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Aims It has been suggested that moist snuff (snus), a smokeless tobacco product that is high in nicotine and widespread in Scandinavia, increases the risk of Type 2 diabetes. Previous studies are however few, contradictory and, with regard to autoimmune diabetes, lacking. Our aim was to study the association between snus use and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood ( LADA). Method Analyses were based on incident cases (Type 2 diabetes, n = 724; LADA, n = 200) and population-based controls ( n = 699) from a Swedish case-control study. Additional analyses were performed on cross-sectional data from the Norwegian HUNT study ( n = 21 473) with 829 prevalent cases of Type 2 diabetes. Odds ratios ( OR) were estimated adjusted for age, BMI family history of diabetes and smoking. Only men were included. Results No association between snus use and Type 2 diabetes or LADA was seen in the Swedish data. For Type 2 diabetes, the OR for > 10 box-years was 1.00 [95% confidence interval ( CI), 0.47 to 2.11] and for LADA 1.01 (95% CI, 0.45 to 2.29). Similarly, in HUNT, the OR for Type 2 diabetes in ever-users was estimated at 0.91 (95% CI, 0.75 to 1.10) and in heavy users at 0.92 (95% CI, 0.46 to 1.83). Conclusion The risk of Type 2 diabetes and LADA is unrelated to the use of snus, despite its high nicotine content. This opens the possibility of the increased risk of Type 2 diabetes seen in smokers may not be attributed to nicotine, but to other substances in tobacco smoke. [ABSTRACT FROM AUTHOR]

Abstract Background Data on the prevalence of dyslipidemia and attainment of goal/normal lipid levels in a Swedish population are scarce. The objective of this study is to estimate the prevalence of dyslipidemia and attainment of goal/normal lipid levels in patients treated with lipid modifying therapy (LMT). Methods This longitudinal retrospective observational study covers time periods before and after treatment. Data were collected from 1994-2007 electronic patient records in public primary healthcare centers in Uppsala County, Sweden. Patients were included if they had been treated with LMT and had at least one lipid abnormality indicating dyslipidemia and if complete lipid profile data were available. Thresholds levels for lipids were defined as per Swedish guidelines. Results Among 5,424 patients included, at baseline, the prevalence of dyslipidemia (≥1 lipid abnormality) was by definition 100%, while this figure was 82% at follow-up. At baseline, 60% had elevated low-density lipoprotein (LDL-C) combined with low high-density lipoprotein (HDL-C) and/or elevated triglycerides (TG s), corresponding figure at follow-up was 36%. Low HDL-C and/or elevated TGs at follow-up remained at 69% for patients with type 2 diabetes mellitus (T2DM), 50% among patients with coronary heart disease (CHD) and 66% among patients with 10 year CHD risk >20%. Of the total sample, 40% attained goal levels of LDL-C and 18% attained goal/normal levels on all three lipid parameters. Conclusions Focusing therapy on LDL-C reduction allows 40% of patients to achieve LDL-C goal and helps reducing triglyceride levels. Almost 60% of patients experience persistent HDL-C and/or triglyceride abnormality independently of LDL-C levels and could be candidates for additional treatments.

There is an increasing need for new biomarkers improving prediction of chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D). We aimed to identify blood-based epigenetic biomarkers associated with incident CKD and develop a methylation risk score (MRS) predicting CKD in newlydiagnosed individuals with T2D. DNA methylation was analysed epigenome-wide in blood from 487 newly-diagnosed individuals with T2D, of whom 88 developed CKD during 11.5-year follow-up. Weighted Cox regression was used to associate methylation with incident CKD. Weighted logistic models and cross-validation (k=5) were performed to test if the MRS could predict CKD. Methylation at 37 sites was associated with CKD development, based on FDR<5% and absolute methylation differences ≥5% between individuals with incident CKD and those free of CKD during follow-up. Notably, 15 genes annotated to these sites, e.g., TGFBI, SHISA3, and SLC43A2 (encoding LAT4), have been linked to CKD or related risk factors including blood pressure, BMI, or eGFR. Using a MRS including 37 sites and cross-validation for prediction of CKD, we generated ROC curves with AUC=0.82 for the MRS and AUC=0.87 for the combination of MRS and clinical factors. Importantly, ROC curves including the MRS had significantly better AUCs versus the one only including clinical factors (AUC=0.72). The combined epigenetic biomarker had high accuracy in identifying individuals free of future CKD (negative predictive value=94.6%). We discovered a high-performance epigenetic biomarker for predicting CKD, encouraging its potential role in precision medicine, risk stratification, and targeted prevention in T2D., (© 2024 by the American Diabetes Association.)

