Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial.
Advanced therapy medicinal product
Cell therapy
Clinical trial
Intervention
Mesenchymal stromal cells
Stem cells
Type 1 diabetes
Umbilical cord
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
10
01
2023
accepted:
22
03
2023
medline:
5
7
2023
pubmed:
24
5
2023
entrez:
23
5
2023
Statut:
ppublish
Résumé
This study aimed to investigate the safety and efficacy of treatment with allogeneic Wharton's jelly-derived mesenchymal stromal cells (MSCs) in recent-onset type 1 diabetes. A combined Phase I/II trial, composed of a dose escalation followed by a randomised double-blind placebo-controlled study in parallel design, was performed in which treatment with allogeneic MSCs produced as an advanced therapy medicinal product (ProTrans) was compared with placebo in adults with newly diagnosed type 1 diabetes. Inclusion criteria were a diagnosis of type 1 diabetes <2 years before enrolment, age 18-40 years and a fasting plasma C-peptide concentration >0.12 nmol/l. Randomisation was performed with a web-based randomisation system, with a randomisation code created prior to the start of the study. The randomisation was made in blocks, with participants randomised to ProTrans or placebo treatment. Randomisation envelopes were kept at the clinic in a locked room, with study staff opening the envelopes at the baseline visits. All participants and study personnel were blinded to group assignment. The study was conducted at Karolinska University Hospital, Stockholm, Sweden. Three participants were included in each dose cohort during the first part of the study. Fifteen participants were randomised in the second part of the study, with ten participants assigned to ProTrans treatment and five to placebo. All participants were analysed for the primary and secondary outcomes. No serious adverse events related to treatment were observed and, overall, few adverse events (mainly mild upper respiratory tract infections) were reported in the active treatment and placebo arms. The primary efficacy endpoint was defined as Δ-change in C-peptide AUC for a mixed meal tolerance test at 1 year following ProTrans/placebo infusion compared with baseline performance prior to treatment. C-peptide levels in placebo-treated individuals declined by 47%, whereas those in ProTrans-treated individuals declined by only 10% (p<0.05). Similarly, insulin requirements increased in placebo-treated individuals by a median of 10 U/day, whereas insulin needs of ProTrans-treated individuals did not change over the follow-up period of 12 months (p<0.05). This study suggests that allogeneic Wharton's jelly-derived MSCs (ProTrans) is a safe treatment for recent-onset type 1 diabetes, with the potential to preserve beta cell function. ClinicalTrials.gov NCT03406585 FUNDING: The sponsor of the clinical trial is NextCell Pharma AB, Stockholm, Sweden.
Identifiants
pubmed: 37221247
doi: 10.1007/s00125-023-05934-3
pii: 10.1007/s00125-023-05934-3
pmc: PMC10317874
doi:
Substances chimiques
Insulin
0
C-Peptide
0
Banques de données
ClinicalTrials.gov
['NCT03406585']
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1431-1441Informations de copyright
© 2023. The Author(s).
