Van Haren Lab Research


What are the avenues by which metabolic disturbances drive neuroinflammation?

Why do peroxisomal disorders like ALD manifest inflammatory demyelinating brain lesions?

What are the factors that explain the stochastic nature of cerebral inflammatory events in ALD and MS?

Why does the risk of inflammation in ALD coincide so tightly with the neurometabolic hurdle of childhood?

Why do inflammatory demyelinating lesions in ALD bear so many resemblances to the lesions seen in multiple sclerosis, which lacks well-defined metabolic components to its pathogenesis?

What is vitamin D’s role in human neurodevelopment?


1. Pilot study of vitamin D supplementation in boys with adrenoleukodystrophy (ALD)

Among boys with ALD, only 40% will develop severe, inflammatory brain demyelination (cerALD), while the remaining 60% will escape early childhood unscathed. Surprisingly, genotype does not predict the likelihood this severe, inflammatory phenotype. Borrowing from what is known about risk modifiers in multiple sclerosis (MS), a disease with striking histologic similarities to the inflammatory demyelination in ALD, our lab identified early-life vitamin D exposure as a potentially protective factor among boys with ALD. We are currently conducting a single-arm, dose titration study to assess the safety, dose efficacy, and metabolic effects of vitamin D supplementation in boys with an inherited disorder affecting the catabolism of very-long chain fatty acids. This study will provide crucial insights necessary to conduct a larger, Phase III study of vitamin D’s efficacy as a preventive therapy for the neuroinflammatory form of ALD. Our current study should also shed insight into vitamin D’s early-life metabolic effects.

2. Characterizing the transcriptional signature of oral vitamin D supplementation in individuals with MS, ALD, and other disorders

Beyond it’s role in calcium maintenance, vitamin D’s role in modulating MS risk has been attributed primarily to vitamin D’s promotion of immune tolerance. Intrigued by the possibility of a therapeutic role of vitamin D in a neurometabolic disorder like ALD, our lab is asking a big question: “What does vitamin D do?” Might vitamin D be playing a larger role in lipid metabolism than is currently appreciated? We are applying a multi-omic analysis to blood samples acquired during clinical trials of vitamin D to investigate the effects of oral vitamin D exposure on human immune cells.

3. Filling in the gaps between metabolic dysfunction and neuroinflammation

Loss of function mutations in the ABCD1 gene is the defining feature of ALD, resulting in an accumulation of very long chain fatty acids in the blood and brains of ALD boys and men. Although we have known the identity of this gene for more than twenty years, we still do not understand one its most fundamental phenomena: why a disturbance in fatty acid metabolism results in such a severe inflammatory injury to the brain. Our lab has uncovered an exciting new possibility and we are racing to unlock this blackbox. We are applying cutting edge technologies, including single nucleus RNA sequencing and mass spectrometry imaging, to analyze donated ALD brain tissue. The project will generate large datasets that will enable both focused hypothesis testing as well as multi-omic discovery analysis to understand the intricate series of events linking the peroxisomal disturbance with the devastating neuroinflammatory process underlying ALD lesions. The knowledge should shed light on essential biological pathways that could help stop this devastating disease process in its tracks. This is a particularly urgent challenge for boys and men affected by ALD brain lesions that are too large to respond to hematopoietic stem cell transplant. Our lab is pursuing a novel hypothesis that may support wholly new therapeutic strategies, but we are leaving no stone unturned.

4. Single-gene disorders with neuroinflammatory phenotypes

Beyond ALD, an increasing number of genetic mutations have been linked to neurologic phenotypes (e.g. CTLA4). Our lab collaborates with other investigators to identify the genetic origin of these disorders and characterize the resulting dysfunction within the brain and the immune system. We have recently identified a potentially immune-responsive, neuropsychiatric syndrome among several patients with SHANK3 mutations.


Clinical Study

Enrollment criteria (brief)

Currently enrolling? Identifier

Stanford IRB#

A pilot study of vitamin D in boys with ALD

(Sponsor: NIH)

Boys with ALD ages 1.5-25yo and normal brain MRIs




Gene therapy for ALD using lentiviral vector

(Sponsor: bluebirdbio, Inc)

Boys with early stage cerebral ALD




RCT for MIN-102 in men with AMN

(Sponsor: Minoryx, Inc)

Men with AMN ages 18-65yo with adrenomyeloneuropathy (AMN)




Clinical outcomes after stem cell transplant in ALD

(Sponsor: bluebirdbio, Inc)

ALD boys who are <2yrs post-transplant




Natural history study of NGLY-1 deficiency

(Sponsor: Grace Science)

Individuals with NGLY-1 mutations




Biobank for inflammatory brain disorders

(Sponsor: VH Lab)

Individuals with suspected inflammatory brain disorders as well as healthy controls