Objectives: Cardiometabolic diseases are a global health concern, affecting socioeconomically disadvantaged groups more adversely. Effective public health interventions targeting preventable risk factors like physical inactivity and unhealthy diets are needed. Codesign with citizens presents a promising opportunity for developing context-relevant and population-relevant interventions, with high chances of adoption by the target population. This study aimed to understand the needs and priorities of key stakeholders to engage in codesign with citizens for the prevention of cardiometabolic diseases, focusing on socioeconomically disadvantaged groups in Uppsala, Sweden., Design: A qualitative case study was conducted using semistructured interviews with stakeholders working with prevention and and promotion of healthy and active living in public, private and civil society sectors. The interviews were audio recorded, transcribed verbatim and analysed using reflexive thematic analysis., Setting: Uppsala, Sweden., Participants: A total of 24 participants were purposively sampled., Results: While participants described the critical value of participatory processes to achieve goals in their work, they struggled to prioritise prevention efforts over time. This adversely affected the continuity of public health interventions and collaborations with other stakeholders. They also described resistance towards inclusive processes from within their organisations, as they were seen as time-consuming and generating unpredictable outcomes. Additionally, the persistence of a siloed system structure of organisations and the risks associated with accessing target populations through local intermediaries added to the challenges., Conclusion: This study highlights the lack of integration of organisational values and functions within and across organisations, hindering cross-sector collaboration and citizen engagement in prevention and health promotion activities. Additionally, the low priority of prevention and ineffective use of codesign hampers continuity and long-term perspectives of prevention and health promotion. To create more conducive conditions for codesign, facilitating intersectoral activities and more inclusive processes is needed and may be enabled by explicit and systematic support., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Allosteric regulators acting as pharmacological chaperones hold promise for innovative therapeutics since they target noncatalytic sites and stabilize the folded protein without competing with the natural substrate, resulting in a net gain of function. Exogenous allosteric regulators are typically more selective than active site inhibitors and can be more potent than competitive inhibitors when the natural substrate levels are high. To identify novel structure-targeted allosteric regulators (STARs) that bind to and stabilize the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed enzyme enhancement therapy (SEE-Tx) technology was applied. SEE-Tx is an innovative drug discovery platform with the potential to identify drugs for treating protein misfolding disorders, such as glutaric acidemia type 1 (GA1) disease. Putative allosteric regulators were discovered using structure- and ligand-based virtual screening methods and validated using orthogonal biophysical and biochemical assays. The computational approach presented here could be used to discover allosteric regulators of other protein misfolding disorders.

Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is haematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible for HSCT (n = 8) or awaiting HSCT (n = 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient died rapidly from coronavirus disease 2019. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS., (© 2024. The Author(s).)

Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose-exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (f mCYP3A4  = 24%) and CYP2C8-mediated (f mCYP2C8  = 45%) metabolism, as well as biliary clearance (f eBIL  = 19.5%) derived from in vitro data, and was verified by comparing the observed versus predicted concentration-time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients., (© 2024 Minoryx Therapeutics S.L. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Diagnostic testing is essential for disease surveillance and test-trace-isolate efforts. We aimed to investigate if residential area sociodemographic characteristics and test accessibility were associated with Coronavirus Disease 2019 (COVID-19) testing rates., Methods: We included 426 224 patient-initiated COVID-19 polymerase chain reaction tests from Uppsala County in Sweden from 24 June 2020 to 9 February 2022. Using Poisson regression analyses, we investigated if postal code area Care Need Index (CNI; median 1.0, IQR 0.8-1.4), a composite measure of sociodemographic factors used in Sweden to allocate primary healthcare resources, was associated with COVID-19 daily testing rates after adjustments for community transmission. We assessed if the distance to testing station influenced testing, and performed a difference-in-difference-analysis of a new testing station targeting a disadvantaged neighbourhood., Results: We observed that CNI, i.e. primary healthcare need, was negatively associated with COVID-19 testing rates in inhabitants 5-69 years. More pronounced differences were noted across younger age groups and in Uppsala City, with test rate ratios in children (5-14 years) ranging from 0.56 (95% CI 0.47-0.67) to 0.87 (95% CI 0.80-0.93) across three pandemic waves. Longer distance to the nearest testing station was linked to lower testing rates, e.g. every additional 10 km was associated with a 10-18% decrease in inhabitants 15-29 years in Uppsala County. The opening of the targeted testing station was associated with increased testing, including twice as high testing rates in individuals aged 70-105, supporting an intervention effect., Conclusions: Ensuring accessible testing across all residential areas constitutes a promising tool to decrease inequalities in testing., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Public Health Association.)

