AAV Episomal Dilution: Vector Genome Loss in a Growing Liver

Vector Dosing

Initial copies / hepatocyte 4

Hepatocyte Turnover

Division rate 4%/yr

Playback speed 1.0×

Live Readouts

Time since dosing

0.00 yr

Divisions so far

Transduced cells

100%

Mean copies / cell

4.00

Relative transgene expression

100%

High vector-genome copy number

Low copy number

Vector lost (0 copies)

How it works

AAV vector genomes (vg) delivered to a hepatocyte mostly stay episomal — circular DNA sitting in the nucleus, not integrated into a chromosome. Episomes don't have their own replication machinery, so when a hepatocyte divides, its episomes are not duplicated first. Each existing copy is inherited by only one of the two daughter cells:

Cell with k copies divides →
  daughter A gets Binomial(k, 0.5) copies
  daughter B gets the remaining (k − that) copies
E[copies per daughter] = k / 2   (dilution by half, in expectation, per division)

After g divisions:  mean copies ≈ k₀ · (1/2)ᵍ

This simulator models a small lobule of hepatocytes (each an instanced sphere). At the chosen division rate, a random subset of cells "divides" every tick: their episomes are split binomially between the cell and a randomly chosen neighbour standing in for the sibling that replaces a naturally turned-over cell, keeping the lobule's cell count constant while still diluting the vector pool exactly as real hepatocyte turnover would.

Division rate — models hepatocyte turnover. A quiescent adult liver turns over only a few percent of cells per year; a growing pediatric liver, or one recovering from injury, turns over far faster.
Trigger Liver Regeneration Event — a one-off burst of ~35% of the lobule dividing at once, mimicking a partial hepatectomy or acute liver injury.
Relative transgene expression — assumed roughly proportional to mean vector-genome copies per cell, matching the clinical observation that AAV-delivered clotting-factor levels in hemophilia gene therapy decline over years in a pattern that tracks vector-copy dilution, not immune clearance.

Real-world relevance: this is a documented limitation of first-generation AAV liver gene therapy (e.g. hemophilia A/B trials) — durability is markedly better in adults with low hepatocyte turnover than in children whose livers are still growing, and a regenerative insult (surgery, viral hepatitis, heavy alcohol use) can accelerate the same dilution in an adult.

Lobule: 280 hepatocytes Vector: non-integrating AAV episome

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