Références
Gregory GA, Robinson TIG, Linklater SE et al (2022) Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol 10(10):741–760. https://doi.org/10.1016/S2213-8587(22)00218-2
doi: 10.1016/S2213-8587(22)00218-2
pubmed: 36113507
Steffes MW, Sibley S, Jackson M, Thomas W (2003) Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 26(3):832–836. https://doi.org/10.2337/diacare.26.3.832
doi: 10.2337/diacare.26.3.832
pubmed: 12610045
Ludvigsson J (2016) The clinical potential of low-level C-peptide secretion. Expert Rev Mol Diagn 16(9):933–940. https://doi.org/10.1080/14737159.2016.1210513
doi: 10.1080/14737159.2016.1210513
pubmed: 27388792
Gubitosi-Klug RA, Braffett BH, Hitt S et al (2021) Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia. J Clin Invest 131(3):143011. https://doi.org/10.1172/JCI143011
doi: 10.1172/JCI143011
pubmed: 33529168
Rawshani A, Sattar N, Franzén S et al (2018) Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study. Lancet 392(10146):477–486. https://doi.org/10.1016/S0140-6736(18)31506-X
doi: 10.1016/S0140-6736(18)31506-X
pubmed: 30129464
pmcid: 6828554
Carvalho T (2023) FDA approves first drug to delay type 1 diabetes. Nat Med 29(2):280. https://doi.org/10.1038/d41591-022-00115-y
doi: 10.1038/d41591-022-00115-y
pubmed: 36522439
Spees JL, Lee RH, Gregory CA (2016) Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther 7(1):125. https://doi.org/10.1186/s13287-016-0363-7
doi: 10.1186/s13287-016-0363-7
pubmed: 27581859
pmcid: 5007684
Galipeau J, Sensébé L (2018) Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22(6):824–833. https://doi.org/10.1016/j.stem.2018.05.004
doi: 10.1016/j.stem.2018.05.004
pubmed: 29859173
pmcid: 6434696
Davies JE, Walker JT, Keating A (2017) Concise review: Wharton’s Jelly: the rich, but enigmatic, source of mesenchymal stromal cells. Stem Cells Transl Med 6(7):1620–1630. https://doi.org/10.1002/sctm.16-0492
doi: 10.1002/sctm.16-0492
pubmed: 28488282
pmcid: 5689772
Deuse T, Stubbendorff M, Tang-Quan K et al (2011) Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 20(5):655–667. https://doi.org/10.3727/096368910X536473
doi: 10.3727/096368910X536473
pubmed: 21054940
Selich A, Zimmermann K, Tenspolde M et al (2019) Umbilical cord as a long-term source of activatable mesenchymal stromal cells for immunomodulation. Stem Cell Res Ther 10(1):285. https://doi.org/10.1186/s13287-019-1376-9
doi: 10.1186/s13287-019-1376-9
pubmed: 31547865
pmcid: 6755709
Trivanović D, Jauković A, Popović B et al (2015) Mesenchymal stem cells of different origin: comparative evaluation of proliferative capacity, telomere length and pluripotency marker expression. Life Sci 141:61–73. https://doi.org/10.1016/j.lfs.2015.09.019
doi: 10.1016/j.lfs.2015.09.019
pubmed: 26408916
Petrou P, Kassis I, Levin N et al (2020) Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain 143(12):3574–3588. https://doi.org/10.1093/brain/awaa333
doi: 10.1093/brain/awaa333
pubmed: 33253391
Kamen DL, Wallace C, Li Z et al (2022) Safety, immunological effects and clinical response in a phase I trial of umbilical cord mesenchymal stromal cells in patients with treatment refractory SLE. Lupus Sci Med 9(1):704. https://doi.org/10.1136/lupus-2022-000704
doi: 10.1136/lupus-2022-000704
Carlsson P-O, Korsgren O, Le Blanc K (2015) Mesenchymal stromal cells to halt the progression of type 1 diabetes? Curr Diab Rep 15(7):46. https://doi.org/10.1007/s11892-015-0616-3
doi: 10.1007/s11892-015-0616-3
pubmed: 26003192
Hu J, Yu X, Wang Z et al (2013) Long term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus. Endocr J 60(3):347–357. https://doi.org/10.1507/endocrj.ej12-0343
doi: 10.1507/endocrj.ej12-0343
