Phenotypic Correction of Feline Lipoprotein Lipase Deficiency by Adenoviral Gene Transfer
Bibliographic record
Abstract
Previous studies have revealed that adenovirus-mediated ectopic liver expression of human LPL (huLPL) can efficiently mediate plasma triacylglycerol (TG) catabolism in mice despite its native expression in adipose and muscle tissue. We aimed to explore the feasibility of liver-directed gene transfer and enzyme replacement for human LPL deficiency in a larger, naturally occurring feline animal model of complete LPL deficiency that is remarkably similar in phenotype to the human disorder. A cohort of LPL-deficient (LPL -/-) cats was given an intravenous injection of 8 x 10(9) PFU/kg of a CMV promoter/enhancer-driven, E1/E3-deleted adenoviral (Ad) vector containing a 1.36-kb huLPL cDNA (Ad-LPL) or reporter alkaline phosphatase gene (Ad-AP). After Ad-LPL administration, active, heparin-releasable huLPL was readily detected along with a 10-fold reduction in plasma TGs, disappearance of plasma TG-rich lipoproteins up to day 14, and enhanced clearance of an excess intravenous fat load on day 9. However, antibody against the huLPL protein was detected on day 14 in cats receiving Ad-LPL and adenovirus-specific neutralizing antibody was present 7 days after gene transfer in both cat cohorts. Tissue-specific expression of the huLPL transgene relative to controls was confirmed by RT-PCR. While huLPL expression was evident in the liver, other tissues including spleen and lung expressed huLPL message, in direct correlation with histological evidence of increased Oil red O (ORO)-positive neutral lipid influx. In contrast, intravenous LPL enzyme replacement therapy (ERT) led to rapid disappearance of 9000 mU/kg of active bovine LPL enzyme from the circulation, with t1/2 occurring at <10 min in two LPL-/- cats. Heparin injection 1 hr later released <10% of the original bovine LPL, further indicating its rapid systemic clearance, inactivation, or degradation as well as its ineffectiveness as a viable therapeutic alternative for complete LPL deficiency. Although LPL gene transfer and expression via this first-generation Ad vector was limited by the immune response against both the human LPL protein and adenovirus our results clearly provide a key advance supporting further development of LPL gene therapy as a viable therapeutic option for clinical LPL deficiency.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".