Illustration of AAV-mediated gene therapy targeting BPANIntroduction

Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is a devastating and ultra-rare neurodegenerative disease linked to mutations in the WDR45 gene. Manifesting primarily in females, BPAN results in severe neurological symptoms including developmental delays, seizures, and progressive movement disorders. The hallmark of this disease is iron accumulation in the brain, particularly in the basal ganglia, leading to further neurological decline in adolescence and early adulthood. Currently, there are no approved therapies and treatment is limited to managing symptoms. Researchers from the Massachusetts General Hospital Research Institute and Harvard Medical School have reported a breakthrough approach for AAV-mediated gene therapy for BPAN (source).

The Role of WDR45 and Autophagy

WDR45 encodes the WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), a crucial player in autophagy—a cellular process that recycles damaged components to maintain cellular health. Mutations in WDR45 impair autophagy, contributing to the neurological decline seen in BPAN patients. Despite the understanding of the molecular underpinnings of BPAN, effective therapeutic interventions have remained elusive.

A Novel Mouse Model for BPAN

To explore potential treatments, researchers developed a new mouse model of BPAN (Wdr45_ex9+1g>a) that closely mimics the human disease. This model exhibited hyperactivity and reduced autophagy markers in brain tissue as early as two months of age, making it a valuable tool for preclinical studies.

Gene Therapy: A Promising Approach

In a groundbreaking study, researchers utilized adeno-associated virus (AAV)-mediated gene therapy to deliver the WDR45 gene to the central nervous system (CNS) of the BPAN mouse model. The therapy aimed to restore WIPI4 function and correct the neurological deficits associated with BPAN.

Key Findings

  1. Successful Gene Expression: The AAV-mediated gene transfer resulted in the successful expression of human WDR45 transcripts and WIPI4 protein in the brain tissue of treated mice.
  2. Behavioral Improvements: Treated mice showed a significant reduction in hyperactive behavior, aligning their activity levels closer to healthy controls.
  3. Restoration of Autophagy: The therapy corrected the autophagy markers in the brain, indicating a restoration of cellular recycling processes disrupted by BPAN.


Researchers administered the gene therapy using two approaches:

  1. Systemic Administration: AAV-PHP.eB-WDR45 was injected via the tail vein in symptomatic adult mice. While initial improvements were modest, significant behavioral corrections were observed at later stages.
  2. Neonatal Administration: Intracerebroventricular (ICV) injection of self-complementary AAV9-WDR45 (scAAV9-WDR45) in neonatal mice achieved broader brain distribution and resulted in full prevention of hyperactivity at two months of age.


The study demonstrates that AAV-mediated gene transfer of WDR45 holds promise as a therapeutic strategy for BPAN. By restoring WIPI4 function and correcting autophagy deficits, this innovative approach offers hope for treating a disease with no current cure. As research progresses, gene therapy could transform the landscape of BPAN treatment, offering a lifeline to patients and families affected by this debilitating condition.

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