only observed about 15% engraftment from the corrected cells. The reason that this was able to provide results comparable to donor transplantation is that the ABCD1 gene is overexpressed in the corrected cells (Cartier et al., 2009). These promising results can be made better with more efficient techniques of gene insertion and bone marrow transplantation.
The inherit risks of bone marrow transplant (i.e. invasiveness of procedure, HLA-matching, transplant rejection) make it so that these should be a last resort, rather than the norm (Cartier et al., 2012). The residual β-oxidation seen in X-ALD derived cells is attributed to ABCD2 and ABCD3, thus offering therapeutic drug targets for treating X-ALD. ABCD2 is much more similar to ABCD1, and its ability to transport VLCFA seems to be sufficient to reduce accumulation. Therefore, attempts at upregulating ABCD2 expression have been numerous. The most promising drug was lovastatin, which is an HMGCoA reductase inhibitor. It was demonstrated the cholesterol depletion increased the expression of ABCD2 in mouse models (Weinhofer et al., 2002). Lovastatin has since been discredited as a viable therapeutic target in humans, however. This could be due to the fact that the mouse model system mimics AMN pathology, rather than CALD. While this was not successful, the upregulation ABCD2 is still a subject of research because it would provide a safer, more consistent way of treating X-ALD than bone marrow transplants.
The drug that has shown promise recently is valproic acid, which is used as a mood-stabilizer that has not been shown to have adverse, long-term effects (Salsano et al., 2012). Valproic acid also functions as a non-discriminate histone deacteylase (HDAC) inhibitor. Administration of valproic acid was shown to upregulate ABCD2 expression via this inhibitory mechanism (Figure 2), and this was sufficient to ameliorate oxidative damage (Fourcade et al., 2010). Exactly how valproic acid inhibits HDAC is unknown. Although valproic acid has not been the subject of larger clinical trial for the treatment of X-ALD, another study demonstrated that behavioral disturbances caused by CALD were diminished when on a regimen of valproic acid (Salsano et al., 2012).