Our findings demonstrate the great potential of these hits for the development of a pharmacological chaperone-based corrective treatment of AIP by enhancing wild-type HMBS function independently of the patients' specific mutation.
To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype.
In a recent study published in Nature Medicine (Published online October 8, 2018. doi.org/10.1038/s41591-018-0199-z), the intravenous delivery of human porphobilinogen deaminase (PBGD) mRNA, targeting the liver, demonstrated its efficacy and safety to replace the defective PBGD protein in preclinical models of acute intermittent porphyria.
Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP.
To better interpret the underlying mechanism of clinical phenotypes, we collected 117 <i>HMBS</i> gene mutations from reported individuals with AIP and evaluated the mutations' impacts on the corresponding protein structure and function.
Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency.
Molecular characterization, by digital PCR analysis of four HMBS gene mutations affecting the ubiquitous isoform of Porphobilinogen Deaminase (PBGD) in patients with Acute Intermittent Porphyria (AIP).
In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS.
Finally, full protection against a phenobarbital-induced attack was achieved in AIP mice after the administration of 1 × 1011 gc/kg of rAAV2/8-PBGD-I291M/N340S vector; three times lower than the dose required to achieve full protection with the control rAAV2/8-hPBGD vector.