Date: 19th January 2021
Osteoarthritis (OA) is a long-term chronic disease characterised by the deterioration of cartilage in the joints, and it is the single most common cause of disability in older adults. As such, there is a great unmet clinical need for disease-modifying osteoarthritis drugs, which are currently lacking. Now scientists, use nanoparticles (NPs) conjugated with transforming growth factor–α (TGFα), a potent epidermal growth factor receptor (EGFR) ligand, to attenuate cartilage degeneration and reduced joint paint in osteoarthritic mice.
It has been estimated that in 2020, there were ~ 654 million individuals, over the age of 40, with knee OA worldwide. It is a joint degenerative disease, primarily characterised by destruction of articular cartilage however, it is often accompanied by subchondral bone thickening, osteophyte formation, synovial inflammation, and hypertrophy of the joint capsule. There are currently no cures for OA, and treatments are limited to pain reduction and increasing mobility where possible, with surgery often being a last option.
The outermost superficial layer of articular cartilage is the first line of defence against OA initiation. Previous work had shown that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA, due to defective articular cartilage, implicating EGFR in the OA process.
Now, a team led by Ling Qin and Zhiliang Cheng, from the University of Pennsylvania, US, have constructed two cartilage-specific EGFR over activation models in mice, showing that activation of the EGFR pathway ameliorated cartilage degeneration, subchondral bone plate sclerosis, and joint pain upon induction of OA. In addition, delivery of an EGFR ligand using nanoparticles, attenuated cartilage degeneration and OA progression.
The team hypothesised that targeting the EGFR pathway would be an effective OA therapy, as previous work in their lab had suggested EGFR deficiency accelerated knee OA. To start, the researchers genetically enhanced EGFR activity by placing the human heparin binding EGF-like growth factor (HBEGF), which is a ligand for EGFR, under the control of two different cartilage-specific promoters in mice. They found that in these mice the growth plate and articular cartilage was expanded, without affecting the gross appearance of knee joints. Furthermore, whilst in wild type mice the number of chondrocytes in the superficial zone decreased by ~40% during cartilage maturation, in the EGFR-activated mice this decline did not occur, and in fact the chondrocytes increased nearly 1.8 fold. This suggested that constitutive over activation of EGFR signalling promoted proliferation, survival and lubricant synthesis in chondrocytes.
Next the team wanted to test whether EGFR activation could ameliorate or attenuate OA disease pathology. In order to do this they induced OA by surgically destabilising the medial meniscus (DMM). Two months after surgery the wild type mice started to show signs of OA however, the HBEGFR-mice showed only very mild signs of deterioration. At four months, the animals were assessed for OA severity which was measured by a Mankin score (the most widely used histology evaluation on OA), overexpression of EGF impressively reduced the Mankin score from 10.0 to 2.1. The team were also able to abolish the protective action of over expression of EGFR by the administration of an EGFR-specific inhibitor – gefitinib.
However, whilst this data was encouraging the scientists wanted to develop a potential clinical therapy. So they conjugated one of the most potent EGFR ligands, the activator TGFα, to a polymeric micellar nanoparticle (TGFα-NP) – which they could deliver directly into the knee joint.
The TGFα-NPs were delivered into the knee after DMM once every 3 weeks, and successfully elevated cartilage EGFR activity to that of the sham group. The treatment attenuated OA progression, maintaining cartilage integrity at 2 months after DMM and only displayed minor signs of degeneration at 3 months. In contrast, the control animals showed cartilage degeneration, including erosion and surface fibrillation. Late OA symptoms such as subchondral bone sclerosis and synovitis were seen in the non-treated cohort, but these were both reduced in the treated group.
Importantly, TGFα-NPs were shown to be safe, with no side effects to internal organs including morphological changes, and the treatment was tolerated well, with no signs of gross morphological changes in the knee joints.
The team here have provided genetic evidence that over activation of EGFR signalling modestly thickened the articular cartilage and completely blocked OA progression after DMM surgery. Furthermore, they have developed a NP delivery system that could be administered directly into the knee joint, using TGFα as a potential drug to effectively attenuate OA initiation and development.
The team are now optimising the drug design and plan to test it in large animals before proceeding to clinical trials in the near future. As there are currently no disease-modifying drugs clinically approved for treatment of OA, the team are hoping this therapy will pave the way for new treatments for this common debilitating condition.
Whilst, the TGFα-NP treatment showed promising results for blocking OA initiation, many patients who present at the clinical are already in middle or late stages of OA. The team are planning to optimise the structure and dosage of conjugates, likely using different EGFR ligands, in the hope of achieving favourable treatment outcomes for other stages of the disease.
There has been a rapid increase in aging populations globally, and with it has come an increase in age-related disorders such as osteoarthritis, vascular disease and glaucoma to name but a few. As such we are currently seeing a drive in addressing these degenerative diseases using novel technologies to develop new therapies. For example we have recently seen scientists use gene therapy to restore vision in mice with glaucoma, by restoring youthful DNA methylation patterns or by regeneration of the optic nerve. Whilst, others are exploiting artificial intelligence to deliver digital therapeutics for the treatment of Alzheimer’s disease, or to classify cellular senescence – a hallmark of ageing – and to evaluate anti-senescent agents.
It is hoped that the technology presented here could offer new hope for patients with OA, and deliver a new safe, effective and disease-modifying drug for treatment of this age-related disease, which causes huge mobility issues and greatly impairs the quality of life for so many.
For more information please see the press release from the University of Pennsylvania
Wei, Y., L. Luo, T. Gui, F. Yu, L. Yan, L. Yao, L. Zhong, W. Yu, B. Han, J. M. Patel, J. F. Liu, F. Beier, L. S. Levin, C. Nelson, Z. Shao, L. Han, R. L. Mauck, A. Tsourkas, J. Ahn, Z. Cheng and L. Qin (2021). “Targeting cartilage EGFR pathway for osteoarthritis treatment.” Science Translational Medicine 13(576): eabb3946.