collecting links from twitter
Thread (21 posts)
Thinking Summary
The user is asking me to define "non-oncolytic adenoviral" - this appears to be a follow-up to the discussion about adenoviral gene therapy. Let me break this down: The term "non-oncolytic adenoviral" refers to adenoviral vectors that are NOT designed to kill cancer cells. Let me explain the distinction: 1. Oncolytic adenoviruses: These are engineered or naturally occurring adenoviruses that specifically target and kill cancer cells. They're designed to replicate preferentially in cancer cells and cause cell lysis (destruction), which is their therapeutic mechanism. 2. Non-oncolytic adenoviruses: These are adenoviral vectors used primarily as delivery vehicles for therapeutic genes. They're not meant to kill cells but rather to deliver genetic cargo (like therapeutic proteins, enzymes, or other genes) to target cells. The article mentions that Adstiladrin (nadofaragene firadenovec) is "still the lone FDA-approved non-oncolytic adenoviral therapy" - meaning it's the only approved adenoviral gene therapy that works by delivering therapeutic genes rather than by killing cancer cells directly. This is an important distinction in the field of viral vector therapy.
Non-oncolytic adenoviral refers to adenoviral vectors that function purely as gene delivery vehicles rather than as cancer-killing agents.
The Key Distinction:
Oncolytic adenoviruses:
- Engineered to selectively infect and destroy cancer cells
- Their therapeutic mechanism is cell death (lysis)
- They replicate within tumor cells, causing them to burst
- The virus itself is the therapeutic agent
Non-oncolytic adenoviruses:
- Used as delivery trucks for therapeutic genes
- Designed to deliver genetic cargo without killing the target cells
- The therapeutic effect comes from the expressed gene product (proteins, enzymes, etc.)
- The virus is just the delivery system
Context from the Article:
The piece notes that Adstiladrin is "still the lone FDA-approved non-oncolytic adenoviral therapy" - meaning it's the only approved adenoviral treatment that works by:
- Delivering interferon-alpha gene to bladder cells
- Having those cells produce the therapeutic protein
- NOT by killing the cells themselves
This distinction matters because it highlights how adenoviruses have found more success in cancer applications where their natural cell-killing properties are features rather than bugs - while their use as simple gene delivery vehicles (non-oncolytic) has been much more limited due to manufacturing and immunogenicity challenges.
We have witnessed extensive research efforts to engineer AAV capsids for altered tropism
define tropism
Thinking Summary
The user is asking me to define "tropism" in the context of the article about adenoviruses and AAVs. Looking at the article, they mention tropism several times in relation to viral vectors and cell targeting. From the context in the article, tropism refers to which cells or tissues a virus preferentially infects or targets. The article explains this concept: "Which cells get transduced by the adenoviral capsid depends on its taxonomy, with different species and serotypes preferring different cell surface receptors for entry into the host. Species C adenoviruses, which include the adenovirus 5, use the coxsackie-adenovirus receptor (CAR), many species B use CD46 or desmoglein-2, while some other strains bind sialic acid. Because these receptors are patchily expressed, they dictate tropism." And later: "Adenovirus 5 chiefly targets the airway epithelium in the respiratory tract, yet the instant it meets blood it is hijacked." So tropism is about the natural targeting preference of viruses for specific cell types or tissues, determined by which receptors the virus uses to enter cells.
Tropism refers to the natural preference or affinity of a virus for infecting specific cell types or tissues.
In the context of viral vectors like AAV and adenovirus, tropism is determined by:
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Receptor binding specificity - Different viruses bind to different cell surface receptors to gain entry
- Adenovirus 5 uses the coxsackie-adenovirus receptor (CAR)
- Some species B adenoviruses use CD46 or desmoglein-2
- Others bind sialic acid
-
Receptor distribution - Since these receptors are expressed differently across tissues, they "dictate tropism"
- CAR expression makes Ad5 naturally target respiratory epithelium
- But in blood, factor X hijacks Ad5 and redirects it to the liver
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Therapeutic implications - Natural tropism may not align with therapeutic goals
- You want to deliver genes to specific diseased tissues
- But the virus may naturally prefer other cell types
- Hence the need to engineer "altered tropism" through capsid modifications
The article discusses how capsid engineering aims to redirect viral vectors away from their natural tropism toward therapeutically relevant targets - essentially reprogramming which cells the virus will infect and deliver its genetic cargo to.
