A number of medications have been proposed as treatment options for adrenoleukodystrophy (ALD) and have had promising starts. However, further investigation in clinical trials showed a lack of benefit or mixed results.
What is ALD?
ALD is a rare genetic disorder that primarily affects men, though it can be diagnosed in women.
The disease can manifest as three main types: childhood cerebral ALD (CALD), adrenomyeloneuropathy (AMN), and Addison’s disease. Each type varies in the age of onset of symptoms. However, they all result from mutations in the ABCD1 gene found on the X chromosome.
Mutations in this gene lead to an increase in very-long-chain fatty acids (VLCFAs). These are toxic to the myelin sheath, which is the outer insulation of nerve cells, as well as to the adrenal glands. Damage to the nerve cells and adrenal glands causes the symptoms of the different forms of ALD.
Medications that have not shown clear benefits
Several medications initially showed promise in treating ALD. However, these potential therapies did not show benefits or had mixed results during clinical trials.
Lorenzo’s oil
Lorenzo’s oil is a controversial treatment option for the different forms of ALD. The treatment involves a 4:1 ratio of oleic acid and erucic acid, both of which are unsaturated fatty acids, taken in combination with a reduced-fat diet. Results from studies have reported varying levels of effectiveness for the treatment.
One study showed that the treatment lowered the levels of VLCFAs in the blood but ultimately did not slow down the progression of the disease in six out of eight newly diagnosed ALD patients.
No change in disease symptoms or progression was found in two other studies. One involved 14 men with AMN, five symptomatic women with one mutant copy of the ABCD1 gene, and five boys with presymptomatic AMN. None of the 24 patients showed clinical improvement over the course of the study and many of the men and boys saw their condition deteriorate.
Another study investigated Lorenzo’s oil in two asymptomatic ALD patients, four with Addison’s disease only, 13 with AMN, and three symptomatic women and found that none of the patients improved and many had worsening of the disease.
In contrast, two studies suggested that Lorenzo’s oil may slow disease progression or reduce the risk of patients becoming symptomatic.
In the first, researchers treated 45 men with AMN with Lorenzo’s oil and followed them for an average of 6.3 years. Roughly half of the patients did not show disease progression over that time, and those who did progressed at a slower rate than they had before treatment. The other trial monitored 89 asymptomatic boys with ALD who used Lorenzo’s oil for about 6.9 years and found that only 24% developed abnormalities on MRI scans. Meanwhile, 11% of those boys had MRI abnormalities and neurological symptoms.
All of these studies were open-label, without blinding or a placebo control. That means that both the researchers and participants knew which treatment was being given to each patient — which makes the results hard to interpret. The variability in the results indicates that the treatment may help slow disease progression in some patients and not others.
Immunomodulators and immunosuppressants
The progression of neurological symptoms in ALD is often associated with brain inflammation. This led some researchers to hypothesize that medications that could modify or suppress the immune response might stop or slow down disease progression.
Multiple immunomodulators/immunosuppressants, including cyclophosphamide, interferon-beta, intravenous immunoglobulins (IVIG), and natalizumab (Tysabri), have been tested in clinical trials but none have successfully shown efficacy against disease progression. Some of the trials even combined these treatments with Lorenzo’s oil. However, the medications still did not produce a beneficial effect in patients.
Lovastatin
A research study published in 1998 reported that lovastatin, a cholesterol-lowering medication, could reduce VLCFA levels in the blood of patients with ALD. Since then, researchers have conducted several studies in humans and mouse models of ALD using lovastatin or simvastatin (a similar statin). However, they have not been able to show a clinically meaningful change in VLCFA levels. Some studies did see a small reduction in VLCFA levels. However, they remained two or three times higher than normal.
Immunokine
Some initial anecdotal reports showed that modified cobratoxin (immunokine) may improve clinical symptoms in AMN patients. In a double-blind, randomized, crossover trial, eight patients with AMN received immunokine or a placebo for three months. They then swapped to the other treatment for three months. The results showed no significant improvement.
Last modified: Nov. 11, 2020
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