Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria

Abstract

Systemic and subcutaneous rApoAI-PBGD therapy protects against porphyrin precursor accumulation, pain, and motor neuropathy in AIP mice.

Mechanistic modelling of enzyme‐restoration effects of new recombinant liver‐targeted proteins in acute intermittent porphyria

“…This is also related to the fraction of PBGD in liver: our model describing urinary heme precursor excretion displays a 2.32 times larger hepatic uptake from systemic circulation for rhApoAI‐PBGD and rhApoAI‐PBGD ms than for PBGD‐ApoAI, further confirming that ApoAI position changes PBGD targeting to liver. The larger hepatic uptake of the protein formed by linking ApoAI to the N‐terminus of PBGD may be related to its advantaged incorporation into the HDL fraction, as previously suggested (Córdoba et al, 2022).…”

“…This change, combined with the ApoAI lipoprotein, led to the rhApoAI‐PBGDMS protein. The methodology used for the synthesis and the characterization of the three above ApoAI based formulations are described in detail elsewhere (Córdoba et al, 2022). The synthesis method of rhPBGD‐ApoAI, rhApoAI‐PBGD and rhApoAI‐PBGDMS has changed over time and because of a significant percentage of protein aggregation that had to be reduced/abolished, which reduced the overall reaction efficiency.…”

“…Several dose levels were tested: 300 ( n = 8) and 600 ( n = 7) nmol·kg −1 for rhPBGD‐ApoAI and 300 nmol·kg −1 for rhApoAI‐PBGD ( n = 7) and rhApoAI‐PBGDMS ( n = 6). Total volume of urine excreted was collected daily during the acute attacks and the amount of heme precursors ALA (775 samples), PBG (778 samples) and tPOR (681 samples) was quantified as described elsewhere (Córdoba et al, 2022).…”

“…As an alternative to hemin treatment, several innovative therapies are currently being developed including a small interference RNA targeting the ALAS1 mRNA (Syed, 2021), as well as an mRNA encoding human PBGD (Jiang et al, 2018). Another innovative therapeutic approach is based on a recombinant fusion protein comprised of the human PBGD (hPBGD) enzyme and the apolipoprotein AI (ApoAI), where the addition of the ApoAI protein helps to direct PBGD to the liver in order to increase hepatic PBGD activity and residence time (Córdoba et al, 2022).…”

“…In this study, the previous disease model has been expanded, increasing its mechanistic structure by including data under treatment with different recombinant fusion proteins composed of the hPBGD linked to ApoAI administered at several i.v. dose levels (Córdoba et al, 2022). The integration of all the available experimental data warranted quantitative characterization of main regulatory mechanisms of the heme pathway and allowed to establish a robust tool to be considered within the model‐based drug discovery and development (MID3) paradigm (Marshall et al, 2016).…”