Targeted Therapy For Parkinson's Disease: Breakthrough in Real-Time MRI-Guided Stem Cell Transplantation - Prisys Events

A recent clinical trial utilizing real-time intraoperative MRI (RT-iMRI) to deliver stem cell therapy into the brain for treating Parkinson's disease (PD) has gained approval from U.S. regulatory agencies. Foundational research on this method was published in the Journal of Neurosurgery.

real-time intraoperative MRI (RT-iMRI)

PD is a neurodegenerative disorder primarily affecting dopamine-producing neurons in the brain, leading to motor impairment. Traditional treatments rely on medication to manage symptoms but fail to repair neural damage. In recent years, stem cell transplantation has emerged as a promising approach, where accurate targeting of the injection site is crucial for enhancing transplant success and cell survival.

RT-iMRI generates high-resolution 3D images in real-time, providing dynamic monitoring during surgery to ensure precise placement of surgical instruments and therapeutic agents. Studies show that using RT-iMRI to guide stem cell transplantation in cynomolgus monkeys significantly improves motor function and neural recovery compared to traditional methods.

The research used dopaminergic neuroprogenitor cells (DANPCs) derived from human-induced pluripotent stem cells (iPSCs), precisely delivering these cells to the putamen region of cynomolgus monkeys under RT-iMRI guidance, ensuring high accuracy and efficacy.

Experimental Design and Methods

Researchers immunosuppressed nine cynomolgus monkeys to simulate clinical conditions. RT-iMRI was employed to monitor each step of the brain injection in real-time, ensuring precise cell placement in the targeted striatum.

**Experimental design, dosing regimen, and the MRI-compatible infusion system used for precise delivery of cells or vectors to the target region.** (A) Experimental design and timeline: Nine cynomolgus monkeys received intra-putamenal injections of either vector (V) or cells (C). Animals were assessed for a series of clinical and behavioral outcomes at 7 (V7, C7) or 30 (V30, C30) days post-surgery, followed by euthanasia. (C) and (D): The MRI-compatible stereotaxic frame was modified to a modular design that can accommodate subjects of different sizes and surgical approaches. (G): MRI-compatible Aspen Neuroscience custom SmartFlow Neuro cannula.

Cell Preparation and Injection: Dopaminergic neuroprogenitor cells were suspended in a carrier solution containing an MRI contrast agent (gadoteridol). Each hemisphere of the monkeys' brains received two needle tracks for the injection, using catheters along both dorsal and ventral pathways to deliver varying doses of the cell suspension.

Real-Time Monitoring and Injection Strategy: RT-iMRI allowed researchers to confirm the positioning of the catheter and distribution of injected cells, minimizing risks of cell leakage or damage due to misalignment, which is common with traditional techniques. A slow injection rate (2.5 µL/min) reduced fluid reflux, ensuring accurate deposition of cells in the target area.

Key Findings and Results

All cynomolgus monkeys successfully received bilateral striatal cell injections, and RT-iMRI confirmed precise targeting. Tissue analysis at 7 and 30 days post-injection revealed the survival and differentiation of dopaminergic neuroprogenitor cells in the striatum, showing signs of integration and neural fiber extension. Immunohistochemical staining confirmed positive expression of the human cell marker STEM121, indicating that the transplanted cells survived and dispersed along the injection tracks.

**Intraoperative MRI-guided cell transplantation into a specific brain region and survival and distribution of the transplanted cells at 30 days post-transplantation.** (D), (F), and (H): STEM121-positive human cells were detected at 30 days post-transplantation in three coronal planes corresponding to (C), (E), and (G), demonstrating the survival and distribution of the transplanted cells within the injection site. (d), (f), and (h): Higher magnification images of the boxed regions in (D), (F), and (H), providing a clearer visualization of the distribution of STEM121-positive cells.

Innovation and Significance

This study highlights the enormous potential of RT-iMRI in preclinical central nervous system (CNS) research. With precise targeting, stem cells can be more effectively implanted into the target brain region, improving therapeutic outcomes. The precision and safety demonstrated in stem cell transplantation suggest that RT-iMRI will play a key role in studying diseases such as Parkinson's, facilitating the development of new treatment strategies, and ultimately accelerating clinical translation.

**Differential STEM121 expression in the putamen of cynomolgus monkeys across treatment groups, allowing for assessment of cell transplantation efficacy and cell survival durability.** (A): Coronal brain section from a vector-treated monkey at 7 days (V7-1), immunostained for STEM121 and counterstained with Nissl. (B): Coronal brain section from a cell-treated monkey at 7 days (C7-2), immunostained for STEM121 and counterstained with Nissl. (C): Coronal brain section from a cell-treated monkey at 30 days (C30-1), immunostained for STEM121 and counterstained with Nissl. (a), (b), and (c): Higher magnification images of the boxed regions in (A), (B), and (C), respectively, providing a clearer visualization of the distribution of STEM121-positive cells and fibers. Black arrows: Indicate STEM121-positive fibers.

Prisys Biotechnologies is the first in Asia to introduce the RT-iMRI, integrated with the Orchestral Head Frame for non-human primates and SmartFlow catheters using convection-enhanced delivery (CED) to bypass the blood-brain barrier.

Prisys Biotechnologies' CNS platform integrates RT-iMRI, CT, DSA, and ultrasound technologies to create a highly accurate navigation and delivery system, significantly enhancing the success rate of brain-targeted therapies and the precision and safety of neurosurgical procedures. This platform's application, especially in cynomolgus monkey models, is driving the development of more precise disease simulations and novel therapies, ushering in a new era of precision in large-animal model research.

**Prisys Biotech's Intrastriatal Drug Injection Procedure with Simultaneous Scanning**

Prisys Biotechnologies has successfully established cynomolgus monkey models for various CNS diseases , including Parkinson's disease (PD), cerebral ischemia (MCAO) , epilepsy , and pain . Using RT-iMRI technology, researchers can precisely deliver drugs and interventions in these models. For example, in the PD model, medications can be delivered directly to the target brain region to evaluate their efficacy and mechanisms of action. In the ischemia model, real-time monitoring of ischemic region changes allows for assessment of neuroprotective drug efficacy.

Prisys Biotechnologies is advancing the application of RT-iMRI in CNS disease research and treatment, working alongside researchers to create a future of precision medicine and contribute to conquering CNS disorders.

Reference:

Emborg, M.E., Mancinelli, A., Colwell, J.C., et al. (2024). Preclinical evaluation of transaxial intraputaminal trajectory for enhanced distribution of grafted cells in Parkinson's disease. Journal of Neurosurgery, 1(aop), 1-13.