Key Findings
The preliminary clinical evaluation of the pro-DALAP platform showed no statistically significant difference between the intervention group and the control group regarding body weight and waist circumference over 12 weeks. At week 12, the intervention group showed a mean body weight reduction of −0.76% compared to −0.27% in the control group, and a waist circumference reduction of −3.60% versus −3.69% for the control. An interim week-8 analysis of eight participants per group had shown numerically greater reductions in body weight (−2.29% vs. +0.14%) and waist circumference (−6.34% vs. −2.32%), but these trends were not reproduced in the final analysis. HbA1c reduction favored the control group, while 37 of 40 survey respondents in the intervention group reported no side effects.
Technical Details
The platform utilizes a protease-deficient yeast strain engineered via CRISPR/Cas12a to integrate three expression cassettes. This process yielded 4.05 ± 0.31 mg pro-DALAP/g dry biomass, significantly higher than the 1.27 ± 0.21 mg/g produced by the single-copy strain. The pro-DALAP fusion precursor is engineered with several components to overcome intestinal permeability and enzymatic degradation:
- Maltose-binding protein and a GM1-binding peptide for epithelial uptake.
- A cell-penetrating peptide and an albumin-binding domain for stability and prolonged systemic exposure.
- Furin cleavage sites for proteolytic activation.
In vitro assays confirmed GM1 binding, furin-mediated processing, and activation of both GLP-1 and GIP receptors.
Background & Context
The study addresses the limitations of oral delivery for biologics, specifically enzymatic degradation and poor permeability. To test the platform, a 12-week, open-label, randomized controlled trial was conducted with 98 generally healthy, overweight adults. The intervention consisted of enteric-coated capsules containing lyophilized yeast expressing pro-DALAP. Additionally, intravenous toxicology studies in rats showed no treatment-related adverse findings at doses up to 300 µg/kg/day for seven days.
Significance & Outlook
The results validate the yeast-based production and in vitro functionality of pro-DALAP. However, the lack of statistical significance in the clinical trial indicates that further research is required. The authors state that validated pharmacokinetic measurements and adequately powered, blinded, placebo-controlled trials with longer follow-up periods are necessary to determine systemic exposure and evaluate sustained benefits.
Source: https://www.medrxiv.org/content/10.64898/2026.10.22.26365662v1
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