NurOwn, phase 2, randomized, clinical trial in patients with ALS

Abstract

ObjectiveTo determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial.MethodsThe study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months. CSF was collected before and 2 weeks after transplantation.ResultsThe study met its primary safety endpoint. The rate of disease progression (Revised ALS Functional Rating Scale [ALSFRS-R] slope change) in the overall study population was similar in treated and placebo participants. In a prespecified rapid progressor subgroup (n = 21), rate of disease progression was improved at early time points (p < 0.05). To address heterogeneity, a responder analysis showed that a higher proportion of treated participants experienced ≥1.5 points/month ALSFRS-R slope improvement compared to placebo at all time points, and was significant in rapid progressors at 4 and 12 weeks (p = 0.004 and 0.046, respectively). CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants (p < 0.05) post-transplantation. CSF monocyte chemoattractant protein-1 levels correlated with ALSFRS-R slope improvement up to 24 weeks (p < 0.05).ConclusionA single-dose transplantation of MSC-NTF cells is safe and demonstrated early promising signs of efficacy. This establishes a clear path forward for a multidose randomized clinical trial of intrathecal autologous MSC-NTF cell transplantation in ALS.Classification of evidenceThis phase II study provides Class I evidence.

Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene

“…Abnormal neurotrophic signaling is well documented in ALS ( Mutoh et al, 2000 ; Turner et al, 2004 ), and in particular, deficient neurotrophic signaling is associated with an increased vulnerability to neuronal injury ( Bemelmans et al, 2006 ; Ghavami et al, 2014 ; Kowiański et al, 2018 ; Tooze and Schiavo, 2008 ). There are ongoing efforts to rebalance neurotrophic signaling in ALS patients ( Berry et al, 2019 ); interestingly, neuronal overexpression of CAV1 improves survival and reduces motor neuron death in a mouse model of ALS ( Sawada et al., 2019 ) and is being developed as a therapy for ALS (US patent no. 8969077B2) ( Head et al, 2012 ).…”

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…These studies include both preclinical and clinical trials of either autologous or allogeneic MSCs. Infusion of MSCs has been performed to evaluate their safety and therapeutic efficacy in diseases of the immune[ 3 ], hematological[ 4 ], cardiovascular[ 5 , 6 ], nervous[ 7 , 8 ], respiratory[ 9 ], digestive[ 10 ], skeletal[ 11 ], endocrine[ 12 ], and reproductive[ 13 ] systems[ 14 ]. To date, more than 1000 MSC-based clinical trials have been registered in the United States National Institute of Health database[ 15 , 16 ].…”

Challenges and advances in clinical applications of mesenchymal stromal cells

“…When administered to patients with neurodegenerative diseases, NurOwn delivered multiple NTFs as well as the immunomodulatory components secreted by MSCs. This combination demonstrated impressive therapeutic efficacy in a phase 2 clinical trial (NCT02017912), in which ALS patients got reduced ALS progression 24 months after NurOwn infusion compared to the controls [ 174 ]. So the indication of NurOwn has been expanded to include multiple sclerosis.…”