Breathing pattern in a phase I clinical trial of intraspinal injection of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis

Ruíz-López, Francisco José; Guardiola, Julia; Izura, Virginia; Gómez-Espuch, Joaquín; Martinez, F; Blanquer, Miguel; Román, Javier López-San; Saez, Vicenta; Mingo, P. De; Moraleda, José Marı́a

doi:10.1016/j.resp.2015.11.007

Cited by 16 publications

(11 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results indicated that there were improved motor functions under these conditions following Neuro‐Cells administration. Together, our data provide evidence of the disease‐counteracting and anti‐inflammatory effects of Neuro‐Cells in two experimental models of ALS and are in line with previously published reports on effectiveness of stem cell therapy during this disease, as well as with previous findings with this preparation applied in a spinal cord injury model . They also highlight the importance of compliance in preclinical ALS studies with the internationally accepted guidelines to more accurately approximate the usefulness of novel therapeutics (see Data S1), including stem cells and thus provide a better basis for clinical trials.…”

Section: Discussionsupporting

confidence: 88%

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

et al. 2019

View full text Add to dashboard Cite

Aims:Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants. Methods: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39 × 10 6 mesenchymal and hemopoietic human stem cells, containing 5 × 10 5 of CD34 + cells), which showed antiinflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle.Results: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Celltreated mutants had reduced muscle atrophy and lumbar motor neuron degeneration.This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3ß (GSK-3ß). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group. Conclusion:The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation. | 505MUNTER ET al.

show abstract

Section: Discussionsupporting

confidence: 88%

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The FVC, measured as a percentage, is used to assess respiratory function and is an indicator of disease progression. FVC also decreases with disease progression 15 – 17 .…”

Section: Methodsmentioning

confidence: 96%

“…Patients received 6 doses of 320 mg GM604 or placebo, administered as slow IV bolus injections on Monday, Wednesday, and Friday of weeks 1 and 2. Clinical assessments included the ALS Functional Rating Scale – Revised (ALSFRS-R) 14 , FVC 15 – 17 , timed up & go (TUG) 18 , and hand-held dynamometry (HHD) 19 . Assessements were conducted at screening, before the first dose (baseline), after the last (6 th ) dose at week 2, and at weeks 6 and 12.…”

Section: Methodsmentioning

confidence: 99%

A Phase 2A randomized, double-blind, placebo-controlled pilot trial of GM604 in patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and a single compassionate patient treatment (Protocol GALS-C)

Kindy

Lupinacci

Chau³

et al. 2017

F1000Res

View full text Add to dashboard Cite

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options. Genervon has discovered and developed GM604 (GM6) as a potential ALS therapy. GM6 has been modeled upon an insulin receptor tyrosine kinase binding motoneuronotrophic factor within the developing central nervous system. Methods This was a 2-center phase 2A, randomized, double-blind, placebo-controlled pilot trial with 12 definite ALS patients diagnosed within 2 years of disease onset. Patients received 6 doses of GM604 or placebo, administered as slow IV bolus injections (3x/week, 2 consecutive weeks). Objectives were to assess the safety and efficacy of GM604 based on ALSFRS-R, FVC and selected biomarkers (TDP-43, Tau and SOD1, pNFH). This report also includes results of compassionate treatment protocol GALS-C for an advanced ALS patient. Results Definite ALS patients were randomized to one of two treatment groups (GM604, n = 8; placebo, n = 4). 2 of 8 GM604-treated patients exhibited mild rash, but otherwise adverse event frequency was similar in treated and placebo groups. GM604 slowed functional decline (ALSFRS-R) when compared to a historical control (P = 0.005). At one study site, a statistically significant difference between treatment and control groups was found when comparing changes in respiratory function (FVC) between baseline and week 12 (P = 0.027). GM604 decreased plasma levels of key ALS biomarkers relative to the placebo group (TDP-43, P = 0.008; Tau, P = 0.037; SOD1, P = 0.009). The advanced ALS patient in compassionate treatment demonstrated improved speech, oral fluid consumption, mouth suction with GM604 treatment and biomarker improvements. Conclusions We observed favorable shifts in ALS biomarkers and improved functional measures during the Phase 2A study as well as in an advanced ALS patient. Although a larger trial is needed to confirm these findings, the present data are encouraging and support GM604 as an ALS drug candidate.

show abstract

“…Also, administration of glial-restricted precursors into the cervical spinal cord of a rat model of ALS revealed increased animal survival in addition to moderating the decline in respiratory function in cell-treated rats 34 . Moreover, to our knowledge, only one phase I clinical trial examined the effect of intramedullary infusion of autologous bone marrow mononuclear cells at the thoracic level on the breathing patterns of ALS patients 35 . Results of this study demonstrated safety of the cell injection; however, no significant differences were observed in oxygen saturation or inspiratory flow after 1 year.…”

Section: Introductionmentioning

confidence: 99%

Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis

et al. 2020

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.

show abstract

Breathing pattern in a phase I clinical trial of intraspinal injection of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis

Cited by 16 publications

References 26 publications

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

A Phase 2A randomized, double-blind, placebo-controlled pilot trial of GM604 in patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and a single compassionate patient treatment (Protocol GALS-C)

Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About