Targeted Spinal Cord Therapeutics Delivery: Stabilized Platform and Microelectrode Recording Guidance Validation

Abstract

Background/Aims: No validated delivery technique exists for accurate, reproducible delivery of biological therapies to discrete spinal cord targets. To address this unmet need, we have constructed a stabilized platform capable of supporting physiologic mapping, through microelectrode recording, and cellular or viral payload delivery to the ventral horn. Methods: A porcine animal model (n = 7) has been chosen based upon the inherent morphologic similarities between the human and porcine spine. Animals underwent physiologic mapping and subsequent microinjection of a green-fluorescent-protein-labeled cell suspension. Sacrifice (t = 3 h) was performed immediately following behavioral assessment. Results: Histologic analysis has supported our ability to achieve localization to the ipsilateral ventral horn in the spinal cord. Complications included death due to malignant hyperthermia (n = 1), hindlimb dysfunction attributable to epidural hematoma (n = 1), and hindlimb dysfunction attributable to cord penetration (n = 2). Conclusions: These results indicate an ability to achieve accurate targeting, but the elevated incidence of neurologic morbidity will require further studies with longer follow-ups that incorporate procedural and equipment modifications that will allow for a reduced number of cord penetrations and will account for observed cardiorespiratory-associated cord movement. These initial results reinforce the challenges of translating biological restorative therapies from small to large animal models and ultimately to humans.

Lumbar Intraspinal Injection of Neural Stem Cells in Patients with Amyotrophic Lateral Sclerosis: Results of a Phase I Trial in 12 Patients

“…The surgical apparatus and injection procedures are described in previous publications [17][18][19][20]. Surgery was performed using standard anesthetic and monitoring techniques, including lower extremity somatosensory evoked potentials (all patients) and motor evoked potentials (patients 6-12).…”

Human neural stem cell transplantation in ALS: initial results from a phase I trial

“…This system, previously standardized in animal models [16,17], has now been employed in the first FDA-approved cell-therapy trial for ALS, implanting human neural progenitor cells [18,19]. …”

Intraspinal Stem Cell Transplantation in Amyotrophic Lateral Sclerosis

“…Our laboratory has generated significant preclinical data supporting the reproducible safety and accuracy achievable through a direct intraspinal microinjection approach for delivery of both cell-and gene-based biologics. [6][7][8][9][10] Although this approach is equally applicable to the full spectrum of spinal cord disorders, it is relevant to note that spinal cord pathologies can manifest either focally (eg, spinal cord tumors, trauma [spinal cord injury], and autoimmune [multiple sclerosis] processes) or diffusely (eg, degenerative processes like motor neuron diseases) with involvement of the full extent of the spinal cord. Even in diffuse processes, symptomatology may be observed from disease progression within focal segments.…”