This is why developing new capsid variants through directed evolution is so valuable - it can create vectors that target the specific tissues where gene therapy is needed, rather than where the virus would naturally go.
Adenovirus genomes are compact but busy. In human serotype 5, the workhorse of most adenoviral vector programs, about 36kb of linear, double-stranded DNA encodes three timed sets of genes: early (E1A/B, E2, E3, E4), intermediate (IX, IVa2) and late (L1-L5) (x). In brief summary, E1A turns on the rest, E2 supplies the replication enzymes, E3 modulates host immunity, and the late genes build the capsid and finish assembly.
Can you unpack and contextualize
Thinking Summary
The user is asking me to unpack and contextualize a specific quote from the embedded article about adenoviral vectors. The quote describes the organization of adenoviral genomes, specifically focusing on how adenovirus serotype 5 (Ad5) organizes its genes into temporal expression classes. Let me break this down: 1. The basic structure: 36kb linear double-stranded DNA 2. Three temporal gene expression classes: - Early genes (E1A/B, E2, E3, E4) - Intermediate genes (IX, IVa2) - Late genes (L1-L5) 3. The functions of each class I should contextualize this within: - Why this temporal organization matters for viral replication - How this relates to vector engineering (which genes can be deleted) - Why this creates manufacturing challenges - How this compares to other viral vectors like AAV This is a technical topic so I should explain it clearly but with appropriate depth.
This passage describes the sophisticated temporal gene expression program that makes adenoviruses both powerful and challenging as gene therapy vectors. Let me break down what's happening here:
The Temporal Cascade
Adenoviruses orchestrate their replication through a carefully timed genetic program, like a molecular assembly line:
Early genes (E1-E4) fire first after infection:
- E1A: The master switch - turns on all other viral genes and pushes the host cell into S-phase for DNA replication
- E1B: Works with E1A to overcome cellular apoptosis and tumor suppressor responses
- E2: Provides the DNA replication machinery (DNA polymerase, DNA binding protein, etc.)
- E3: Immune evasion toolkit - helps the virus hide from host immune responses
- E4: Fine-tunes replication and helps with late gene expression
Intermediate genes (IX, IVa2) bridge the transition to late phase, helping with DNA packaging and capsid assembly.
Late genes (L1-L5) encode the structural components - all the proteins needed to build new viral particles.
Why This Matters for Gene Therapy
This temporal organization creates both opportunities and headaches:
The Good: The modular design means you can delete entire gene cassettes (like E1 and E3) to make room for therapeutic cargo while still maintaining viral function - if you provide the missing functions elsewhere.
The Bad: Every gene you delete requires compensating infrastructure:
- Delete E1? Need special packaging cell lines that express E1 proteins
- Delete E2 or E4? Need even more complex cell lines
- This is why vector manufacturing gets progressively more difficult with each "generation"
The Manufacturing Tax
Compare this to AAV, which has a much simpler genome (~4.7kb vs 36kb) with just a few genes. AAV's simplicity means:
- Easier to clone and manipulate
- Higher transformation efficiency
- More predictable production yields
- Simpler quality control
Adenovirus's complexity means that even basic molecular biology steps (cloning, transfection, amplification) become bottlenecks. The passage mentions that only 1 in 600 million adenoviral genomes successfully produces infectious virus in standard protocols - that's the "manufacturing tax" of complexity.
This is why, despite adenovirus's 7x larger cargo capacity, the field has gravitated toward AAV for most applications. The question is whether recent advances in manufacturing and engineering can finally make that cargo space worth the complexity cost.
can you be more precise about exactly what point constitutes “infection” and how the described phases connect to that? ie expand those phases into an end to end timeline
Thinking Summary
The user wants me to be more precise about the timeline of adenoviral infection, specifically when "infection" starts and how the temporal phases connect to create an end-to-end timeline. Let me think through the adenoviral lifecycle step by step: 1. Initial binding and entry 2. Nuclear entry and uncoating 3. Early gene expression (immediate early vs delayed early) 4. DNA replication 5. Late gene expression 6. Assembly and release I need to be precise about what constitutes "infection" - is it binding? Entry? Nuclear delivery? First gene expression? And then map out the temporal cascade with actual timing where possible.