Purpose: This study aims to determine initiation and persistence for patients with type 2 diabetes receiving their first prescription of an antidiabetic agent and the associations with socioeconomic factors., Methods: A cohort study including 8515 patients with type 2 diabetes who were prescribed their first antidiabetic medication between 2012 and 2019 in Uppsala, Sweden, was followed during 2 years. Medical records were linked to national registers on dispensed drugs and socioeconomic data. Adherence was assessed based on patients' medication claims within 30 days of prescription (initiation) and continued claims after 24 months (persistence). Multivariable logistic regression was used to determine the associations with the socioeconomic factors age, sex, living status, country of birth, education, occupation, and income., Results: Within 30 days, 92.4% of the patients claimed their first prescription, and 64.0% were still being dispensed the initially prescribed medication after 24 months. Unemployed patients had lower initiation rates, and women had lower persistence rates. Factors associated with both low initiation and persistence were low income, young or old age, birth outside Europe, and being prescribed other diabetes drugs than metformin monotherapy., Conclusion: Socioeconomic factors have different impact on the initiation of a new medication and the persistence to treatment in type 2 diabetes. It is important to acknowledge these differences to develop appropriate interventions to improve medication nonadherence., (© 2023. The Author(s).)

Background: Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment., Methods: We have thoroughly described mitochondrial performance in two Rett models, patients' primary fibroblasts and female Mecp2 tm1.1Bird-/+ mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPARγ agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel., Results: We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity., Conclusions: Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial., (© 2023. The Author(s).)

Aims: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newly-diagnosed individuals with type 2 diabetes., Methods and Results: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for ∼ 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin's effects on HbA1c., Conclusion: Metformin-associated alterations in DNA methylation partially mediates metformin's antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood-brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.

Background: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy., Methods: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing., Findings: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group., Interpretation: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy., Funding: Minoryx Therapeutics., Competing Interests: Declaration of interests AF received grants or contracts from Minoryx Therapeutics, Autobahn Therapeutics, Poxel, SwanBio Therapeutics, and Affinia Therapeutics; has royalties or licences with Ashvattha Therapeutics; is coinventor of patent WO2017075580A1; and has been a member of a data safety monitoring board for Bluebird Bio. ES has received honoraria from Orphazyme and received payments to his institution from Minoryx Therapeutics for the conduct of this study. FE is the principal investigator of clinical trials for Bluebird Bio and Minoryx Therapeutics; has received consulting fees from Autobahn, Poxel, SwanBio Therapeutics, and Taysha Gene Therapies; has received payment from UpToDate; and has patents and stock or stock options with SwanBio Therapeutics. FM has received grants or contracts to her institution from Minoryx Therapeutics; and consulting fees from Minoryx Therapeutics and Poxel. ME has received grants or contracts from Autobahn Therapeutics, Bluebird Bio, the European Leukodystrophy Association, the Netherlands Organization for Scientific Research, Minoryx Therapeutics, and SwanBio Therapeutics; payments to his institution from Minoryx Therapeutics; consulting fees from Autobahn Therapeutics and Poxel; meeting honoraria and travel support from Minoryx Therapeutics; and has been an unpaid advisor for the United Leukodystrophy Foundation. WK has received grants or contracts from Bluebird Bio, Minoryx Therapeutics, and SwanBio Therapeutics; consulting fees from Alexion, Bristol Myers Squibb, Minoryx Therapeutics, Poxel, Pharmaelle, Roche, and Vigil; honoraria or travel support from Bayer, Biogen, and Minoryx Therapeutics; and has been an unpaid advisor for the European Leukodystrophy Association, Myelin Project Germany, and the United Leukodystrophy Foundation. ET is an employee of, has patents with, and has stock options in Minoryx Therapeutics and has received the Torres Quevedo grant issued to Minoryx Therapeutics. AV is an employee of and has stock options in Minoryx Therapeutics. AM, MP, SP, GP, PP, LR-P, MR, and AV are employees of, have patents with, and have stock options in Minoryx Therapeutics. MM is co-founder of and has patents with and stock options in Minoryx Therapeutics. UM is a former employee of and has stock options in Minoryx Therapeutics. IM-U, JG, MJM, JS, and RL declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective in ameliorating the mitochondrial defects that characterize an hiPS-derived model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). PKAN is caused by a genetic alteration in the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway, and for which no effective cure is available. The PKAN hiPS-derived astrocytes are characterized by mitochondrial dysfunction, cytosolic iron deposition, oxidative stress and neurotoxicity. We monitored the effect of leriglitazone in comparison with CoA on hiPS-derived astrocytes from three healthy subjects and three PKAN patients. The treatment with leriglitazone did not affect the differentiation of the neuronal precursor cells into astrocytes, and it improved the viability of PKAN cells and their respiratory activity, while diminishing the iron accumulation similarly or even better than CoA. The data suggest that leriglitazone is well tolerated in this cellular model and could be considered a beneficial therapeutic approach in the treatment of PKAN.