@misc{Ligęzka_Anna_Clinical_2023,
 author={Ligęzka, Anna},
 address={Kraków},
 howpublished={online},
 year={2023},
 school={Rada Dyscypliny Nauki farmaceutyczne},
 language={eng},
 abstract={PMM2-CDG is a rare metabolic disease with highly variable, broad range of symptoms, and interindividual difference in the severity of presentation. Although PMM2-CDG was discovered in the 80s, and since then more than 160 CDG types have been discovered, there is no comprehensive patient registry, no prospective data on outcome, the screening test for CDG diagnosis is not reliable and there is no therapy for most CDG types. The Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) was established to define the natural history of CDG, validate patient-reported outcomes, develop therapies, and share CDG knowledge across an international network of more than 20 research sites. In this thesis my aims were threefold: 1) to develop and validate new biochemical diagnostic techniques and therapeutic biomarkers which can be used in the future for clinical trials, 2) to restore appropriate glycosylation in Congenital Disorders of Glycosylation to improve clinical symptoms and quality of life of patients and their families and 3) to better define the natural history, validate patient reported outcomes and share knowledge on Congenital Disorders of Glycosylation. The genetic, laboratory, metabolic, and clinical data of 50 PMM2-CDG patients enrolled in the FCDGC natural history study were evaluated. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a chil},
 abstract={d with PMM2-CDG for 12 months. In vitro measurements included PMM enzyme measurements, immunoblotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) in PMM2-deficient fibroblasts. Additionally, proteomics and glycoproteomics were used for the first time to confirm the effectiveness of CDG treatment. Disease severity was assessed using the Nijmegen Progression CDG Rating Scale (NPCRS) tool. The NPCRS was completed based on a physical exam, laboratory testing and medical interview process. First, we describe our findings with a new, repurposed drug, epalrestat, which improves PMM enzyme activity, N-glycosylation and glycosylation biomarkers in vitro. We also trialed epalrestat in a single patient trial and found the drug well-tolerated and leading to significant clinical improvements in a pediatric PMM2-CDG patient. Second, we detected elevated sorbitol in urine and also proposed urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. Identifying patients with increased risk for thrombotic events could prevent serious complications and even mortality. Thus, we evaluated antithrombin 3 activity (ATIII) and factor XI (FXI) activity as potential biomarkers for PMM2-CDG based on the data of the natural history project for CDG. Although coagulation parameters improved with age and time, abnor},
 abstract={mal results in individual patients generally remained in the abnormal range (and normal results remained stable), suggesting that antithrombin 3 activity is a good potential biomarker for future clinical trials. Last we validated patient-reported outcomes (PROs) to measure important aspects of disease burden in PMM2-CDG. We evaluated the PROs and correlation between clinical disease severity scoring and reported quality of life (QoL) in a PMM2-CDG patient cohort of twenty-five patients. We found a strong correlation between NPCRS 1 (current functional ability) and three out of ten PROMIS (Patient-Reported Outcomes Measurement Information System) subscales. Additionally, our findings indicated the worst function in the categories such as physical activity, strength impact, mobility, and satisfaction in social roles in PMM2-CDG. Here, we found that PROMIS is an informative additional tool to measure CDG disease burden, which could be used as clinical trial outcome measures. In summary, an advanced biochemical analysis including measurements of enzyme activity, polyol levels, proteomics, and glycoproteomics allowed us to demonstrate the positive effect of epalrestat on PMM enzyme upregulation and the glycosylation, at the molecular level, in parallel with clinical improvement. We were successful in both developing new biomarkers and improve our knowledge on natural history in PM},
 abstract={M2-CDG. Our findings could be used to improve care and quality of life and develop new clinical trials for our patients.},
 title={Clinical and basic investigations on aldose reductase inhibitors in Congenital Disorders of Glycosylation},
 type={Praca doktorska},
 keywords={congenital disorders of glycosylation, rare disorders, sorbitol, metabolism, aldose reductase inhibitors, biomarkers},
}