DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Manufacture Articular Cartilage from Human Adipose-Derived Stromal/Stem Cells for Cartilage Repair

Principal Investigator: YOU, ZONGBING
Institution Receiving Award: TULANE UNIVERSITY
Program: PRORP
Proposal Number: OR140380
Award Number: W81XWH-15-1-0444
Funding Mechanism: Expansion Award
Partnering Awards:
Award Amount: $1,645,663.00


PUBLIC ABSTRACT

Rationale and Objectives:

About 24.3 million American adults have osteoarthritis (OA). Articular cartilage injuries leave Soldiers liable to OA. The rate of OA in the general population is 12.4 per 1,000 people. In contrast, the OA rate in the U.S. military population is 26.9 per 1,000 military persons, which is more than twice of that in the general population. Arthritis causes pain and loss of motion. Therefore, treatment of articular cartilage injury and OA is a critical need of the Armed Forces and the U.S. Veteran population. However, no effective treatment has been developed other than joint replacement surgery. New ways to treat cartilage damage are being developed, and there are about 84 clinical trials. However, so far only one product, Carticel® (Genzyme, Cambridge, MA), has been approved by the U.S. Food and Drug Administration. Carticel® requires two surgeries. The first surgery takes normal cartilage from the non-weight bearing region of the patient's joint and sends the specimen to a laboratory, so the cells inside the cartilage will be cultured to amplify the number. The second surgery will put back these cells into the defect and let them grow into cartilage. It is clear that Carticel® does not work if the patient has no good cartilage to use, which is often the case in severe OA. Thus, other techniques are developed to use a donor's cartilage (so called allograft). Again, this is limited if donor material is not available. Tissue engineering (a technique to change cell growth and make them build new tissues) using human fat tissue-derived adult stem cells (ASCs) may overcome the limitation. ASCs are special cells in our body that can become many different tissues such as cartilage, bone, and fat, if proper inductive signals are present. ASCs from fat are technically unlimited in sources because 35% of U.S. adults are obese and about 280,000 liposuction procedures are done annually in the U.S. Our laboratory has discovered a gene called doublecortin (DCX) that may help human ASCs to become articular chondrocytes, hence forming real articular cartilage. Therefore, we have formulated a hypothesis that consistent expression of DCX in ASCs may promote differentiation of the ASCs into articular chondrocytes that can be used to treat combat-related cartilage injuries. The overall research goals for this study are: (1) to test this hypothesis using a pellet culture bioreactor to manufacture cartilage tissues in a large scale and (2) to test a novel Pellet Chondrocytes Implant (PCI) technique to repair rabbit and monkey knee defects and evaluate the histological and biomechanical properties of the tissue engineered cartilage as well as the safety. We will achieve two specific aims: (1) develop a chemically defined tissue engineering system to manufacture articular cartilage and (2) test the tissue engineered articular cartilage in repair of knee defects in both the rabbit and nonhuman primate models. If successful, we may provide a novel technique to treat cartilage damage.

The Ultimate Applicability of This Study:

-- This study will help all patients with joint diseases or injuries that damage their articular cartilage, including 24.3 million OA patients, many of whom are military personnel with twice the risk of developing OA. This study will develop a new technique called PCI, which may use tissue engineered cartilage and chondrocytes to repair the defects in the damaged joints of these patients.

-- This study will benefit the research field by providing a proof-of-principle that DCX can promote ASCs to become articular chondrocytes, which is a significant advancement over the current knowledge that DCX is a unique marker of articular chondrocytes. This study will benefit the clinical practice by providing a novel PCI technique in the treatment of cartilage damage. There is very little risk associated with the PCI technique because the viruses we used to get DCX gene into ASCs will no longer be reproduced in the cartilage. Therefore, there is rarely any risk to form new viruses, and we will prove that this is the case in this study.

-- This study is a preclinical study. If successful, we will immediately start a Phase 0/I clinical trial in human patients. Because we are testing human ASCs products, if our efficacy and safety outcomes are clear from this preclinical study, we can quickly move to clinical trials and eventually use this PCI technique in clinical practice.

Military Benefit: More than 27,400 U.S. casualties have been incurred in the wars in Iraq and Afghanistan. Injured extremities (including articular cartilage) have increased to about 70% of all injuries. Injuries to articular cartilage do not heal spontaneously and often proceed to degenerative OA, which has no effective treatment. This study addresses a critical need of the U.S. military population by potentially providing a new treatment for their cartilage damages incurred either during the war or through OA.