Great question - let me map out the precise adenoviral infection timeline:
Phase 0: Entry (0-2 hours post-infection)
"Infection" begins when the virus binds to cellular receptors (CAR for Ad5), triggers endocytosis, escapes the endosome, and delivers its genome to the nucleus. The viral DNA remains as an episome - it doesn't integrate into the host chromosome.
Phase 1: Immediate Early (2-6 hours post-infection)
- E1A expression starts immediately - this is the first viral gene transcribed
- E1A protein accumulates and begins activating other viral promoters
- E1A also pushes the quiescent cell into S-phase by inactivating Rb protein
- This is when the cell's fate is sealed - E1A expression commits it to supporting viral replication
Phase 2: Delayed Early (6-12 hours post-infection)
- E1B comes online to suppress p53-mediated apoptosis (cells would otherwise kill themselves when forced into S-phase)
- E2 genes activate, producing DNA replication machinery
- E3 genes express immune evasion proteins
- E4 genes begin low-level expression
- The cell is now fully reprogrammed as a viral factory
Phase 3: DNA Replication (8-24 hours post-infection)
- Viral DNA replication begins around 8 hours
- This is driven by the E2-encoded replication proteins
- DNA synthesis continues for ~16 hours
- Viral genome copy number increases dramatically
Phase 4: Late Gene Expression (12-36 hours post-infection)
- Late genes (L1-L5) ramp up as DNA replication peaks
- These encode all structural proteins: hexon, penton, fiber, etc.
- E4 expression also peaks, helping optimize late gene expression
- Massive amounts of capsid proteins are produced
Phase 5: Assembly and Lysis (24-48 hours post-infection)
- Viral genomes get packaged into capsids in the nucleus
- Mature virions accumulate
- Cell eventually lyses, releasing 10,000-100,000 new viral particles
Key Temporal Control Points
The transition from early to late phases is triggered by DNA replication initiation around 8 hours. This acts as the molecular switch - before replication, early genes dominate; after replication begins, late genes take over.
For gene therapy vectors, this timeline explains why different generations have different problems:
- 1st gen (E1/E3 deleted): Late genes still express at low levels → ongoing immunogenicity
- 2nd gen (additional deletions): Disrupted temporal cascade → manufacturing problems
- 3rd gen (gutless): No viral genes at all → minimal immunogenicity but needs helper virus
The manufacturing challenges stem from trying to recreate this precisely timed, interdependent cascade in cell culture while missing key regulatory components.
can you elaborate on what the article means when referring to “leaky gene expression” after changing E1?
Thinking Summary
The user is asking about "leaky gene expression" in the context of E1-deleted adenoviral vectors. Let me think through what's happening here. When you delete E1 from an adenoviral vector, the goal is to make it replication-defective. E1A is the master regulatory protein that turns on the entire adenoviral gene expression program. So in theory, if you delete E1, the vector shouldn't be able to express any other viral genes and should just deliver its therapeutic cargo without producing viral proteins that would trigger immune responses. However, the article mentions that in practice, there's still "leaky" expression of remaining viral genes, particularly late genes, even without E1. This happens because: 1. Host cells have their own transcription factors that can sometimes activate viral promoters 2. The viral genome still contains all the promoter sequences for the other genes 3. These promoters weren't evolved to be completely dependent on E1A - they can be activated at low levels by cellular factors This is problematic because: - Late genes encode capsid proteins - Expression of these viral proteins triggers immune responses - This defeats part of the purpose of deleting E1 in the first place The article mentions this contributes to the immunogenicity of first-generation vectors, beyond just the initial immune response to the capsid proteins from the original infection.
The "leaky gene expression" issue gets to the heart of why first-generation adenoviral vectors aren't as clean as we'd like them to be.
The Theory vs. Reality
The Plan: Delete E1A (the master switch) → no viral gene expression → vector just delivers cargo and stays quiet → reduced immunogenicity
What Actually Happens: Even without E1A, other viral genes still get expressed at low levels, particularly the late genes that encode capsid proteins.
Why This Leakiness Occurs
E1A is the primary activator of viral gene expression, but the viral promoters aren't completely dependent on it. Here's what's happening:
-
Cellular transcription factors: The host cell contains transcription factors that can weakly activate viral promoters. These weren't the intended activators, but molecular biology is messy - promoters often respond to multiple signals.
-
Promoter promiscuity: Viral promoters evolved to be responsive to cellular conditions that indicate good replication opportunities. Some of these cellular signals are present even without E1A.
