Reprogrammed stem cells iPS treat full paralysis caused by spinal cord injury

Good news, but slow progress! Positive results seem mixed. Only four individuals involved in this trial.

"A paralysed man can stand on his own after receiving an injection of neural stem cells to treat his spinal cord injury. The Japanese man was one of four individuals in a first-of-its-kind trial that used reprogrammed stem cells to treat people who are fully paralysed.

Another man can now move his arms and legs following the treatment, but the two others did not show substantial improvements. The results were announced at a press conference and have not yet been peer reviewed, but they suggest that the treatment is safe, say researchers."

"... Previous trials using other types of stem cell have also demonstrated that the therapy is safe, but have so far shown mixed results. “Nothing’s really worked so far,” ...

In this trial, iPS cells derived from a donor were used to create neural precursor cells. Two million of these were injected into each patient’s injury site, in the hope that they would eventually develop into neurons and glial cells.

The trial’s first surgery was performed in December 2021; the other three were conducted between 2022 and 2023. All four recipients were adult males and two were aged 60 or older. They all had surgery between two and four weeks after the damage was done ...

At the one-year follow-up, the researchers did not observe any serious adverse effects.

All individuals started the trial with the highest injury classification of A, as measured by the American Spinal Injury Association Impairment Scale (AIS). People with this level of impairment have no sensory or motor function below the point of injury.

Two of the participants did not show improvements in their ability to feel or move in the lowest section of their spinal cord.

One individual moved up to a classification of C in the period after surgery, and can move some of their arm and leg muscles but cannot stand on their own. Another individual improved to a level D (normal function is classified as E) and can stand independently. ..."

Nature Briefing: Translational Research

Paralysed man stands again after receiving ‘reprogrammed’ stem cells (limite public access) "Another man also regained some movement, but two others experienced minimal improvement."

Deep Brain stimulation helps partially paralyzed patients walk again after spinal cord injury

Good news!

"Two patients with spinal injuries have seen improvements in their ability to walk again, thanks to deep brain stimulation (DBS). Intriguingly, the therapy targets a region of the brain that normally isn’t associated with motor skills. ...

Now, DBS has been used to help two people with partial paralysis regain mobility in their legs. Researchers at EPFL and Lausanne University Hospital surgically implanted electrodes into the lateral hypothalamus (LH) region of their brains, while the patients were fully awake. ... 

Patients showed immediate improvement to their mobility when the deep brain stimulation was switched on during rehabilitation. Patients could walk and even climb stairs with less aid than usual. Importantly, those improvements persisted even after the stimulation was switched off. ..."

"In the study published in Nature Medicine, not only did the DBS show immediate results to augment walking during rehabilitation, but patients also showed long-term improvement that persisted even when the stimulation was turned off. These findings suggest that the treatment promoted a reorganization of residual nerve fibers that contribute to sustained neurological improvements. ..."

From the abstract:

"A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space–time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LHVglut2) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking. We translated this discovery into a deep brain stimulation therapy of the LH (DBSLH) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBSLH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBSLH was turned off. There were no serious adverse events related to DBSLH. These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI. Further trials must establish the safety and efficacy profile of DBSLH, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions."

Brain stimulation helps partially paralyzed patients walk again

Stimulating hypothalamus restores walking in paralyzed patients (original news release)

Hypothalamic deep brain stimulation augments walking after spinal cord injury (no public access)

A patient with a partial spinal cord injury walks with the help of Deep Brain Stimulation

Targeted gene therapy helps completely paralyzed mice walk again

Good news!

"... The EPFL team had previously managed to regenerate nerve fibers using gene therapy, but had limited success.

“Five years ago, we demonstrated that nerve fibers can be regenerated across anatomically complete spinal cord injuries,” ...

To fix the issue, the researchers studied the natural repair processes that take place after a partial spinal cord injury. Using a technique called single-cell nuclear RNA sequencing, the team identified the specific axons that need to be repaired to restore motor function, and how they can find the right target on the other side of the injury.

From this analysis, the researchers developed a new gene therapy that works in a few ways at once to boost the reconnection of nerves. The therapy activates growth programs in certain neurons to regenerate the key nerve fibers, upregulates certain proteins that help the neurons grow through the damaged tissue, and added molecules that guide those regenerating nerves to their targets on the other side.

In tests in mice with complete spinal cord injuries, the team found that the treated animals regained the ability to walk in a matter of months, ending up with a gait similar to those of mice that had recovered from a partial injury. ..."

From the editor's summary and abstract:

"Editor’s summary

Although several experimental approaches have shown positive results in axonal regeneration after spinal cord injury (SCI), complete recovery of motor functions remains an elusive target. Squair et al. hypothesized that restoration of complete axonal projection of a selected neuronal population to their natural target could promote better functional recovery. After using single-cell RNA sequencing to identify the most promising neuronal population, the authors showed that promoting axonal growth and path guidance to their natural target in this population restored walking in mice after complete SCI. By contrast, broad axonal restoration across the lesion had no effect, suggesting that a more targeted approach is necessary for functional recovery after SCI. ...

