Elsevier

Cytotherapy

Volume 14, Issue 2, February 2012, Pages 247-256
Cytotherapy

Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients

https://doi.org/10.3109/14653249.2011.629645Get rights and content

Abstract

Background aims

TissueGene-C (TG-C) represents a cell-mediated gene therapy for localized delivery of allogeneic chondrocytes expressing transforming growth factor (TGF)-β1 directly to the damaged knee joint. Untransduced human chondrocytes (hChonJ cells) have also been incorporated into the TG-C product at a 3:1 ratio with TGF-β1-expressing chondrocytes (hChonJb#7) in order to help fill in the defect and as target cells for the actions of the expressed TGF-β1.

Methods

A phase I dose-escalating clinical trial was performed to evaluate the safety and biologic activity of TG-C in patients with advanced osteoarthritis of the knee joint (full thickness cartilage defect) that was refractory to existing non-operative therapies. Following a single intra-articular injection into the joint space of the damaged knee, patients were monitored for safety, and an evaluation was performed to assess the pharmacokinetics and biologic activity of TG-C.

Results

There were no treatment-related serious adverse events. Swelling, effusion and minor localized reactions such as warming sensation or itching were observed in a dose-dependent manner at the injection site. Knee evaluation scores seemed to indicate a dose-dependent trend toward efficacy; however, patient numbers were not sufficient to determine statistical significance.

Conclusions

Overall, there were no significant safety issues related to the administration of TG-C, with only some minor injection site reactions observed. Additionally, knee scoring analyzes indicated a possibility that TG-C may contribute to improvement of arthritic symptoms. More study is warranted to evaluate further the safety and determine the potential efficacy of TG-C.

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.

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