-
Chromatin context: When the viral DNA enters the nucleus, it doesn't immediately get packaged into repressive chromatin. During this window, cellular machinery can access and transcribe from viral promoters.
Why This Matters
The leaky expression is particularly problematic because:
- Late genes = capsid proteins: The "leaky" genes are often the late genes (L1-L5) that encode structural proteins like hexon, penton, and fiber
- MHC presentation: These viral proteins get processed and presented on MHC class I molecules, marking the cell as "infected"
- T-cell activation: This triggers adaptive immune responses against the transduced cells
- Persistent antigen: Unlike a normal infection that's cleared, these vector-transduced cells keep leaking viral proteins over time
The Immunological Consequence
This creates a two-hit immune problem:
- Immediate: Innate immune response to the viral capsid and DNA
- Delayed: Adaptive immune response to the leaked viral proteins being presented on transduced cells
This is why even "replication-defective" first-generation vectors still provoke substantial immune responses, and why the field moved toward gutless vectors that remove nearly all viral coding sequences. The goal is to get down to just the therapeutic cargo with minimal viral "noise" that could trigger immunity.
It's a reminder that in virology, "turning off" a genetic program is much harder than turning it on - evolution built these systems to be robust, not easily silenced.
Production of these E1-deleted vectors requires specialized packaging cell lines that stably express the E1 proteins in trans (e.g. the HEK239T derivative Ad239T, and Janssen’s PER.C6) to complement the E1 deletion
what does this production entail?
Thinking Summary
The user is asking about what the production of E1-deleted adenoviral vectors entails when using specialized packaging cell lines. Let me break down what this process involves based on the context from the article. The article mentions that E1-deleted vectors need specialized packaging cell lines like HEK239T derivative Ad239T and Janssen's PER.C6 to complement the E1 deletion. Let me explain what this production process entails: 1. The E1 genes are essential for adenoviral replication - they're the "master switch" that turns on the rest of the viral replication program 2. When you delete E1 from the vector to make space for therapeutic genes, the vector can no longer replicate on its own 3. So you need packaging cell lines that stably express the E1 proteins to provide them "in trans" (meaning from a different location/source) 4. The production process involves introducing the E1-deleted vector DNA (usually as a plasmid) into these specialized cells 5. The cells provide the missing E1 function, allowing the vector to replicate and be packaged into viral particles I should explain this clearly and also touch on some of the complexities and challenges involved.
The production of E1-deleted adenoviral vectors is essentially a "complementation" system where specialized cell lines provide the missing viral functions. Here's what it entails:
The Core Process
Packaging Cell Lines: Companies like Janssen developed cell lines (e.g., PER.C6) that stably integrate and express the essential E1A and E1B proteins. These cells become permanent "factories" that can support adenoviral replication.
Vector Introduction: The therapeutic adenoviral vector DNA - typically as a large plasmid containing:
- The transgene of interest
- Remaining adenoviral sequences (minus E1)
- Regulatory elements
...is introduced into these packaging cells via transfection.
Complementation: The cell-provided E1 proteins "rescue" the defective vector by:
- E1A activating the viral replication program
- E1B helping with DNA replication and late gene expression
- Together enabling packaging of progeny viral genomes into capsids
Production Challenges
The article hints at why this is more cumbersome than AAV production:
- Scale complexity: Need to maintain specialized cell lines with stable E1 expression
- Lower efficiency: The ~36kb genome is harder to package efficiently
- Cytotoxicity: Adenovirus kills its host cells more aggressively than AAV, limiting culture density
- Timeline: Multiple amplification rounds needed, stretching production to weeks/months
This manufacturing "tax" is part of why AAV became dominant despite its smaller cargo capacity - it's simply easier to produce at scale.
Third-generation, “helper-dependent” or “gutless,” vectors take a different approach. They remove nearly everything except the inverted terminal repeats and packaging signal. A separate helper virus supplies all replication functions.
how does this tiered replication system work?
