Gene Therapy for Restoring Lost Neural Connections: Breakthrough with PS Gene-Editing

In a groundbreaking advancement for patients afflicted with Hurler syndrome, an uncommon genetic cerebral condition, a recent study by the University of Minnesota has heralded the dawn of gene therapy’s potential to reinstate neuronal interconnections. This pioneering research substantiates gene therapy as a prospective therapeutic avenue for individuals grappling with cerebral irregularities akin to Hurler syndrome, a disorder with profoundly detrimental consequences for those it affects.

The scholarly findings have been published in Scientific Reports.

Hurler syndrome, recognized interchangeably as mucopolysaccharidosis type I (MPS I), constitutes an inherited ailment that manifests in neonates, bestowing substantial physical and cognitive detriments. The pathology stems from the inadequacy of a pivotal lysosomal enzyme, IDUA, to undergo proper synthesis due to inherent genetic aberrations, thereby instigating insidious cerebral deterioration, or gradual brain damage in simple words.

Tragically, the syndrome culminates in fatality by age 10, a somber outcome further compounded by the inadequacy of the current therapeutic modalities. Lifelong enzyme substitution proves futile in halting the relentless progression of cerebral degradation, while bone marrow transplants are risky.

In a pioneering endeavor, the University of Minnesota’s researchers turned to the PS gene-editing framework, an innovative gene therapy methodology, to assess mice afflicted with Hurler syndrome. Employing this methodology, a copious supply of unimpaired enzymes were generated within the liver, subsequently cascading into the cerebral circulation. Commencing their investigation with high-resolution resting-state functional MRI (rs-fMRI) – a secure, noninvasive, and whole-brain activity imaging diagnostic modality, the researchers meticulously identified compromised neural networks. This was followed by an evaluation of how the gene therapy facilitated cerebral connectivity and functionalities.

Stemming from their thorough exploration, the researchers discerned that the PS gene-editing paradigm propagated the restoration of physiological hepatic enzymes that, in turn, facilitated the reinstatement of normalcy within discrete cerebral networks.

The technological innovation for high-resolution rs-fMRI brain connectome imaging was conceived by Wei Zhu, a promising postgraduate from the University’s Center for Magnetic Resonance Research.

Walter Low, a co-senior author and professor in the U of M Medical School, referred to the study as a breakthrough, noting, “This is the first demonstration of a gene therapy that has corrected a neurological disorder resulting in the restoration of brain connectivity as confirmed by rs-fMRI.”

“A similar rs-fMRI approach as applied in this preclinical study should be translatable to the clinical setting and patients, especially for those with genetic brain disorders, and for examining the efficacy of brain network restoration and function after gene treatment,” said Wei Chen, a co-senior author and professor in the U of M Medical School and Center for Magnetic Resonance Research.

“The aeonic production of normal IDUA in the liver of mice with Hurler syndrome and the ability to traffic enzymes across the blood-brain barrier to correct abnormalities in the brain is a significant achievement,” added Chester Whitley, a co-author and professor in the U of M Medical School.

This new approach will enable the monitoring of brain connectivity in other lysosomal disorders that affect brain function following gene-editing,” stated Perry Hackett, a co-author and professor in the College of Biological Sciences.

Other participants in this study include Xiao-Hong Zhu, a professor at the University of Minnesota Medical School and Center for Magnetic Resonance Research, Lin Zhang, an associate professor in the School of Public Health, Ying Zhang, an informatics analyst at the Minnesota Supercomputing Institute, Isaac Clark, a graduate student in the Biomedical Engineering Program, and Li Ou, a former member of the faculty at the University of Minnesota Medical School.

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