Wharton's jelly-derived mesenchymal stem cell therapy to improve β-cell function in patients with type 1 diabetes and ketoacidosis: a single-centre, single-group, open-label, phase 2 trial

Abstract Background Infusion with Whartonu0027s jelly-derived mesenchymal stem cells (WJ-MSCs) might restore the function of islet β cell in patients with type 1 diabetes. However, whether WJ-MSCs can preserve islet β-cell function in patients with type 1 diabetes and a history of diabetic ketoacidosis has not been tested. Methods We did a single-group, open-label, phase 2 trial at Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China. We recruited patients aged 12–35 years with type 1 diabetes diagnosis within 12 months and a history of diabetic ketoacidosis during this period, developing at least one of the glutamic acid decarboxylase antibody (GADA), protein tyrosine phosphatase antibody (IA-2A), islet cell antibody (ICA), and insulin autoantibody (IAA), regardless of sex and serum basal or stimulated C-peptide levels. WJ-MSCs were isolated from healthy newborn infants, cultured, and purified, and the cells at passage 2–5 was used for treatment. Patients were infused intravenously once with 1 × 10 6 WJ-MSCs/kg and followed up at 3, 6, 12, and 24 months post treatment to monitor adverse effects, exogenous insulin doses, blood HbA 1c , serum fasting C-peptide (FCP), and peak postprandial C-peptide (PCP). The primary outcome was safety of allogenic WJ-MSC therapy. At each visit, treatment-related adverse effects, including infection, malignant disease, and hypoglycaemic and hyperglycaemic events, were recorded. Clinical response was defined as a reduction in exogenous insulin doses by at least 30%, an increase in serum FCP levels by at least 30%, or an increase in PCP by more than 50% for at least 3 months. Written informed consent was obtained from individuals or their guardian, and the experimental protocols were approved by the Ethics Committee of the Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital. This study is registered with ClinicalTrials.gov, number NCT02763423, and is ongoing. Findings Between March 1, 2009 and July 11, 2012, we recruited 17 patients (mean age 15·8 years [SD 1·5]). Following WJ-MSC therapy, two patients were lost to follow-up and excluded from the analysis. No treatment-related death or serious adverse events were recorded. Compared with HbA 1c concentrations at baseline (mean 10·7% [SD 1·4]), HbA 1c concentrations in all patients continually reduced throughout the follow-up period (7·5% [3·4; 0·041] at 3 months, 6·8% [2·3; 0·032] at 6 months, 7·6% [3·3; 0·047] at 12 months, and 7·5% [2·6; 0·043] at 24 months). Eight (53%) of 15 patients responded to WJ-MSC treatment—ie, they reduced exogenous insulin doses by more than 30% to maintain normal blood glucose ( 1c was noted between responders and non-responders (7·3% [1·1] vs 7·6% [1·7; p=0·71] at 3 months, 6·5% [1·8] vs 7·0% [0·4; p=0·10] at 6 months, 7·1% [1·7] vs 8·1% [0·7; p=0·064] at 12 months, and 7·3% [0·7] vs 7·6% [3·7; p=0·90] at 24 months). However, mean exogenous insulin doses (IU/kg per day) required to maintain normal blood glucose were significantly lower in responders than in non-responders (0·5 [0·2] vs 0·7 [0·1; p=0·008 at 3 months, 0·4 [0.1] vs 0·5 [0·3; p=0·041] at 6 months, 0·6 [0·1] vs 0·7 [0·1; p=0·043] at 12 months). Compared with non-responders, responders had significantly higher serum FCP (243·1 pmol/L [97·2] vs 203·5 pmol/L [78·8; p=0·039] at 3 months, 447·8 pmol/L [141·3] vs 206·5 pmol/L [184·1; p=0·003] at 6 months, and 133·1 pmol/L [45·2] vs 81·6 pmol/L [63·8; p=0·027] at 12 months) and peak PCP (757·2 pmol/L [323·6] vs 607·7 pmol/L [294·9; p=0·021 at 3 months). The mean duration of type 1 diabetes before WJ-MSC therapy in responders was significantly shorter than that in non-responders (0·4 months [0·3] vs 2·5 months [1·9]; p=0·016). Interpretation WJ-MSC therapy is safe and feasible for preservation of islet β cell function in patients with type 1 diabetes and a history of diabetic ketoacidosis, and duration of disease before transplantation might affect the efficacy of WJ-MSC therapy. Funding National Natural Science Foundation of China (81500638), Project of Nanjing Science and Technology Development (201402031), and Key Project of Nanjing Medical Science and Technology Development (ZKX14016).