# Effects of ABCD1 deficiency on endothelial function and permeability to leukocytes in Cerebral X-linked Adrenoleukodystrophy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $394,800

## Abstract

X-linked adrenoleukodystrophy (ALD) is a devastating neurologic disorder caused by mutations in the
ABCD1 gene characterized by the accumulation of very long-chain fatty acids that affects 1:17,000 individuals
in the U.S. Approximately 60% of male patients with ALD will convert to a devastating rapidly progressive
form of inflammatory demyelination that leads to incapacitation or death within 2-3 years (cerebral ALD). Age
of onset and phenotype varies even among individuals with the same mutation but a constant initial event in
cerebral ALD is blood brain barrier (BBB) disruption with migration of leukocytes to the brain. The precise
molecular and cellular mechanisms controlling BBB function during the course of ALD disease progress
remain poorly understood given lack of cellular or animal models that faithfully recapitulate cerebral ALD.
To address this critical knowledge gap, Dr. Musolino’s laboratory recently developed an ALD ex-vivo model
system using gene-editing strategies and human brain microvascular endothelial cells. Dr. Musolino’s initial
studies provide evidence that loss of ABCD1 directly impairs brain endothelial barrier integrity by increasing
TGFβ1 levels in a manner correlated with severe transcriptional downregulation of Claudin 5 and increased
permeability to small molecules. These alterations precede the accumulation of very-long chain fatty acids
suggesting that the BBB dysfunction is not a direct consequence of their accumulation. As with patients, in
addition to ABCD1 deficiency in this model, a second event, endothelial activation by inflammatory cytokines
or flow sheer stress, is necessary to increase the permeability to leukocytes. Building upon these strong
preliminary data Dr. Musolino’s hypothesizes that levels of ABCD1 expression in brain microvascular endothelium
controls transcriptional regulation of tight junction proteins via TGFβ1-regulated pathways and determines the
permeability to leukocytes during endothelial activation in a dose-dependent manner.
To test this hypothesis Dr. Musolino will probe the effect of ABCD1 deficiency upon the BBB by (1) Identifying
the molecular mechanisms governing tight junction disruption and increased permeability of ABCD1-
deficient brain endothelium (Aim 1), (2) Determining functional consequences of downregulation of tight
junction proteins and main regulatory pathways (Aim 2), and (3) Quantifying ABCD1 gene-dose effect on
endothelial barrier function (Aim 3). Upon successful completion of these studies Dr. Musolino will have
leverage the ability to model the impact of a single-gene mutation to unravel the mechanisms governing the
traffic of cells across the BBB in ALD setting forth a strategy to identify the molecular and cell biological
mechanisms underlying the conversion to cerebral disease, develop functional assays to test novel therapeutic
approaches, and inform the field of neuroinflammation.

## Key facts

- **NIH application ID:** 10249979
- **Project number:** 5R01NS117575-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Patricia L Musolino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,800
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249979

## Citation

> US National Institutes of Health, RePORTER application 10249979, Effects of ABCD1 deficiency on endothelial function and permeability to leukocytes in Cerebral X-linked Adrenoleukodystrophy (5R01NS117575-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10249979. Licensed CC0.

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