Mechanistics of Liver Injury by AAV(9)

Another very interesting paper by the Wilson lab.

Several studies have shown that when going above 1x10^14 GC/KG, AAV induce liver injury that can be fatal. Hordeaux et al were able to determine the probable liver injury mechanism in NHP when delivering high AAV9 or AAV9-derived capsids intravenously.

Toxic effects, consistent across various transgenes at doses ≥1×10^14 GC/kg, suggest a dose-dependent risk of AAV to cause sinusoidal platelet microthrombi and liver sinusoidal endothelial injury.

Strenghts

• NHP
• Using clinically relevant dosages
• Strong integrated data set suggesting specific mechanism

Weaknesses

• Only used AAV9 and derivative capsids. Is this an AAV9-dependent mechanism or is it general?

Oportunities

• Designer AAV can be developed to lower effective dosages and prevent liver injury, while increasing target-cell specificity, especially capsids as CAP-B10
• Do LV cause the same injury? If not, may IDLV provide a suitable alternative?
• Development of prophylactic regimes that can be used in a clinical setting in a drug+AAV formulation

Threats

• If this pathogenic mechanism is general, it may be difficult to use AAV for liver-targeted approaches.
• Will any systemic AAV approach be limited?

High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury

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