一般桿狀病毒做為基因傳遞載體時，需利用超高速離心濃縮過後的病毒液與作為轉導環境溶液的培養基（如：DMEM）混合至適當體積後，在37˚C下轉導哺乳動物細胞。然而，本實驗室先前發現到細胞生長所需的培養基會阻礙桿狀病毒載體的基因傳送，但是培養基中的哪一種成分造成此種抑制效應尚未可知。因此本研究希望找出何關鍵培養基成分使得轉導效率不佳。我們首先利用帶有不同啟動子的重組桿狀病毒轉導BHK細胞，發現於以DMEM為環境溶液的轉導結果不佳並非與其啟動子有關。在分組探討培養基成分的實驗中，結果顯示平衡鹽類溶液會抑制桿狀病毒的轉導能力。於分別去除平衡鹽溶液中的鹽類後，我們赫然發現培養基中作為緩衝溶液的NaHCO3抑制了桿狀病毒的轉導能力，並且其抑制效果與濃度有關。此外，藉由免疫螢光染色標定病毒套膜上的GP64蛋白，再以共軛焦顯微鏡觀察，我們發現NaHCO3並不影響病毒附著於細胞表面，但即時偵測同步定量聚合酶連鎖反應（quantitative real-time polymerase chain reaction, Q-PCR）分析則顯示NaHCO3確實會影響細胞內病毒的含量。總言之，本研究證實了轉導溶液中若含有NaHCO3會抑制桿狀病毒進入哺乳動物細胞，因此在未來的應用當中，我們更可進一步的將轉導環境溶液改為不含有NaHCO3的DMEM，不僅可以達到較佳的轉導效率，也可以避免細胞長時間處於PBS中，影響細胞狀況。
桿狀病毒傳遞轉殖基因的表現期一般在20天內，為延長轉殖基因的表現期，我們也探討以肌細胞做為基因治療之標的細胞的可能性，以拓展桿狀病毒於基因治療上的應用性。我們首先證實桿狀病毒可有效地轉導肌母細胞，並且無論是在肌母細胞株或是初代肌母細胞，只要分化成肌管細胞，桿狀病毒所帶轉殖基因都可表現至少60天以上。利用反轉錄聚合酶反應，我們也證實肌管細胞分化標識基因MyoD與myogenin之mRNA的表現隨時間表現增加至一定程度，並且桿狀病毒在C2C12分化出的肌管細胞中表現期的確比不會分化的對照組HeLa細胞長久，顯示長期表現與分化現象呈正相關，因此桿狀病毒在肌管細胞中能長期表現很有可能是與其終端分化有關。此外，於轉導後不同時間點分析C2C12細胞內病毒DNA與mRNA之含量的結果顯示，病毒DNA與mRNA於C2C12細胞中的降解速度確實較在HeLa中慢，並且於轉導後第21天之後的降解速度趨於平緩，存留的病毒mRNA甚至約達轉導後第1天的25%，相較之下病毒在HeLa細胞中無論是DNA或mRNA的殘留量都於轉導後第14天趨近於0%。這些結果在在都顯示以肌細胞做為基因治療標的細胞的可行性及潛力。往後我們將更進一步評估桿狀病毒/肌細胞之基因治療系統的安全性。

Baculovirus transduction of cultured mammalian cells is typically performed by incubating the cells with virus using culture medium (e.g. DMEM) as the surrounding solution. However, we previously uncovered that DMEM hinders the baculovirus-mediated gene transfer. In this study, we demonstrated that the poorer transduction by using DMEM as the surrounding solution is independent of the promoter. Examination of the medium constituents group by group revealed that the balanced salt solution suppresses the baculovirus transduction. By omitting individual salt species in the balanced salt solution, we surprisingly uncovered that NaHCO3, a common buffering agent, exerts the inhibitory effects in a concentration-dependent manner. Intriguingly, NaHCO3 did not debilitate the baculovirus, nor did it inhibit virus binding to the cells as revealed by immunofluorescence/confocal microscopy. Instead, NaHCO3 inhibited baculovirus transduction by reducing the intracellular virus number as demonstrated by quantitative real-time PCR. To our best knowledge, this is the first report unraveling the significance of NaHCO3 in gene transfer. Our finding suggests that baculovirus-mediated gene transfer can be readily enhanced by omitting NaHCO3 from the medium during the transduction period.
Furthermore, we explored the feasibility of employing baculovirus in muscle-based gene therapy in order to augment the short baculovirus-mediated expression. We demonstrated that baculovirus transduces myoblast cells efficiently and the duration of baculovirus-mediated expression is prolonged to at least 60 days after the myoblast cells differentiate into multi-nuclei myotubes. The prolonged expression also paralleled the increased cellular expression of MyoD and myogenin as demonstrated by RT-PCR, and resulted from slower degradation of viral DNA and persistent presence of the transgene mRNA, as confirmed by quantitative real-time PCR. These data collectively suggested a correlation between the prolonged expression and myogenic differentiation which resulted in extended existence of viral DNA and transgene mRNA, implicating the tremendous potential of baculovirus vector in muscle-based gene therapy.

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