Correction of PKD by Gene Transfer into Pkd1-Null Mouse Model
Bibliographic record
Abstract
Background: Autosomal dominant polycystic kidney disease(ADPKD) causes renal cysts and insufficiency due mainly to PKD1 mutations. Since microscopic cysts in ADPKD kidneys are likely formed in utero, we re-expressed wild-type Pkd1/Pc1 protein in Pkd1-/- mouse via germ line by series of complementary gene transfer to assess for longterm cure of severe cystogenesis and neonatal death. Methods: Pc1 re-expression in the most severe mouse model Pkd1-/- was assessed by 3 strategies using genomic Pkd1 under its own regulatory elements (Pkd1wt), driven by kidney specific regulatory elements (900nt SB, SBPkd1) or Pkd1Minigene. Renal molecular (qPCR, IB), tubular (stainings, IF, RNAscope) and functional (BUN, hct) analyses were performed. Results: Pkd1-/- mice targeted with 2 distinct Pkd1wt gene transfers, of ˜8-fold overexpression and intense RNAscope signal over all tubular segments and glomeruli similarly to endogenous cell profile, fully rescued PKD phenotype. SBPkd1 one- and highcopy gene transfers conveyed 0.6- or 7-fold Pkd1 endogenous levels respectively. Onecopy SBPkd1 transfer initiates cysts after birth ˜P3 and confer sufficient Pkd1 expression during maturation to correct proximal tubules and glomeruli, to minimize distal cyst and to postpone but not prevent cyst in collecting ducts. This transfer extended Pkd1-/- life survival by 4-fold. High-copy SBPkd1 transfer provide proper targeting and expression levels for complete rescue during renal maturation, and significantly retard cyst in proximal and collecting tubules at post-maturation but is insufficient to prevent distal cysts. This transfer increased lifespan by 25-fold. SBPkd1 transfers show that collecting tubules require higher Pkd1 expression during maturation and that SB regulatory elements appreciably overlap with those of the endogenous promoter. High-copy renal Pkd1Mini transfer resulted in similar expression to endogenous Pkd1 with widespread and homogeneous weak Pkd1 cellular signal, partially rescuing glomeruli and all cystic tubular segments during maturation and attained therapeutic levels with increased lifespan by 4-fold. Conclusions: Our study determined that Pkd1 intragenic sequences not only control levels of expression but alike the upstream sequences, also regulate spatio-temporal expression pattern. One-copy SBPkd1 is sufficient to substantially delay cystogenesis. Pc1 re-expression can considerably extend lifespan or eliminate PKD. Funding: Government Support - Non-U.S.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".