RESUMEN
BACKGROUND: Perinatal depression (including antenatal-, postnatal-, and depression that spans both timepoints) is a prevalent disorder with high morbidity that affects both mother and child. Even though the full biological blueprints of perinatal depression remain incomplete, multiple studies indicate that, at least for antenatal depression, the disorder has an inflammatory component likely linked to a dysregulation of the enzymatic kynurenine pathway. The production of neuroactive metabolites in this pathway, including quinolinic acid (QUIN), is upregulated in the placenta due to the multiple immunological roles of the metabolites during pregnancy. Since neuroactive metabolites produced by the pathway also may affect mood by directly affecting glutamate neurotransmission, we sought to investigate whether the placental expression of kynurenine pathway enzymes controlling QUIN production was associated with both peripheral inflammation and depressive symptoms during pregnancy. METHODS: 68 placentas obtained at birth were analyzed using qPCR to determine the expression of kynurenine pathway enzymes. Cytokines and metabolites were quantified in plasma using high-sensitivity electroluminescence and ultra-performance liquid chromatography, respectively. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) throughout pregnancy and the post-partum. Associations between these factors were assessed using robust linear regression with ranked enzymes. RESULTS: Low placental quinolinate phosphoribosyl transferase (QPRT), the enzyme responsible for degrading QUIN, was associated with higher IL-6 and higher QUIN/kynurenic acid ratios at the 3rd trimester. Moreover, women with severe depressive symptoms in the 3rd trimester had significantly lower placental expression of both QPRT and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD); impaired activity of these two enzymes leads to QUIN accumulation. CONCLUSION: Overall, our data support that a compromised placental environment, featuring low expression of critical kynurenine pathway enzymes is associated with increased levels of plasma cytokines and the dysregulated kynurenine metabolite pattern observed in depressed women during pregnancy.
Asunto(s)
Depresión , Inflamación , Quinurenina , Placenta , Ácido Quinolínico , Humanos , Femenino , Embarazo , Quinurenina/metabolismo , Quinurenina/sangre , Placenta/metabolismo , Adulto , Inflamación/metabolismo , Depresión/metabolismo , Ácido Quinolínico/metabolismo , Ácido Quinolínico/sangre , Citocinas/metabolismo , Complicaciones del Embarazo/metabolismo , Carboxiliasas/metabolismo , PentosiltransferasaRESUMEN
Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, ß-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost-benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.