Adrenoleukodystrophy (ALD) is a rare genetic disorder characterized by the accumulation of saturated very long-chain fatty acids (VLCFAs) that leads to the destruction of myelin, the protective sheath that insulates nerve cells in the brain.

Available treatments for ALD, Lorenzo’s oil and stem cell therapy, are aimed at inhibiting the progression of the disease by halting the demyelination of nerve cells. The efficacy of Lorenzo’s oil has, however, not been demonstrated in randomized clinical trials, and standard stem cell therapy carries fatal risks.

Experimental treatments are intended to overcome these shortcomings, with some aimed at restoring myelination, which would not only halt disease progression but could potentially reverse brain damage.


Oxidative stress is thought to contribute to demyelination in ALD.

Neuroscience company Orpheris is developing OP-101 to reduce oxidative stress and inflammation. OP-101 works by inhibiting the NF-κB pathway, a biological pathway that is usually activated through oxidative and inflammatory stress conditions and that leads to an increase of proinflammatory molecules.

A Phase 1 safety study (NCT03500627) testing OP-101 in healthy volunteers was recently completed, but results are not yet published.

Reducing inflammation

VLCFA accumulation causes inflammation, which is also thought to contribute to demyelination in ALD. Inhibiting inflammation may, therefore, prevent demyelination in ALD.

MIN-102, developed by Minoryx, is a compound that reduces inflammation. It is thought to work by inhibiting proinflammatory and activating anti-inflammatory genes, resulting in less inflammation and overall improved cellular function.

A Phase 1 clinical trial showed that MIN-102 is well-tolerated and safe. Following these results, the company started a Phase 2/3 randomized, placebo-controlled trial (NCT03231878) assessing the efficacy of MIN-102 in slowing the progression of adrenomyeloneuropathy (AMN), a type of ALD. The study is ongoing, and results are expected at the end of 2020.

In 2016, the European Medicines Agency granted MIN-102 an orphan drug designation, followed by the U. S. Food and Drug Administration in 2017.

ABCD2 upregulation

ABCD2 is a gene whose function is very similar to that of ABCD1, the gene that is mutated in ALD. Like ABCD1, ABCD2  also provides instructions to build a transport protein that imports VLCFAs into peroxisomes. It is thought that the increased activity of the ABCD2 gene could compensate for the loss of function of ABCD1.

Startup company NeuroVia developed NV1205, which upregulates the ABCD2 gene. A Phase 1/2 dose-escalation study (NCT03196765), intended to determine the most effective dose of NV1205, is currently recruiting patients in France, Australia, Ukraine, Chile, Argentina, Colombia, the Russian Federation, and the U.K. After the dose-escalation part, participants will enter a long-term treatment phase.

Gene therapy

Gene therapy for ALD is an advancement of stem cell therapy — the standard of care for patients with childhood cerebral ALD (CALD). Standard stem cell therapy requires a donor whose bone marrow stem cells are transplanted into the patient that then, hopefully, develop into nerve cells in the brain.

The problem with this approach is that it requires the severe weakening of the patient’s immune system to avoid their immune cells attacking the donor cells.

Gene therapy circumvents this problem by using a patient’s own stem cells genetically engineered to contain a healthy copy of the ABCD1 gene. Because this approach uses patient-derived cells, the risk that the body rejects the cells is very low.

Bluebird Bio used this approach to develop Lenti-D. Preliminary data from a Phase 2/3 trial (NCT01896102) showed that Lenti-D is a safe treatment for CALD. Following these positive data, Lenti-D received the FDA’s breakthrough therapy designation in May 2018.

Two Phase 1/2 trials in Guangdong, China, employ the same approach. They are both recruiting, with one (NCT02559830) taking place at the Shenzhen Second People’s Hospital, and the other (NCT03727555) at Shenzhen Geno-Immune Medical Institute. Both are evaluating the efficacy and safety of transplanting genetically modified patient-derived bone marrow stem cells.


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