AAV2/1-TNFR:Fc gene delivery prevents periodontal disease progression

Abstract

SUMMARYPeriodontal disease is a chronic inflammatory condition induced by tooth-associated microbial biofilms that induce a host immune response. Therapeutic control of progressive tissue destruction in high-risk patients is a significant challenge in therapy. Soluble protein delivery of antagonists to tumor necrosis factor alpha (TNF-α) inhibits alveolar bone resorption due to periodontitis. However, protein therapy raises several concerns, such as recurrence of disease activity after treatment cessation and repeated dosing regimens. In this study, we used pseudotyped adeno-associated virus vector based on serotype 1 (AAV2/1) to deliver the TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene to rats subjected to experimental Porphyromonas gingivalis (Pg)-lipopolysaccharide (LPS)-mediated bone loss. Animals received Pg-LPS delivered to the gingivae thrice weekly for 8 weeks, vehicle alone, Pg-LPS and intramuscular delivery of pseudotyped AAV2/1-TNFR:Fc vector (1×1011 DNase I-resistant particles) or AAV2/1-TNFR:Fc vector delivered to naïve animals. AAV2/1-TNFR:Fc therapy led to sustained therapeutic levels of serum TNFR protein and protected against Pg-LPS-mediated loss of bone volume and density. Furthermore, AAV2/1-TNFR:Fc administration reduced local levels of multiple pro-inflammatory cytokines and osteoclast-like cells at the periodontal lesions. These findings suggest that delivery of AAV2/1-TNFR:Fc may be a viable approach to modulate periodontal disease progression.

Herpes Simplex Virus Vector Mediated Gene Therapy of Tumor Necrosis Factor-α Blockade for Bladder Overactivity and Nociception in Rats

“…5,6 Since we used an acute model of bladder pain and overactivity induced by bladder irritation, our results might not directly be applied to treat IC/BPS, which is a chronic disorder. In patients with IC/BPS proinflammatory cytokines such as IL-2, 6 and 8, and TNF␣ are increased in the bladder and/or urine.…”

“…When TNF␣ activity is neutralized using anti-TNF␣ antibody or TNF␣sR, nociception is suppressed, as observed in several rat pain models. 3,[5][6][7][8] Anti-TNF␣ antibody and recombinant TNF␣sR are used clinically to treat several inflammatory diseases. 9,10 However, concern exists that systemic administration of these molecules may lead to a wide range of side effects due to the importance of TNF␣ in generating a powerful immune response to infectious agents and other insults.…”

A comparison of the thresholding strategies of micro-CT for periodontal bone loss: a pilot study

“…Under general anaesthesia using a mixture of ketamine and xylazine, a 4-0 silk ligature was secured at the gingival sulcus level of the second molar (M2) of all animals as previously described. 10 Animals were killed on Day 7 (early stage, n 5 5) and on Day 21 (late stage, n 5 5) and the maxillae were harvested and fixed in 10% formaldehyde at 4°C for 3 days and transferred to 70% ethanol for subsequent examinations.…”

RNA Interference-Mediated Silencing of Atp6i Prevents Both Periapical Bone Erosion and Inflammation in the Mouse Model of Endodontic Disease

“…NS, not significant; *, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.005. Fc (TNFR:Fc) (41) reduced P. gingivalis-induced periodontal bone loss by approximately 50% in a mouse model, with parallel reductions in proinflammatory cytokines and osteoclasts (41). In the latter study, the AAV-TNFR:Fc vector was delivered three times per week for 8 weeks, compared to two injections of AAVsh-Atp6i in the present work.…”