Development of an advanced cell therapy product indicated for the treatment of gonarthrosis

Abstract

Background Gonarthrosis is the most common cause of pain and disability in middle-aged and elderly people [1,2]. The lack of long-lasting effective treatments for repairing degenerated articular cartilage has spurred research into novel cell-based therapies aiming at reducing pain, slowing the degeneration of cartilage and, ultimately, reverting the natural history of osteoarthritis (OA) [3]. Herein we report the development of a mesenchymal stromal cell (MSC)-based therapy, from conception up to completion of a Phase I/IIa prospective, open-label, single-dose, single-arm clinical trial. Materials and methods All animal care and experimental procedures adhered to the recommendations of local, national, and European laws and were approved by the appropriate Ethical Committees on Human and Animal Experimentation. A GMP-compliant bioprocess was designed for the production of the investigational cell-based medicinal product. Characterisation of MSC adhered to the minimal criteria established by the International Society for Cellular Therapy [4]. For the clinical study (EUDRA-CT: 2009-016449-24; ClinicalTrials.gov Identifier: NCT01227694), fifteen patients with grade II/ III OA (Kellgren & Lawrence score [5]) and chronic pain were treated intraarticularly with clinical grade MSC and were followed up to 12 months. Primary endpoints were safety and tolerability. Additionally, therapeutic efficacy was measured by the Visual Analogue Scale (VAS) for daily activity and on exertion [6], Health Assessment Questionnaire (HAQ) [7], the SF-36 questionnaire [8], the Western Ontario and McMaster Universities Arthritis (WOMAC) and Lequesne functional indexes [9]. Cartilage integrity was assessed by magnetic resonance imaging (MRI) and T2 relaxation time mapping [10,11]. Results and discussion Along the development programme, Good Scientific Practice (GxP) quality standards were implemented gradually in our laboratory (Figure 1) [12]. The preclinical package included a proof-of-principle study in a large animal model of chronic OA and three regulatory preclinical studies in murine animal models (Table 1 Figure 1). The intra-articular injection of autologous MSC was safe, as judged by the lack of local or systemic adverse effects and evidence of regeneration of articular cartilage and meniscus was found in specific macroscopic and histological parameters [13]. Three further regulatory preclinical studies were performed in murine animal models in order to 1) assess subchron…