Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients
Introduction
The Arthritis Foundation estimates that osteoarthritis (OA) currently affects more than 25 million Americans, and a World Health Organization (WHO) study claims that world-wide 40% of people over the age of 70 suffer from OA (1). This study also reported that 80% of patients with OA have a certain limitation of movement, while 25% of them cannot perform the major daily activities of life, further emphasizing the severity of the world's most prevalent articular disease (1). As the average age of the population gets older, and with the drastic increase in the percentage of people currently exceeding their ideal body mass index (BMI), it is estimated that the incidence of OA of the knee will increase sharply over the next several years.
Manifestations of OA include inflammation and the breakdown and eventual loss of the cartilage of the joints. Among the more than 100 different types of arthritic conditions, OA is the most common. It usually affects hands, feet, spine and large weight-bearing joints, such as the hips and knees. The primary pathogenesis of the disease is degeneration of the hyaline articular cartilage, which becomes deformed, fibrillated and eventually excavated during the course of the disease (2). If degenerated articular cartilage could be regenerated, most patients would be able to function better without debilitating pain.
Regarding application to numerous areas of orthopedics, several cellular signal transduction pathways are being considered as suitable candidates for the treatment of orthopedic diseases. For example, bone morphogenic proteins (BMP) have been identified as effective stimulators of bone formation (3., 4., 5.). Analogously, transforming growth factor-β proteins (TGF-β) have been reported to induce osteogenesis and chondrogenesis (6,7). Among the TGF-β, TGF-β1 is known to be the most important factor in the biologic process of cartilage formation. TGF-β1 plays crucial roles in tissue regeneration, cell differentiation and extracellular matrix protein synthesis (6). Studies have suggested that TGF-β1 stimulates proteoglycan synthesis in chondrocytes (8,9) and the growth of articular chondrocytes (10., 11., 12.). In addition to its stimulatory action on chondrocytes, TGF-β has been shown to possess anti-inflammatory and immune suppressive properties (13). This has led to recent reports on the therapeutic value of TGF-β proteins in the orthopedic field, such as in the treatment of OA (14., 15., 16., 17.). However, widespread clinical applications of this protein have been limited because of its short-term effects as a result of a short half-life. Therefore, a new method for the long-term and effective delivery of TGF-β1 is required for the treatment of OA.
TissueGene-C (TG-C) is a cell-mediated gene therapy for the regeneration of cartilage tissue. TG-C is a 3:1 mixture of normal allogeneic human chondrocytes (hChonJ) and irradiated allogeneic human chondrocytes that express TGF-β1 (designated hChonJb#7) (Figure 1). We have identified a proprietary technology to deliver TGF-β1 to degenerative joints in a minimally invasive manner that does not require surgery (18). Human chondrocytes were transfected with a viral vector containing the human TGF-β1 gene. The transduced human chondrocytes, when injected into the damaged knee joints of rabbits and dogs, have exhibited sustained TGF-β1 release and proliferation of regenerative cartilage (19). Uninfected chondrocytes are included as additional cells for filling the defect site. These cells also serve as additional target cells for TGF-β1 expressed from transfected cells because TGF-β1 has a paracrine mode of action (20).
We report the results of a phase I safety study conducted in 12 patients with severe OA of the knee joint. In general, the aim of this study was to assess the feasibility, from a safety perspective, of utilizing allogeneic cells for tissue regeneration and to determine whether there are any unforeseen risks associated with the use of allogeneic human chondrocytes expressing TGF-β1.
The primary objective of this study was to evaluate the safety and biologic activity of intra-articularly administered TG-C as evidenced by observation of the injected joint for the incidence and severity of any adverse events, and the changes in findings of physical examination and laboratory tests. The secondary objectives of this study were to evaluate the dose–response of the hChonJb#7 cells in forming cartilage, as determined by magnetic resonance imaging (MRI), and to evaluate the biologic activity of TG-C on joint pain, range of motion and function.
Section snippets
Overall study design and patient population
A single-center, open-label, dose-escalation study was conducted to evaluate the dose–response of three dose levels of TG-C in 12 adult patients. The patients had severe OA of the knee that has been refractory to previous medical and physical treatments. The diagnosis of OA of the knee for this study was based on characteristic radiographic changes in the knee joint using the grading system introduced by Kellgren & Lawrence (21). The knees with Kellgren & Lawrence grade 4 were included in the
Adverse events
Serious adverse events related to the treatment were not seen following administration of TG-C at any of the dose levels. No dose-limiting toxicity was observed, and dosing proceeded to the highest planned dose level of 3 × 107 cells. The most commonly reported adverse event was effusion (fluid collection) in the joint (Table II).
At the low dose level of 3 × 106 cells, one patient noted a mild warming sensation and itching in the injected joint, which subsequently disappeared spontaneously. One of
Discussion
OA is the most frequently encountered orthopedic disease associated with cartilage damage, and is known to impact 1 in 7 people. Almost all joints in the body, such as the knees, hips, shoulders and hands, are susceptible to cartilage damage. Current methods for treating OA include pharmacologic treatments, physical therapy and surgery. The primary goal of these treatments is to reduce the symptomatic pain associated with the arthritis. However, these treatments do not result in physiologic or
Acknowledgments
These studies were partially supported by a grant from the Korean Government [Korea Health 21 R&D Project (02-PJ2-PG4-PT01-0001) and BioStar Project (10024054)].
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References (25)
- et al.
Effect of transforming growth factor-β on proteoglycan synthesis by chondrocytes in relation to differentiation stage and the presence of pericellular matrix
Matrix Biol
(1998) - et al.
Transforming growth factor β regulates the metabolism of proteoglycans in bovine cartilage organ cultures
J Biol Chem
(1988) - et al.
Characterization of proteoglycans synthesized by rabbit articular chondrocytes in response to transforming growth factor-beta (TGF-β)
Biochim Biophys Acta
(1991) - et al.
The effect of exogenous transforming growth factor-β2 on healing fractures in the rabbit
Bone
(1995) - et al.
The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Disease, Injury and Risk Factors in 1990 and Projected to 2020
World Health Organization
(1996) The response of articular cartilage to mechanical injury
J Bone Joint Surg Am
(1982)- et al.
Bone formation with use of rhBMP-2 (recombinant human bone morphogenetic protein-2)
J Bone Joint Surg Am
(1997) - et al.
Use of recombinant human osteogenic protein-1 for the repair of subchondral defects in articular cartilage in goats
J Biomed Mater Res
(2000) - et al.
Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2)
J Bone Joint Surg Am
(2000) - et al.
Peptide growth factors are multifunctional
Nature
(1988)
Transforming growth factor-β and the initiation of chondrogenesis and osteogenesis in the rat femur
J Cell Biol
Transforming growth factor-β1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint
Lab Invest
Cited by (116)
Current therapies for osteoarthritis and prospects of CRISPR-based genome, epigenome, and RNA editing in osteoarthritis treatment
2024, Journal of Genetics and GenomicsCartilage Injuries: Basic Science Update
2023, Foot and Ankle ClinicsStreamlined, single-step non-viral CRISPR-Cas9 knockout strategy enhances gene editing efficiency in primary human chondrocyte populations
2024, Arthritis Research and TherapyPotential therapeutic strategies for osteoarthritis via CRISPR/Cas9 mediated gene editing
2024, Reviews in Endocrine and Metabolic DisordersThe New Frontiers of Gene Therapy and Gene Editing in Inflammatory Diseases
2024, Human Gene Therapy