pubmed: 23154532
Lu J, Shen S-M, Ling Q et al (2021) One repeated transplantation of allogeneic umbilical cord mesenchymal stromal cells in type 1 diabetes: an open parallel controlled clinical study. Stem Cell Res Ther 12(1):340. https://doi.org/10.1186/s13287-021-02417-3
doi: 10.1186/s13287-021-02417-3
pubmed: 34112266
pmcid: 8194026
Carlsson P-O, Schwarcz E, Korsgren O, Le Blanc K (2015) Preserved β-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes 64(2):587–592. https://doi.org/10.2337/db14-0656
doi: 10.2337/db14-0656
pubmed: 25204974
Izadi M, Sadr Hashemi Nejad A, Moazenchi M et al (2022) Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial. Stem Cell Res Ther 13(1):264. https://doi.org/10.1186/s13287-022-02941-w
doi: 10.1186/s13287-022-02941-w
pubmed: 35725652
pmcid: 9208234
Carlsson P-O, Svahn MG (2018) Wharton’s jelly derived allogeneic mesenchymal stromal cells for treatment of type I diabetes: study protocol for a double-blinded, randomizes, parallel, placebo-controlled trial. Clin Trials Degenerative Dis 3(2):32–37. https://doi.org/10.4103/2542-3975.235141
doi: 10.4103/2542-3975.235141
Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317. https://doi.org/10.1080/14653240600855905
doi: 10.1080/14653240600855905
pubmed: 16923606
Burahmah J, Zheng D, Leslie RD (2022) Adult-onset type 1 diabetes: a changing perspective. Eur J Intern Med 104:7–12. https://doi.org/10.1016/j.ejim.2022.06.003
doi: 10.1016/j.ejim.2022.06.003
pubmed: 35718648
Diaz-Valencia PA, Bougnères P, Valleron A-J (2015) Global epidemiology of type 1 diabetes in young adults and adults: a systematic review. BMC Public Health 15:255. https://doi.org/10.1186/s12889-015-1591-y
doi: 10.1186/s12889-015-1591-y
pubmed: 25849566
pmcid: 4381393
Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA, Hattersley AT (2018) Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. Lancet Diabetes Endocrinol 6(2):122–129. https://doi.org/10.1016/S2213-8587(17)30362-5
doi: 10.1016/S2213-8587(17)30362-5
pubmed: 29199115
pmcid: 5805861
Thunander M, Petersson C, Jonzon K et al (2008) Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden. Diabetes Res Clin Pract 82(2):247–255. https://doi.org/10.1016/j.diabres.2008.07.022
doi: 10.1016/j.diabres.2008.07.022
pubmed: 18804305
Weng J, Zhou Z, Guo L et al (2018) Incidence of type 1 diabetes in China, 2010–13: population based study. BMJ 360:j5295. https://doi.org/10.1136/bmj.j5295
doi: 10.1136/bmj.j5295
pubmed: 29298776
pmcid: 5750780
Siwakoti P, Rennie C, Huang Y et al (2022) Challenges with cell-based therapies for type 1 diabetes mellitus. Stem Cell Rev Rep. https://doi.org/10.1007/s12015-022-10482-1
doi: 10.1007/s12015-022-10482-1
pubmed: 36434300
Le Blanc K, Davies LC (2018) MSCs-cells with many sides. Cytotherapy 20(3):273–278. https://doi.org/10.1016/j.jcyt.2018.01.009
doi: 10.1016/j.jcyt.2018.01.009
pubmed: 29434007
Davies LC, Alm JJ, Heldring N et al (2016) Type 1 diabetes mellitus donor mesenchymal stromal cells exhibit comparable potency to healthy controls in vitro. Stem Cells Transl Med 5(11):1485–1495. https://doi.org/10.5966/sctm.2015-0272
doi: 10.5966/sctm.2015-0272
pubmed: 27412884
pmcid: 5070499
Froelich K, Mickler J, Steusloff G et al (2013) Chromosomal aberrations and deoxyribonucleic acid single-strand breaks in adipose-derived stem cells during long-term expansion in vitro. Cytotherapy 15(7):767–781. https://doi.org/10.1016/j.jcyt.2012.12.009
doi: 10.1016/j.jcyt.2012.12.009
pubmed: 23643417
Crisostomo PR, Wang M, Wairiuko GM et al (2006) High passage number of stem cells adversely affects stem cell activation and myocardial protection. Shock 26(6):575–580. https://doi.org/10.1097/01.shk.0000235087.45798.93