Abstract

Axon regeneration can be induced across anatomically complete spinal cord injury (SCI), but robust functional restoration has been elusive. Whether restoring neurological functions requires directed regeneration of axons from specific neuronal subpopulations to their natural target regions remains unclear. To address this question, we applied projection-specific and comparative single-nucleus RNA sequencing to identify neuronal subpopulations that restore walking after incomplete SCI. We show that chemoattracting and guiding the transected axons of these neurons to their natural target region led to substantial recovery of walking after complete SCI in mice, whereas regeneration of axons simply across the lesion had no effect. Thus, reestablishing the natural projections of characterized neurons forms an essential part of axon regeneration strategies aimed at restoring lost neurological functions."

Targeted gene therapy helps completely paralyzed mice walk again (secondary news source) A complete spinal cord injury results, tragically, in total paralysis of all limbs and muscles below the injury site. But now, scientists at EPFL have demonstrated in mice a new gene therapy that can regenerate nerves and restore the ability to walk.

Regeneration across complete spinal cord injuries reverses paralysis (primary news source) A complete spinal cord injury leads to irreversible paralysis. Scientists at .NeuroRestore report in Science that they have developed a gene therapy that was proven in mice to stimulate nerve regrowth across such injuries and guide nerves to reconnect to their natural targets below the injuries in order to restore motor function.

Recovery of walking after paralysis by regenerating characterized neurons to their natural target region (no public access)

Paralyzed for 12 years, man walks after bluetooth connects his brain and spine

Amazing stuff! Wonderful!

‘Biohybrid’ device could restore function in paralysed limbs

Good news!

"... Previous attempts at using neural implants to restore limb function have mostly failed, as scar tissue tends to form around the electrodes over time, impeding the connection between the device and the nerve. By sandwiching a layer of muscle cells reprogrammed from stem cells between the electrodes and the living tissue, the researchers found that the device integrated with the host’s body and the formation of scar tissue was prevented. The cells survived on the electrode for the duration of the 28-day experiment, the first time this has been monitored over such a long period. The researchers say that by combining two advanced therapies for nerve regeneration – cell therapy and bioelectronics – into a single device, they can overcome the shortcomings of both approaches, improving functionality and sensitivity. ...
The researchers designed a biocompatible flexible electronic device that is thin enough to be attached to the end of a nerve. A layer of stem cells, reprogrammed into muscle cells, was then placed on the electrode. This is the first time that this type of stem cell, called an induced pluripotent stem cell, has been used in a living organism in this way. ..."

From the abstract:

"The development of neural interfaces with superior biocompatibility and improved tissue integration is vital for treating and restoring neurological functions in the nervous system. A critical factor is to increase the resolution for mapping neuronal inputs onto implants. For this purpose, we have developed a new category of neural interface comprising induced pluripotent stem cell (iPSC)–derived myocytes as biological targets for peripheral nerve inputs that are grafted onto a flexible electrode arrays. We show long-term survival and functional integration of a biohybrid device carrying human iPSC-derived cells with the forearm nerve bundle of freely moving rats, following 4 weeks of implantation. By improving the tissue-electronics interface with an intermediate cell layer, we have demonstrated enhanced resolution and electrical recording in vivo as a first step toward restorative therapies using regenerative bioelectronics."

‘Biohybrid’ device could restore function in paralysed limbs Researchers have developed a new type of neural implant that could restore limb function to amputees and others who have lost the use of their arms or legs.

Functional neurological restoration of amputated peripheral nerve using biohybrid regenerative bioelectronics (open access)

Fig. 1. A biohybrid peripheral neural interface.

Scientists Identify Neurons Needed to Walk After Paralysis

Good news! Neurons are phenomenal!

"... The team identified two neural populations that appeared to orchestrate the rewiring of connections between nerve cells following injury in the animal model. ...

In 2018, scientists first recognized that stimulating nerves near the site of injury—a process known as epidural electrical stimulation (EES)—could ease a person’s pain following a spinal cord injury and restore their ability to walk when combined with intensive physical therapy. ...

Specifically, the algorithm identified two subpopulations of excitatory interneurons—nerve cells that connect motor and sensory neurons—that expressed the genetic markers Vsx2 and Hoxa10 as potential drivers of the animals’ recovery. When the scientists applied optogenetics to inactivate these cells, the mice lost their ability to walk again, regaining it only when the cells were activated. In mice without a spinal cord injury, silencing the cells did nothing, suggesting that such cells only become essential to movement following an injury ..."

From the abstract:

"A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord applied during neurorehabilitation (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencingand spatial transcriptomics to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours."

Scientists Identify Neurons Needed to Walk After Paralysis | The Scientist Magazine® Nine people with spinal injuries walked again after electrical stimulation, allowing researchers to pinpoint neurons likely underlying their recovery.

The neurons that restore walking after paralysis (open access)

Fig. 1: EESREHAB remodels the spinal cord of humans and mice