Chondrocyte-specific viral vector improves osteoarthritis gene therapy in mice [PreClinical]
1. A helper-dependent adenoviral vector (HDV) was modified with an antibody (a10mab) that specifically targeted molecules on the chondrocyte cell surface, in order to improve delivery of the proteoglycan 4 (PRG4) gene.
2. In a mouse model of osteoarthritis (OA), the targeted vector performed better than the non-targeted vector in terms of disease prevention and disease treatment.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Because OA is a localized disease, it is a good candidate for targeted gene therapy. Previous studies and clinical trials have used viral vectors, but showed poor gene delivery efficiency or low levels of integrated gene expression. In this study, researchers sought to improve gene delivery by modifying an HDV with a10mab that targeted α-10 integrin, a collagen receptor expressed only on chondrocytes.
When injected into mouse knee joints, a10mabHDV targeted chondrocytes, while the wild-type HDV did not. PRG4, a gene previously found to slow OA development, was then added to the a10mabHDV and control HDV. After both treatments were injected into mouse knee joints, OA was induced by cruciate ligament transection. Mice that received a10mabHDV-PRG4 ultimately developed a less severe form of OA and also required a lower dose of the therapy to have the same benefit. In a separate experiment, a10mabHDV-PRG4 was injected after OA induction. Cartilage was better preserved in these mice, and the animals showed a larger bone area covered by the cartilage.
Since there are current clinical trials testing similar methods of viral vector gene therapy, the results of this study could be translated to humans in a timely manner. Further studies should evaluate the effects of this therapy on the cells surrounding chondrocytes as well as the joint capsule microenvironment, to determine whether any toxicity is caused by this treatment.
Click to read the study in Molecular Therapy- Methods & Clinical Development
Relevant Reading: The Future of Osteoarthritis Therapeutics: Targeted Pharmacological Therapy
In-Depth [animal study]: The a10mabHDV was synthesized by genetically fusing a biotin acceptor peptide to the outside of the virus, and then conjugating the peptide to the biotinylated a10mab. Control HDV or a10mabHDV, both expressing the LacZ gene, was injected into the knee joints of normal mice or mice with OA induced by cruciate ligament transection. Histology and staining for LacZ expression showed that while the control vector only targeted synoviocytes, a10mabHDV targeted both synoviocytes and chondrocytes.
The PRG4 gene was then incorporated into both vectors. 24 hours after injecting 108 viral particles/joint into the knee joints of mice, cruciate ligament transection was performed to induce OA. 1 and 2 months later, histology sections were taken and microCT was performed to visualize the area. At both time points, the histology sections from animals injected with a10mabHDV-PRG4 had a lower score than animals with no treatment on the histological scale of the Osteoarthritis Research Society International (OARSI), indicating less severe OA (p<0.01). In addition, a 108 particle/joint dose used for a10mabHDV-PRG4 achieved similar results as the control HDV-PRG4 at a dose of 109 particles/joint, showing a 10-fold therapeutic index improvement with the targeted vector.
Finally, the efficacy of a10mabHDV-PRG4 post-injury was examined by injecting 108 particles/joint into the mice knee joints 2 weeks after cruciate ligament transection. Using histology sections and OARSI scoring, greater preservation of cartilage was found compared to no treatment (p<0.01), and a larger bone area was covered by cartilage (p<0.01).
Image: PD
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