Therapeutic developments for neurodegenerative GM1 gangliosidosis.

GM1 gangliosidosis (GM1) is a rare but fatal neurodegenerative disease caused by dysfunction or lack of production of lysosomal enzyme, ß-galactosidase, leading to accumulation of substrates. The most promising treatments for GM1, include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy and gene editing. However, effectiveness is limited for neuropathic GM1 due to the restrictive nature of the blood-brain barrier (BBB). ERT and SRT alleviate substrate accumulation through exogenous supplementation over the patient's lifetime, while gene editing could be curative, fixing the causative gene, GLB1, to enable endogenous enzyme activity. Stem cell therapy can be a combination of both, with ex vivo gene editing of cells to cause the production of enzymes. These approaches require special considerations for brain delivery, which has led to novel formulations. A few therapeutic interventions have progressed to early-phase clinical trials, presenting a bright outlook for improved clinical management for GM1.

Nanoparticle-mediated delivery of non-viral gene editing technology to the brain.

Neurological disorders pose a significant burden on individuals and society, affecting millions worldwide. These disorders, including but not limited to Alzheimer's disease, Parkinson's disease, and Huntington's disease, often have limited treatment options and can lead to progressive degeneration and disability. Gene editing technologies, including Zinc Finger Nucleases (ZFN), Transcription Activator-Like Effector Nucleases (TALEN), and Clustered Regularly Interspaced Short Palindromic Repeats-associated Protein 9 (CRISPR-Cas9), offer a promising avenue for potential cures by targeting and correcting the underlying genetic mutations responsible for neurologic disorders. However, efficient delivery methods are crucial for the successful application of gene editing technologies in the context of neurological disorders. The central nervous system presents unique challenges to treatment development due to the blood-brain barrier, which restricts the entry of large molecules. While viral vectors are traditionally used for gene delivery, nonviral delivery methods, such as nanoparticle-mediated delivery, offer safer alternatives that can efficiently transport gene editing components. Herein we aim to introduce the three main gene editing nucleases as nonviral treatments for neurologic disorders, the delivery barriers associated with brain targeting, and the current nonviral techniques used for brain-specific delivery. We highlight the challenges and opportunities for future research in this exciting and growing field that could lead to blood-brain barrier bypassing therapeutic gene editing.

Spinal cord stimulation programming: a crash course.

The aim of this comprehensive review is to provide an instructional guide for providers regarding the parameters and programming of spinal cord stimulation (SCS) devices. Knowing these fundamentals will aid in providing superior pain relief to patients. SCS has four programmable parameters: contact (electrode) selection, amplitude, pulse width, and frequency. Each parameter needs to be accounted for when assessing which program works for which patient. Traditional open-loop systems allow for different "programs," or combinations of these four parameters, to be pre-set by the provider and medical device representative. These allow for flexibility in the type of stimulation delivered to the patient depending on activity. Patients are also given control over programs and changing the amplitudes of these programs. However, some open-loop systems place the burden of toggling between programs to manage pain control on patients, though this tends to be less in subparesthesia programs. Newer closed-loop systems make it possible for stimulation settings to automatically adjust in response to accelerometry and evoked compound action potential feedback, and therefore have the potential to streamline the patient experience. This article provides practitioners with the basic knowledge of SCS parameters and programming systems. Understanding their use is essential to providing optimal pain relief to patients.

Effect of Directional Deep Brain Stimulation on Sensory Thresholds in Parkinson's Disease.

OBJECTIVE: Previous studies showed that deep brain stimulation (DBS) relieves pain symptoms in Parkinson disease (PD) patients when programmed for motor-symptom relief. One factor involved in pain processing is sensory perception of stimuli. With the advent of directional leads, we explore whether directional DBS affects quantitative sensory testing (QST) metrics acutely. METHODS: PD patients with subthalamic (STN) DBS and directional leads were tested in 5 settings (DBS-OFF, DBS-ON with omnidirectional stimulation, and DBS-ON) for each of three directional segments of contact used for clinical programming. The Unified Parkinson's Disease Rating Scale (UPDRS-III) assessed patient's motor skills at time of study visit at clinical contact and at contact which produced optimal sensory threshold (defined by the greatest tolerance to mechanical stimuli). Correlation analyses were performed between stimulation parameters [amplitude, frequency, pulse width (PW), total electrical energy delivered (TEED)] and outcome metrics. RESULTS: Sensory thresholds were obtained in nine patients. Directional stimulation did not significantly alter patient perceptions of sensory stimulus [cold pain (p = 0.69), warm pain (p = 0.99), Von frey fibers (p = 0.09), pin-prick (p = 0.88), vibration (p = 0.40), pressure (p = 0.98)]. With correlation analysis, increasing PW at the posterior contact increased pin prick and vibration sensitivity (p < 0.001). Additionally, an increase in TEED caused a decrease in sensitivity to warm detection when using the anterior (p = 0.04), lateral (p = 0.02), and medial contacts (p = 0.03), and also caused a decrease in sensitivity to cold detection when using the medial contact (p = 0.03). UPDRS-III remained stable during testing. CONCLUSION: Motor benefit can be acutely maintained at directional contacts, whereas directional stimulation can modulate thermal and mechanical sensitivity. Further investigation will determine whether these changes are maintained chronically or can be improved with optimized programming.