Spinal muscular atrophy. SMA is a genetic disorder characterized by skeletal muscle atrophy GeCure Solution

What is BPAN?

BPAN (Beta-propeller Protein-Associated Neurodegeneration) is a rare genetic neurological disorder characterized by early developmental delay followed by progressive neurodegeneration later in life. It belongs to a group of disorders known as Neurodegeneration with Brain Iron Accumulation (NBIA), in which excessive iron gradually accumulates in specific regions of the brain. BPAN is caused by pathogenic variants in the WDR45 gene, which plays an essential role in autophagy—the cellular process responsible for recycling damaged proteins and organelles.

Symptoms usually begin in infancy or early childhood with global developmental delay, intellectual disability, limited or absent speech, hypotonia (poor muscle tone), epilepsy, and autistic features in some individuals. Although many patients remain relatively stable during childhood, a second phase of the disease typically begins during adolescence or early adulthood.

During this progressive stage, individuals develop worsening neurological symptoms, including parkinsonism, dystonia, muscle rigidity, impaired balance and coordination, progressive loss of mobility, cognitive decline, and increasing dependence on caregivers. Brain MRI often demonstrates characteristic iron accumulation within the basal ganglia, particularly the substantia nigra and globus pallidus.

The severity and progression of BPAN vary considerably among affected individuals. Some retain the ability to walk into adulthood, while others gradually lose independent mobility and require wheelchair assistance. Difficulties with swallowing and respiratory complications may also develop as the disease progresses.

Currently, there is no disease-modifying treatment for BPAN. Clinical management focuses on supportive care, including physical, occupational, and speech therapy, seizure control, management of movement disorders, nutritional support, and rehabilitation. Ongoing research is investigating gene replacement, CRISPR-based genome editing, and therapies targeting autophagy dysfunction as potential future treatment strategies.

Gene Therapy Solutions for BPAN Treatment and Management

Our therapeutic strategy is based on AAV-mediated delivery of a functional WDR45 gene to neurons with the goal of restoring normal autophagic function. Owing to the compact size of the WDR45 coding sequence, the gene can be efficiently packaged into conventional AAV vectors, making this approach well suited for targeted delivery to the central nervous system.

Potential routes of administration include intrathecal (IT) and intracerebroventricular (ICV) delivery, as well as systemic administration using next-generation CNS-targeting technologies to enhance vector distribution within the brain. Restoration of WDR45 expression is expected to normalize autophagic pathways, improve intracellular clearance of damaged proteins and organelles, reduce neuronal degeneration, and potentially slow disease progression.

In parallel, additional therapeutic strategies—including CRISPR-based genome editing, mRNA therapy, pharmacological modulation of autophagy, and iron chelation therapy—are under active investigation and may complement future gene therapy approaches. However, AAV-mediated WDR45 gene replacement is currently considered one of the most promising therapeutic strategies for addressing the underlying molecular cause of BPAN.

Gene therapy solutions for SMA treatment and management

SMA is a unique example of severe genetic disorder, that have received efficient curing solution. Zolgensma (onasemnogene abeparvovec) is a groundbreaking gene therapy approved for the treatment of SMA. Zolgensma's mode of action involves delivering a functional copy of the SMN1 gene directly into a patient's cells to restore normal SMN protein levels. It uses an adeno-associated virus (AAV9) as a vector. The AAV9 vector is engineered to carry a functional copy of the SMN1 gene but is replication-deficient to ensure safety. Once administered, the vector enters the cells, and the SMN1 gene is expressed, producing the SMN protein and halting the progression of the disease.
Structurally, Zolgensma is a viral vector-based gene therapy. The AAV9 capsid envelops the recombinant DNA that encodes the human SMN protein. This design allows it to cross the blood-brain barrier, reaching motor neurons and other cells in the central nervous system, which is critical for its effectiveness in treating SMA. Zolgensma was approved by the FDA in May 2019.
Due to the immense price of such treatment, acute need for alternative gene therapeutic solutions exist. This could be achieved by AAV pseudotyping in order to create unprecedented variants of AAV-like particles.