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Open access

Richard G. Fessler, Reza Ehsanian, Charles Y. Liu, Gary K. Steinberg, Linda Jones, Jane S. Lebkowski, Edward D. Wirth III, and Stephen L. McKenna

OBJECTIVE

The primary objective of this study was to evaluate the safety of 3 escalating doses of oligodendrocyte progenitor cells (LCTOPC1; previously known as GRNOPC1 and AST-OPC1) administered at a single time point between 21 and 42 days postinjury to participants with subacute cervical spinal cord injuries (SCIs). The secondary objective was to evaluate changes in neurological function following administration of LCTOPC1.

METHODS

This study was designed as an open-label, dose-escalation, multicenter clinical trial. Twenty-five participants with C4–7 American Spinal Injury Association Impairment Scale grade A or B injuries received a single dose of either 2 × 106, 1 × 107, or 2 × 107 LCTOPC1 delivered via intraparenchymal injection into the spinal cord at the site of injury using a custom-designed syringe positioning device. Low-dose tacrolimus was administered until day 60. Outcome measures included adverse event (AE) monitoring and neurological function as measured by the International Standards for Neurological Classification of Spinal Cord Injury.

RESULTS

All 25 participants experienced at least one AE, with a total of 534 AEs (32 study-related vs 502 study-unrelated anticipated complications of SCI) reported at the completion of 1-year follow-up. There were 29 serious AEs reported. Two grade 3 serious AEs (CSF leak in one participant and a bacterial infection in another) were considered related to the injection procedure and to immunosuppression with tacrolimus, respectively. The CSF leakage resolved with sequelae, including self-limited altered mental status, and the infection resolved with antibiotic therapy. For all participants, MRI scans demonstrated no evidence of an enlarging mass, spinal cord damage related to the injection procedure, inflammatory lesions in the spinal cord, or masses in the ventricular system. At 1-year follow-up, 21/22 (96%) of the intention-to-treat group recovered one or more levels of neurological function on at least one side of their body, and 7/22 (32%) recovered two or more levels of neurological function on at least one side of their body.

CONCLUSIONS

LCTOPC1 can be safely administered to participants in the subacute period after cervical SCI. The injection procedure, low-dose temporary immunosuppression regimen, and LCTOPC1 were well tolerated. The safety and neurological function data support further investigation to determine the efficacy of LCTOPC1 in the treatment of SCI.

Clinical trial registration no.: NCT02302157 (ClinicalTrials.gov)

Free access

Tobias Prasse and Christoph P. Hofstetter

Open access

Stephen L. McKenna, Reza Ehsanian, Charles Y. Liu, Gary K. Steinberg, Linda Jones, Jane S. Lebkowski, Edward Wirth III, and Richard G. Fessler

OBJECTIVE

The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site.

METHODS

This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 × 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations.

RESULTS

No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site.

CONCLUSIONS

This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell–derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157).

Free access

Richard G. Fessler, Charles Y. Liu, Stephen McKenna, R. David Fessler, Jane S. Lebkowski, Catherine A. Priest, and Edward D. Wirth III

OBJECTIVE

This study was conducted as a final proof-of-safety direct injection of oligodendrocyte progenitor cells into the uninjured spinal cord prior to translation to the human clinical trials.

METHODS

In this study, 107 oligodendrocyte progenitor cells (LCTOPC1, also known as AST-OPC1 and GRNOPC1) in 50-μL suspension were injected directly into the uninjured spinal cords of 8 immunosuppressed Göttingen minipigs using a specially designed stereotactic delivery device. Four additional Göttingen minipigs were given Hanks’ Balanced Salt Solution and acted as the control group.

RESULTS

Cell survival and no evidence of histological damage, abnormal inflammation, microbiological or immunological abnormalities, tumor formation, or unexpected morbidity or mortality were demonstrated.

CONCLUSIONS

These data strongly support the safety of intraparenchymal injection of LCTOPC1 into the spinal cord using a model anatomically similar to that of the human spinal cord. Furthermore, this research provides guidance for future clinical interventions, including mechanisms for precise positioning and anticipated volumes of biological payloads that can be safely delivered directly into uninjured portions of the spinal cord.

Free access

Angad S. Gogia, Roberto Martin Del Campo-Vera, Kuang-Hsuan Chen, Rinu Sebastian, George Nune, Daniel R. Kramer, Morgan B. Lee, Ali R. Tafreshi, Michael F. Barbaro, Charles Y. Liu, Spencer Kellis, and Brian Lee

OBJECTIVE

Motor brain-computer interface (BCI) represents a new frontier in neurological surgery that could provide significant benefits for patients living with motor deficits. Both the primary motor cortex and posterior parietal cortex have successfully been used as a neural source for human motor BCI, leading to interest in exploring other brain areas involved in motor control. The amygdala is one area that has been shown to have functional connectivity to the motor system; however, its role in movement execution is not well studied. Gamma oscillations (30–200 Hz) are known to be prokinetic in the human cortex, but their role is poorly understood in subcortical structures. Here, the authors use direct electrophysiological recordings and the classic “center-out” direct-reach experiment to study amygdaloid gamma-band modulation in 8 patients with medically refractory epilepsy.

