title: Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.
abstract: Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in the knee joint.
  
  
  
  The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosaminoglycan (sGAG). The mono-iodoacetate (MIA)-induced preclinical model of OA has been used to demonstrate pain reduction and cartilage formation. In the clinical study, 60 OA patients were randomized to receive different doses of cells (25, 50, 75, or 150 million cells) or placebo. Stempeucel® was administered by intra-articular (IA) injection into the knee joint, followed by 2 ml hyaluronic acid (20 mg). Subjective evaluations-visual analog scale (VAS) for pain, intermittent and constant osteoarthritis pain (ICOAP), and Western Ontario and McMaster Universities Osteoarthritis (WOMAC-OA) index-were performed at baseline and at 1, 3, 6, and 12 months of follow-up. Magnetic resonance imaging of the knee was performed at baseline, and at 6 and 12 months follow-up for cartilage evaluation.
  
  
  
  Stempeucel® differentiated into the chondrogenic lineage in vitro with downregulation of Sox9 and upregulation of Col2A genes. Furthermore, Stempeucel® differentiated into chondrocytes and synthesized a significant amount of sGAG (30 ± 1.8 μg/μg GAG/DNA). In the preclinical model of OA, Stempeucel® reduced pain significantly and also repaired damaged articular cartilage in rats. In the clinical study, IA administration of Stempeucel® was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters (VAS, ICOAP, andWOMAC-OA scores), although this was not statistically significant when compared to placebo. Adverse events were predominant in the higher dose groups (50, 75, and 150 million cells). Knee pain and swelling were the most common adverse events. The whole-organ magnetic resonance imaging score of the knee did not reveal any difference from baseline and the placebo group.
  
  
  
  Intra-articular administration of Stempeucel® is safe. A twenty-five-million-cell dose may be the most effective among the doses tested for pain reduction. Clinical studies with a larger patient population are required to demonstrate a robust therapeutic efficacy of Stempeucel® in OA.
  
  
  
  Clinicaltrials.gov NCT01453738 . Registered 13 October 2011.
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India. pawan.gupta@stempeutics.com.
authors.forename: Pawan Kumar
authors.initials: PK
authors.lastname: Gupta
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Chullikana
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
authors.forename: Mathiyazhagan
authors.initials: M
authors.lastname: Rengasamy
authors.affiliation: M.S Ramaiah Medical College & Hospitals, MSR Nagar, MSRIT Post, Bangalore, 560054, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Shetty
authors.affiliation: Kasturba Medical College and Hospital, Madhav Nagar, Manipal, 576104, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Pandey
authors.affiliation: Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Agarwal
authors.affiliation: Jehangir Clinical Development Center, Jehangir Hospital, 33, Sasoon Road, Pune, 411001, India.
authors.forename: Shrikant Yeshwant
authors.initials: SY
authors.lastname: Wagh
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
authors.forename: Prasanth Kulapurathu
authors.initials: PK
authors.lastname: Vellotare
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
authors.forename: Devi
authors.initials: D
authors.lastname: Damodaran
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
authors.forename: Pachaiyappan
authors.initials: P
authors.lastname: Viswanathan
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.|Manipal University, Manipal, India.
authors.forename: Charan
authors.initials: C
authors.lastname: Thej
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No. 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore, 560066, India. anish.majumdar@stempeutics.com.
authors.forename: Anish Sen
authors.initials: AS
authors.lastname: Majumdar
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001853:Bone Marrow; D002454:Cell Differentiation; D005260:Female; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000601:surgery*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar
keywords: Cell therapy; Mesenchymal stromal cells; Osteoarthritis