doi: 10.1097/01.shk.0000235087.45798.93
pubmed: 17117132
von Bahr L, Sundberg B, Lönnies L et al (2012) Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant 18(4):557–564. https://doi.org/10.1016/j.bbmt.2011.07.023
doi: 10.1016/j.bbmt.2011.07.023
Cernea S, Raz I, Herold KC et al (2009) Challenges in developing endpoints for type 1 diabetes intervention studies. Diabetes Metab Res Rev 25(8):694–704. https://doi.org/10.1002/dmrr.1002
doi: 10.1002/dmrr.1002
pubmed: 19771545
Kota DJ, Wiggins LL, Yoon N, Lee RH (2013) TSG-6 produced by hMSCs delays the onset of autoimmune diabetes by suppressing Th1 development and enhancing tolerogenicity. Diabetes 62(6):2048–2058. https://doi.org/10.2337/db12-0931
doi: 10.2337/db12-0931
pubmed: 23349496
pmcid: 3661629
Jurewicz M, Yang S, Augello A et al (2010) Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 59(12):3139–3147. https://doi.org/10.2337/db10-0542
doi: 10.2337/db10-0542
pubmed: 20841611
pmcid: 2992776
Lee RH, Seo MJ, Reger RL et al (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 103(46):17438–17443. https://doi.org/10.1073/pnas.0608249103
doi: 10.1073/pnas.0608249103
pubmed: 17088535
pmcid: 1634835
Melief SM, Geutskens SB, Fibbe WE, Roelofs H (2013) Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin-10-producing phenotype by production of interleukin-6. Haematologica 98(6):888–895. https://doi.org/10.3324/haematol.2012.078055
doi: 10.3324/haematol.2012.078055
pubmed: 23349310
pmcid: 3669444
Melief SM, Schrama E, Brugman MH et al (2013) Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells 31(9):1980–1991. https://doi.org/10.1002/stem.1432
doi: 10.1002/stem.1432
pubmed: 23712682
Moll G, Rasmusson-Duprez I, von Bahr L et al (2012) Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells 30(7):1565–1574. https://doi.org/10.1002/stem.1111
doi: 10.1002/stem.1111
pubmed: 22522999
de Witte SFH, Luk F, Sierra Parraga JM et al (2018) Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells 36(4):602–615. https://doi.org/10.1002/stem.2779
doi: 10.1002/stem.2779
pubmed: 29341339
Jitschin R, Mougiakakos D, Von Bahr L et al (2013) Alterations in the cellular immune compartment of patients treated with third-party mesenchymal stromal cells following allogeneic hematopoietic stem cell transplantation. Stem Cells 31(8):1715–1725. https://doi.org/10.1002/stem.1386
doi: 10.1002/stem.1386
pubmed: 23554294
Erkers T, Kaipe H, Nava S et al (2015) Treatment of severe chronic graft-versus-host disease with decidual stromal cells and tracing with (111)indium radiolabeling. Stem Cells Dev 24(2):253–263. https://doi.org/10.1089/scd.2014.0265
doi: 10.1089/scd.2014.0265
pubmed: 25162829
von Bahr L, Batsis I, Moll G et al (2012) Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 30(7):1575–1578. https://doi.org/10.1002/stem.1118
doi: 10.1002/stem.1118
Dantas JR, Araújo DB, Silva KR et al (2021) Adipose tissue-derived stromal/stem cells + cholecalciferol: a pilot study in recent-onset type 1 diabetes patients. Arch Endocrinol Metab 65(3):342–351. https://doi.org/10.20945/2359-3997000000368
doi: 10.20945/2359-3997000000368
pubmed: 33939911
pmcid: 10065343
Cai J, Wu Z, Xu X et al (2016) Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care 39(1):149–157. https://doi.org/10.2337/dc15-0171
doi: 10.2337/dc15-0171
pubmed: 26628416
Hao W, Gitelman S, DiMeglio LA, Boulware D, Greenbaum CJ (2016) Fall in C-peptide during first 4 years from diagnosis of type 1 diabetes: variable relation to age, HbA1c, and insulin dose. Diabetes Care 39(10):1664–1670. https://doi.org/10.2337/dc16-0360
doi: 10.2337/dc16-0360
pubmed: 27422577
pmcid: 5033079