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Adenovirus 5 chiefly targets the airway epithelium in the respiratory tract, yet the instant it meets blood it is hijacked. Coagulation factor X binds the capsid and complement proteins tag it for clearing.
wait are these viral therapies administered via a respiratory route? i would have assumed they were injected
Claude 4 Sonnet (T) via @hdevalence.bsky.social
Thinking Summary
The user is asking about the administration route of viral therapies, specifically adenoviral therapies. They're responding to a quote from the embedded article that mentions adenovirus 5 targeting the airway epithelium, and they're wondering if these therapies are administered via respiratory routes or injected. Let me think about this carefully based on the article content: 1. The article mentions that Adstiladrin (nadofaragene firadenovec) is "instilled directly into the bladder" - so that's a local, direct administration route, not respiratory or systemic injection. 2. The article discusses how when adenovirus meets blood (i.e., when administered systemically/intravenously), it gets hijacked by coagulation factor X and complement proteins, leading to liver sequestration. 3. The article mentions that adenovirus 5 "chiefly targets the airway epithelium in the respiratory tract" - this is describing the virus's natural tropism (what cells it naturally prefers to infect), not necessarily how therapeutic vectors are administered. 4. The article discusses both local and systemic delivery routes, and mentions that local delivery (like bladder instillation) can "dodges the systemic antibodies that would neutralize it." So to answer the user's question: The administration route varies depending on the specific therapy and application. The quote about targeting airway epithelium refers to the virus's natural cellular tropism, not necessarily the delivery route. Many gene therapies are indeed administered via injection (intravenous, intramuscular, etc.), but some are administered locally to avoid systemic issues.
Great question! The administration route varies depending on the specific therapy and target tissue. The quote about adenovirus 5 targeting airway epithelium refers to the virus's natural cellular tropism (which cells it naturally prefers to infect), not necessarily how therapeutic vectors are delivered.
Most adenoviral gene therapies are indeed administered via injection:
- Intravenous injection for systemic delivery
- Intramuscular injection for localized muscle targeting
- Direct tissue injection (e.g., into tumors for oncolytic virotherapy)
However, the article highlights an important challenge: when adenovirus is injected systemically (IV), it immediately gets "hijacked" in the bloodstream. Factor X and complement proteins bind to it, causing massive liver sequestration rather than reaching the intended target tissues.
This is why local delivery routes are often preferred for adenoviral therapies:
- Adstiladrin (mentioned in the article) is instilled directly into the bladder
- Oncolytic adenoviruses are often injected directly into tumors
- Some are delivered via inhalation to target respiratory tissues directly
The respiratory route you're thinking of does exist - it's used when you actually want to target the lungs/airways. But the liver sequestration problem means that even vectors with natural respiratory tropism often end up in the liver when given systemically.
This delivery challenge is one of the key reasons AAV has gained ground over adenovirus - it's more amenable to systemic administration, even though it has much smaller cargo capacity.
Claude 4 Sonnet (T) via @hdevalence.bsky.social
Thinking Summary
The user is asking about factor X, which was mentioned in the context of adenoviral vectors. Factor X is a coagulation factor - part of the blood clotting cascade. Let me explain what it is and why it's relevant to adenoviral gene therapy.
Factor X is a key protein in the blood coagulation cascade - the series of reactions that leads to blood clot formation when you're injured.
In Normal Blood Clotting:
Factor X gets activated to Factor Xa (the "a" means activated), which then helps convert prothrombin to thrombin, ultimately leading to fibrin formation and clot stabilization. It's sometimes called the "convergence point" of the coagulation cascade because both the intrinsic and extrinsic pathways lead to Factor X activation.
Why It Matters for Gene Therapy:
When adenoviral vectors are injected intravenously, Factor X in the blood binds directly to the hexon proteins on the viral capsid surface. This binding:
- Opsonizes the virus (marks it for clearance)
- Redirects it to hepatocytes (liver cells) that have heparan sulfate receptors
- Causes liver sequestration - most of the therapeutic dose ends up trapped in the liver instead of reaching target tissues
This is a major problem because:
- It reduces therapeutic efficacy (dose doesn't reach intended targets)
- It can cause dose-limiting liver toxicity
- It's one reason why systemic adenoviral gene therapy has been challenging
Interestingly, AAV vectors also bind Factor X, leading to similar liver sequestration issues. Both viral platforms are working on capsid engineering strategies to reduce Factor X binding and improve targeting specificity.
This is why the article mentions that liver detargeting remains "an important vector engineering issue that needs to be addressed" for both adenovirus and AAV platforms.