METHODS

The study population consisted of 8 epilepsy patients (2 men; age range 21–62 years) who underwent implantation of micro-macro depth electrodes for seizure localization and EEG monitoring. Data from the macro contacts sampled at 2000 Hz were used for analysis. The classic center-out direct-reach experiment was used, which consists of an intertrial interval phase, a fixation phase, and a response phase. The authors assessed the statistical significance of neural modulation by inspecting for nonoverlapping areas in the 95% confidence intervals of spectral power for the response and fixation phases.

RESULTS

In 5 of the 8 patients, power spectral analysis showed a statistically significant increase in power within regions of the gamma band during the response phase compared with the fixation phase. In these 5 patients, the 95% bootstrapped confidence intervals of trial-averaged power in contiguous frequencies of the gamma band during the response phase were above, and did not overlap with, the confidence intervals of trial-averaged power during the fixation phase.

CONCLUSIONS

To the authors’ knowledge, this is the first time that direct neural recordings have been used to show gamma-band modulation in the human amygdala during the execution of voluntary movement. This work indicates that gamma-band modulation in the amygdala could be a contributing source of neural signals for use in a motor BCI system.

Free access

Daniel R. Kramer, Krista Lamorie-Foote, Michael Barbaro, Morgan B. Lee, Terrance Peng, Angad Gogia, George Nune, Charles Y. Liu, Spencer S. Kellis, and Brian Lee

OBJECTIVE

Stimulation of the primary somatosensory cortex (S1) has been successful in evoking artificial somatosensation in both humans and animals, but much is unknown about the optimal stimulation parameters needed to generate robust percepts of somatosensation. In this study, the authors investigated frequency as an adjustable stimulation parameter for artificial somatosensation in a closed-loop brain-computer interface (BCI) system.

METHODS

Three epilepsy patients with subdural mini-electrocorticography grids over the hand area of S1 were asked to compare the percepts elicited with different stimulation frequencies. Amplitude, pulse width, and duration were held constant across all trials. In each trial, subjects experienced 2 stimuli and reported which they thought was given at a higher stimulation frequency. Two paradigms were used: first, 50 versus 100 Hz to establish the utility of comparing frequencies, and then 2, 5, 10, 20, 50, or 100 Hz were pseudorandomly compared.

RESULTS

As the magnitude of the stimulation frequency was increased, subjects described percepts that were “more intense” or “faster.” Cumulatively, the participants achieved 98.0% accuracy when comparing stimulation at 50 and 100 Hz. In the second paradigm, the corresponding overall accuracy was 73.3%. If both tested frequencies were less than or equal to 10 Hz, accuracy was 41.7% and increased to 79.4% when one frequency was greater than 10 Hz (p = 0.01). When both stimulation frequencies were 20 Hz or less, accuracy was 40.7% compared with 91.7% when one frequency was greater than 20 Hz (p < 0.001). Accuracy was 85% in trials in which 50 Hz was the higher stimulation frequency. Therefore, the lower limit of detection occurred at 20 Hz, and accuracy decreased significantly when lower frequencies were tested. In trials testing 10 Hz versus 20 Hz, accuracy was 16.7% compared with 85.7% in trials testing 20 Hz versus 50 Hz (p < 0.05). Accuracy was greater than chance at frequency differences greater than or equal to 30 Hz.

CONCLUSIONS

Frequencies greater than 20 Hz may be used as an adjustable parameter to elicit distinguishable percepts. These findings may be useful in informing the settings and the degrees of freedom achievable in future BCI systems.

Restricted access

Michael F. Barbaro, Kelsi Chesney, Daniel R. Kramer, Spencer Kellis, Terrance Peng, Zack Blumenfeld, Angad S. Gogia, Morgan B. Lee, Janet Greenwood, George Nune, Laura A. Kalayjian, Christianne N. Heck, Charles Y. Liu, and Brian Lee

Closed-loop brain-responsive neurostimulation via the RNS System is a treatment option for adults with medically refractory focal epilepsy. Using a novel technique, 2 RNS Systems (2 neurostimulators and 4 leads) were successfully implanted in a single patient with bilateral parietal epileptogenic zones. In patients with multiple epileptogenic zones, this technique allows for additional treatment options. Implantation can be done successfully, without telemetry interference, using proper surgical planning and neurostimulator positioning.

Trajectories for the depth leads were planned using neuronavigation with CT and MR imaging. Stereotactic frames were used for coordinate targeting. Each neurostimulator was positioned with maximal spacing to avoid telemetry interference while minimizing patient discomfort. A separate J-shaped incision was used for each neurostimulator to allow for compartmentalization in case of infection. In order to minimize surgical time and risk of infection, the neurostimulators were implanted in 2 separate surgeries, approximately 3 weeks apart.

The neurostimulators and leads were successfully implanted without adverse surgical outcomes. The patient recovered uneventfully, and the early therapy settings over several months resulted in preliminary decreases in aura and seizure frequency. Stimulation by one of the neurostimulators did not result in stimulation artifacts detected by the contralateral neurostimulator.

Free access

Charles Y. Liu, Brian Lee, Nicholas Boulis, and Ali R. Rezai

Free access

Howard M. Eisenberg, Charles Y. Liu, and Oren Sagher