Engineering Organoids for in vitro Modeling of Phenylketonuria

Abstract

Phenylketonuria is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function leads to the accumulation of neurotoxic phenylalanine levels in the brain. Severe cognitive and neuronal impairment are observed in untreated/late-diagnosed patients, and even early treated ones are not safe from life-long sequelae. Despite the wealth of knowledge acquired from available disease models, the chronic effect of Phenylketonuria in the brain is still poorly understood and the consequences to the aging brain remain an open question. Thus, there is the need for better predictive models, able to recapitulate specific mechanisms of this disease. Human induced pluripotent stem cells (hiPSCs), with their ability to differentiate and self-organize in multiple tissues, might provide a new exciting in vitro platform to model specific PKU-derived neuronal impairment. In this review, we gather what is known about the impact of phenylalanine in the brain of patients and highlight where hiPSC-derived organoids could contribute to the understanding of this disease.

High phenylalanine concentrations induce demyelination and microglial activation in mouse cerebellar organotypic slices

“…Evidence was found in immature chicks that high Phe concentrations inhibit these enzymes (Castillo et al, 1988), negatively impacting myelin but indirectly because of the importance of cholesterol for myelination. Future studies will need to integrate and explore these aspects, which would benefit from the development of promising novel threedimensional models, such as brain-vascular organoid systems (Borges et al, 2022), for instance, but cannot be resolved with our OSC model. acquisition, conceptualization, methodology, supervision, and writing -review and editing.…”

Mutational analysis in sodium-borate cotransporter SLC4A11 in consanguineous families from Punjab, Pakistan

“…The majority of the cases have been found, in Pakistan, India, Saudi Arabia, Myanmar (Burma), and Ireland, in children of consanguineous parents. More than 100 mutations in the SLC4A11 gene have been recognized so far, the majority of which are missense mutations with a few frameshift deletions [ 4 , 7 ]. Congenital hereditary endothelial dystrophy (Phenotype MIM number: 217700) is characterized by bilateral diffuse clouding of both corneas from infancy and it is a rare disease.…”

Impact of Fluorinated Ionic Liquids on Human Phenylalanine Hydroxylase—A Potential Drug Delivery System

“…PKU is characterized by an increase in the concentration of circulating L-Phe (hyperphenylalaninemia), leading, in the central nervous system, to high levels of L-Phe and low concentrations of L-Tyr and L-Trp, the precursors of amine neurotransmitters [ 23 ]. Due to L-Phe neurotoxicity and neurotransmitters depletion, untreated patients may present severe psycho-motor delays [ 24 ]. The current treatments for PKU include lifelong dietary restrictions of L-Phe sources (dietetic approach) and pharmacological therapies such as supplementation with BH 4 (acting as a pharmacological chaperone) and enzyme substitution therapy with a pegylated form of the non-human enzyme phenylalanine ammonia lyase (PEG-PAL) [ 21 , 22 , 25 ].…”