Thinking Summary
The user is asking about how the tiered replication system works in third-generation "gutless" adenoviral vectors. Let me break this down based on the information provided in the embedded article. From the article, I can see that: 1. Third-generation/"gutless" vectors remove nearly everything except the inverted terminal repeats (ITRs) and packaging signal 2. A separate helper virus supplies all replication functions 3. The helper virus is modified with loxP sites bracketing its packaging signal 4. Cre recombinase (expressed by cell lines like HEK293) cuts out the helper virus's packaging signal 5. This makes the helper virus genome unable to be packaged but still able to replicate 6. The helper virus trans-complements the replication of the gutless vector Let me explain this system clearly and comprehensively.
The third-generation adenoviral vector system creates a clever division of labor between two genetic elements:
The Gutless Vector
- Contains only the inverted terminal repeats (ITRs) and packaging signal from the original adenovirus
- Carries the therapeutic cargo (up to ~36kb)
- Cannot replicate on its own - lacks all viral genes needed for replication
The Helper Virus
- Contains all the replication machinery (E1, E2, E4, late genes)
- Modified with loxP sites flanking its packaging signal
- Can replicate but cannot be packaged into virions
The Production Process
-
Co-transfection: Both gutless vector and helper virus are introduced into producer cells (like HEK293)
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Cre-mediated excision: The producer cells express Cre recombinase, which recognizes the loxP sites and cuts out the helper virus's packaging signal
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Selective packaging: Only genomes with intact packaging signals (the gutless vectors) get packaged into virions. The helper virus replicates but remains unpackaged
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Trans-complementation: The helper virus provides all the replication functions in trans, allowing the gutless vector to replicate and be packaged
The Challenge
In practice, some helper virus "leaks through" with intact packaging signals, contaminating the final product with immunogenic helper virus. This contamination is the main manufacturing hurdle - you need extensive purification to separate therapeutic gutless vectors from contaminating helper virus.
Recent innovations include helper plasmids (instead of helper viruses) and self-inactivating helpers that destroy their own packaging signals after one replication round.
how does the biolab separate the gutless and helper virions? they need to collect only gutless virions to deliver to the patient correct?
Thinking Summary
This is a great question about the purification process for third-generation adenoviral vectors. The user is asking about how labs separate the therapeutic gutless vectors from contaminating helper virus particles, since only the gutless vectors should be delivered to patients. From the article, I know that helper virus contamination is a major manufacturing challenge. The helper virus that leaks through would be fully immunogenic and defeat the purpose of using gutless vectors. Let me think about the separation methods that would be used: 1. The gutless vectors and helper virus particles would have different properties that could be exploited for separation 2. The main difference would be size/density - gutless vectors carry the therapeutic cargo (~36kb) while helper virus particles would contain the helper virus genome 3. Traditional viral purification methods would likely be used The most common methods for separating viral particles of similar but different sizes/densities would be: - Cesium chloride (CsCl) density gradient centrifugation - Iodixanol gradient centrifugation - Chromatography methods The article mentions this is a "manufacturing tax" and that contamination is the main issue, so the separation must be technically challenging and not always 100% effective.
Exactly right - only the gutless vectors should reach patients, making this separation a critical manufacturing step. The contaminating helper virus particles would trigger the full immunogenic response that gutless vectors are designed to avoid.
Primary Separation Method: Density Gradient Centrifugation
Cesium chloride (CsCl) gradients are the gold standard:
- Gutless vectors (carrying ~36kb therapeutic cargo) have different buoyant density than helper virus particles
- During ultracentrifugation, particles settle at different positions based on their density
- Gutless vectors typically band at ~1.34 g/mL, helper virus at slightly different density
- Multiple rounds may be needed to achieve adequate separation
Iodixanol gradients offer a gentler alternative with similar principles.
Secondary Methods
- Ion exchange chromatography - exploits surface charge differences
- Size exclusion chromatography - separates based on particle size
- Hydrophobic interaction chromatography - uses surface hydrophobicity differences
The Manufacturing Challenge
This separation is never 100% efficient, which is why helper virus contamination remains the major "manufacturing tax" mentioned in the article. Even small amounts of contaminating helper virus can:
- Trigger immune responses
- Reduce therapeutic efficacy
- Cause safety concerns during regulatory review
Recent Innovations
Newer approaches try to eliminate this purification bottleneck entirely:
- Helper plasmids instead of helper viruses (no virions to contaminate)
- Self-inactivating helpers that destroy their own packaging signals
- Site-specific integration systems for cleaner production
The purification complexity is one reason why gutless adenoviral vectors haven't achieved the same clinical success as AAVs, despite their superior cargo capacity.
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
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.
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.