Current Delivery Vectors Accumulate in the Liver — Most Organs Are Unreachable

Both AAV and LNP vectors naturally end up mostly in the liver after IV injection. This is great for liver diseases but means lungs, kidneys, pancreas, and immune cells receive very little therapy. Cystic fibrosis lung gene therapy has failed for 30 years because of this delivery problem.

ApoE adsorbs onto LNP surfaces during circulation, targeting them to hepatocyte LDL receptors. AAV8/9 preferentially transduce hepatocytes via AAVR and galactose binding. For lungs: mucus barrier, tight junctions, and glycocalyx block transduction from both airway and vascular routes. SORT-LNPs (Selective ORgan Targeting, Siegwart lab) demonstrate organ-selective delivery by incorporating charged lipids. SCGE Consortium funded AAV capsid engineering for lung, brain, muscle, and eye. Investment driven by need for extra-hepatic delivery vehicles.

Why It Matters

CF: 100,000 patients worldwide, 30 years of failed lung gene therapy. Type 1 diabetes: 1.6M Americans (pancreas unreachable). CKD: 37M Americans (kidney unreachable). Only 5-10% of genetic diseases primarily affect the liver.

Startup Approach

License SORT-LNP technology and develop organ-targeting formulations. Or use directed evolution of AAV capsids with selection pressure for specific organ tropism. A 'lung delivery platform' alone could address CF, alpha-1 antitrypsin deficiency, and primary ciliary dyskinesia.

NIH Funding

SCGE Consortium made non-liver targeting Tier 1 priority. NHLBI funds lung delivery for CF. NIDDK funds pancreas/kidney delivery. CFF provides non-NIH funding for lung delivery.

Who's Working On It

Daniel Siegwart lab (UT Southwestern, SORT-LNPs), ReCode Therapeutics (inhaled mRNA for CF), Krystal Biotech (HSV vector for skin, Vyjuvek approved), Arbor Biotechnologies (novel delivery), SCGE Consortium