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Stem Cells Pass First Trial for ALS. “Lumbar intraspinal injection of neural stem cells in patients with ALS - Results of a Phase I trial in 12 patients”




Amyotrophic lateral sclerosis (ALS) causes muscle weakness and atrophy throughout the body and is caused by the degeneration of motor neurons.   Stem cell therapy has been proposed as a possible treatment for ALS through cell replacement or through additional support to affected neurons (Lunn et al).   Human spinal cord-derived stem cells (HSSCs) derived from an 8-week gestation foetus (Guo et al) have shown some therapeutic benefit in rat models of ALS and ischemic spinal cord injury (SCI) (Cizkovaet aland Xu et al) and therefore suggests that they may also be applicable to stem cell therapy in humans.   Now, published in Stem Cells, the results of a successful phase I trial of intraspinal injections of fetal-derived neural stems cells (NSCs) in patients with ALS have been reported (Glass et al).

Phase I studies generally concentrate on safety and toxicity of any given therapy, in this case focusing on safety issues surrounding this novel surgical technique and the implantation of HSSCs into ALS patients.   The neural stem cells utilised (NSI-566RSC) have been previously described (Guo et al, Johe et aland Yan et al) and these were expanded and stored under cGMP (current good manufacturing practice) conditions and then supplied to the surgery site on the morning of surgery.   Of 368 initial applicants, 15 patients were deemed suitable and subsequent to a screening visit, 12 were enrolled.   Of the 12 patients, all were men aged between 37 and 66 years old with disease duration of between 1.5 and 13 years and 2 were chronically ventilated.   All operations ranged in time from 3 to 4.5 hours, with no problems noted and no immediate postoperative respiratory difficulties, and all patients returned home after 4 or 5 days.   The authors suggest that the few adverse events or toxicities noted after surgery could not with certainty be attributed to the HSSCs.   These effects included mild and transient radicular-type pain and/or sensory, perhaps related to the injection procedure, severe bilateral groin pain in one patient following surgery which dissipated before discharge from hospital, a dural fistula (abnormal connection between arteries and venous channels) and spinal fluid leak in one patient which required re-operation, definitely related to surgery, and finally wound dehiscence (rupture of surgical sutures) requiring re-suturing in one patient.   MRI scans taken over the period of a year post-operation showed the accumulation of extradural fluid at the site of the intraspinal injection in all patients, which resolved spontaneously.

There were however some serious adverse effects and 2 deaths.   The severe effects were one occurrence of a recurrent but transient encephalopathy attributed to the use of immunosuppressant drugs, two occurrences of bronchitis and pneumonia attributed to the progression of ALS and 2 cases of pulmonary emboli attributed to immobility and ALS.  One patient’s death was likely cardiac arrhythmia at 8 months post-surgery, although his ALS was progressing, while the other patients death was attributed to respiratory failure due to progression of his ALS 13 months following surgery.   Non-serious adverse effects were linked to the use of immunosuppressant drugs. Treatments with basiliximab and prednisone were tolerated but only 7 patients could tolerate full doses of both mycophenolate mofetil and tacrolimus.  These drugs tended to lead to gastrointestinal (GI) toxicity, and doses were either reduced or stopped only after attempts to control GI symptoms with antigas and anti-diarrhoeal agents.

The presence of HLA antibodies as a measure of cellular rejection were examined (HSSCs do not express HLA antigens; however, the HLA genotypes are known) at monthly intervals.   In 10 patients, no HLA antibodies were found, while 2 patients who had low class I HLA antibodies at study entry also showed the generation of new HLA antibodies.   Further testing for infection due to the immunocompromised state found no occurrences of active infection, although previous CMV infection in 7 patients led to the use of oral valganciclovir for 3 months following surgery.

Disease status, as measured with standard clinical examinations (FVC (forced vital capacity), ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale) and HHD (hand held dynamometry)) found no obvious or consistent acceleration of disease progression in any patient, and indeed, in one patient, measures of HHD and ALSFRS-R improved postoperatively.

Overall, the trial has been considered successful, as the surgical procedure itself bore little problems and there were no toxicities directly associated with the presence of NSCs in the spinal cord.   Although the main purpose of this trial was to study the safety of the procedure, the authors do report consistent positive changes in one patient, although note that the improvements must be interpreted with caution.   However, potential problems may exist with the current regimen of immunosuppressants with some patients having problems with full doses, although no major opportunistic infections associated with the immunosuppression were observed.



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  • Glass JD et al, Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells. 2012 Jun;30(6):1144-51.
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