On the Cusp of a Clinical Breakthrough: Focused Ultrasound Gene Delivery for the Treatment of Neurological Disorders

Key Points A recent review article outlines the state of the field, current challenges, and barriers to clinical translation for focused ultrasound–mediated gene delivery in the brain.  Gene therapy has the potential to treat many neurodegenerative diseases, as has already been proven in at least two of them.  Focused Ultrasound Gene Delivery for the Treatment of Neurological Disorders  This review article outlines gene therapy delivery techniques for the central nervous system (CNS) that might be improved with focused ultrasound. Many lessons have been learned from discoveries to date; therefore, the authors explore past studies while summarizing ongoing technical challenges and outlining barriers to clinical translation.  Rikke Hahn Kofoed, PhD, a postdoctoral fellow in the Departments of Neurosurgery and Clinical Medicine at Aarhus University in Denmark, and Isabelle Aubert, PhD, a senior scientist at Sunnybrook Research Institute and professor at the University of Toronto, have written a comprehensive review of the technical aspects of using focused ultrasound to augment gene delivery across the blood-brain barrier (BBB) for the treatment of neurological disorders.  The team explains how focused ultrasound is being combined with intravenously (IV)-delivered ultrasound-responsive particles (URPs) to disrupt the blood-brain barrier (BBB) in patients with neurological disorders. This type of BBB disruption gives therapeutics, including various types of gene therapies access to the brain.  “The ultimate goal is to provide new treatment options to patients with Alzheimer’s disease, Parkinson’s disease, Huntington disease, ALS, and other neurodegenerative disorders,” said Dr. Aubert. “For each of these conditions, patients will likely require treatments for decades–which can be achieved with a single gene delivery. Focused ultrasound offers a tremendous range of gene delivery options to the CNS, and this without the need for invasive and complex surgical procedures.”  The article outlines the research breakthroughs from the past 10 years that show how focused ultrasound is effectively being combined with various types of gene therapy in preclinical experiments. Focused ultrasound has enabled the delivery of IV-administered gene vectors across the BBB, blood–retina barrier, and blood–spinal cord barrier. It can significantly reduce the dose required to achieve similar levels of transduction as those attained without focused ultrasound.  Several existing challenges must be overcome to provide safe and effective gene therapy to the CNS. When the current challenges have been solved, gene therapy has the potential to treat and perhaps even cure many neurodegenerative diseases, as has already been proven with spinal muscular atrophy and Leber congenital amaurosis. Some of the current technical challenges include reducing gene and vector transduction of peripheral organs, such as the liver, spleen, and lungs, when delivery is meant for the brain. Uptake by these organs causes peripheral side effects and toxicity. Potential methods for solving this challenge are the combination of focused ultrasound and gene vectors with modified surfaces to reduce their peripheral transduction and maximize their entry to the brain at lower doses administered IV, or in the cerebrospinal fluid (CSF).  The paper suggests that clinical translation of focused ultrasound–mediated gene therapy for a variety of neurodegenerative conditions will become possible when:  The safety limitations of single or repeated focused ultrasound–URP applications have been established – especially related to the use of non-viral vectors needing repeated administrations.  The impact of aging and disease on focused ultrasound gene delivery efficiency and safety have been determined.  Focused ultrasound gene delivery achieves therapeutically relevant gene delivery to large brain areas – possibly through the translation of preclinically established strategies such as focused ultrasound preconditioning, vector engineering, and administration of gene vectors through different routes tailored to the specific therapeutic needs (e.g. intravenous, intranasal, intra-arterial, intra-CSF).  Large animal studies have demonstrated that the breakthroughs that could have the greatest clinical impact are those that can increase the efficiency of gene delivery to the brain including strategies that enhance gene delivery beyond the theoretical size of the focused ultrasound targeted area or decrease the vector dose needed to reach therapeutic efficacy. Overall, fine tuning the technologies to achieve safe and therapeutic gene delivery is needed.  “The combination of focused ultrasound with gene therapy is on the cusp of a clinical breakthrough,” says Dr. Kofoed. “The increasing number of clinically approved gene therapies together with advances in using focused ultrasound to disrupt the blood-brain barrier are creating unprecedented possibilities.”  “We believe that focused ultrasound can play a crucial role in gene therapy for neurodegenerative diseases, addressing unmet needs by offering long-lasting treatment effects through a non-surgical delivery platform,” said Frédéric Padilla, PhD, the director of the Foundation’s Gene Therapy Program. “This paper does a great job of outlining the promising clinical potential of current research in the field, including the projects funded by the Foundation’s Gene and Cell Therapy Program.”  See Trends in Molecular Medicine 
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