Van Haren Lab Research

PREMISE & MISSION

The human brain is our species’ most distinguishing feature. For millions of years, humanity’s evolutionary divergence has been shaped by our uniquely outsized investment in brain size and complexity. The consequences of this investment are perhaps most apparent during childhood when the brain’s consumes more than half of the body’s total energy production, prompting a reordering of traditional developmental programs in order to accommodate the brain’s enormous energy demands. Whereas most vertebrates expend ~5% of basal energy on brain function, children  expend more than 50% of their energy on brain function. By this measure, human evolution constitutes an astonishing feat of bioengineering in which the gearing, ordering, and efficiency of our metabolic systems have been refined to enable a decades long investment in the human brain.

And yet, our unique and relatively recent evolutionary adaptations pose at least two important conundrums. First, unique adaptations pose unique vulnerabilities. A preponderance of neurometabolic and neuroinflammatory diseases appear to cluster within the first decade, when neurometabolic demand is at its peak. Second, our “uniqueness” implies (and often demonstrates) a degree of biological nuance that sometimes evades non-human biological models.

Childhood-onset neurometabolic and neuroinflammatory diseases are increasingly characterized by single-gene mutations. Clinical and biological insights gleaned from disease causing mutations in humans offer a critical avenue toward understanding the uniquely human aspects of neurobiology.

Dr Van Haren specializes in the diagnosis and treatment of children with neurometabolic and neuroinflammatory disorders. Our lab’s foremost purpose is to alleviate the suffering created by these devastating childhood disorders. The knowledge gleaned from these disorders offers insights into broader aspects of human neurodevelopment.

APPROACH

Our lab leverages insights directly from human neurometabolic & neuroinflammatory disorders. The clinical and molecular features that characterize these disorders serve as our starting point for understanding the functional relevance of single human genes as they relate to human neurodevelopment. Although we employ a variety of in vivo and in vitro models, we anchor our investigations in human data. In particular, our lab is among a handful of investigators pioneering the use of multi-omic analysis of clinical trial data to generate major new insights into human disease and therapy. We leverage clinical and laboratory insights from these disorders to unravel the molecular mechanisms of human neuroinflammation.

Although our lab has a broad interest in childhood brain disorders with metabolic and/or inflammatory etiologies, we maintain a particular focus on two distinct neuroinflammatory disorders: adrenoleukodystrophy (ALD) & multiple sclerosis (MS). These two disorders offer complementary perspectives on metabolism and inflammation in the developing brain and have generated a remarkable number of new and unexpected insights challenging widely held assumptions about neuroinflammation and metabolism.

CORE PRINCIPLES

Science is humanity’s largest and most important non-zero sum endeavor. And for those who enjoy puzzles, it also happens to be enormously fun. Accordingly, our lab is committed to the principles of rigor, reproducibility, collaborative data-sharing, and an appreciation for the joy of scientific discovery.

MAJOR QUESTIONS ANIMATING OUR LAB

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?

CURRENT PROJECTS

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

Among boys with ALD, only 40% will develop inflammatory brain demyelination. Risk of cerebral inflammation is not predicated by genotype. Borrowing from what is known about risk modifiers in multiple sclerosis (MS), our lab identified early-life vitamin D exposure as a potentially protective factor among boys with ALD. Our lab is 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

Our lab is using human tissues to unravel important details about why disturbances in fatty acid metabolism, such as those seen in ALD, result in inflammatory demyelination that resembles prototypical neuroinflammatory disorders like MS.

4. Single-gene disorders with neuroinflammatory phenotypes

Beyond ALD, an increasing number of genetic mutations have been linked to neurologic phenotypes (e.g. CTLA-4 mutation syndrome). 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.

ONGOING CLINICAL TRIALS

Clinical Study

Enrollment criteria (brief)

Currently enrolling?

ClinicalTrials.gov 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

Yes

NCT02595489

30805

Gene therapy for ALD using lentiviral vector

(Sponsor: bluebirdbio, Inc)

Boys with early stage cerebral ALD

Yes

pending

47493

RCT for MIN-102 in men with AMN

(Sponsor: Minoryx, Inc)

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

No

NCT03231878

46285

Clinical outcomes after stem cell transplant in ALD

(Sponsor: bluebirdbio, Inc)

ALD boys who are <2yrs post-transplant

Yes

NCT02204904

31193

Natural history study of NGLY-1 deficiency

(Sponsor: Grace Science)

Individuals with NGLY-1 mutations

Yes

n/a

47335

Biobank for inflammatory brain disorders

(Sponsor: VH Lab)

Individuals with suspected inflammatory brain disorders as well as healthy controls

Yes

n/a

23596