Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT.

Cystic Fibrosis Treatment Options Discrepancy Globally

Cystic fibrosis, or rather known as CF, is a common monogenic disease caused by genetic mutation on CFTR on chromosome 7. Progressive obstructive pulmonary disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility are all characteristics of the disease. Persistent pulmonary infections are caused by a lack of CFTR or its decreased function, leading to bronchiectasis and progressive lung destruction. Despite the fact that CF patients' lives are shortening, early diagnosis has helped improve patients' life span to a median age of around 50 years, including newborn screening, mild form identification, and a proactive therapy approach. Pancreatic enzyme replacement, respiratory physiotherapy, mucolytics, and strong antibiotic therapy are among treatments for CF. For the majority of people with severe symptoms, a lung or liver transplant is necessary. The CFTR protein is affected by a large number of mutations, each of which have diverse effects. Despite advances in our understanding of CFTR function and contemporary therapy, most of our knowledge of cystic fibrosis remains unclear. With the recent addition of mutation-specific treatments, future advances in health and quality of life for people with CF are likely to improve. The focus of research is on novel medications that restore CFTR function, some of which are now accessible and have a positive therapeutic impact, while others are showing promising preliminary results.

Modern aspects of diagnosis and treatment of chronic pancreatitis in children: experience of the center Center for the treatment of developmental anomalies and diseases of the hepatopancreatobiliary system in children

Chronic pancreatitis is one of the most pressing problems of pediatric gastroenterology and surgery of hepatopancreatobiliary organs. Diagnosis and treatment of this category of patients requires a comprehensive examination using modern highly sensitive research methods and the collegial participation of a surgeon, gastroenterologist and endocrinologist. Due to the fact that the algorithm for managing these patients is not regulated, patients often receive enzyme replacement therapy for a long time, with indications for surgical treatment. In addition, the non-specificity of complaints and clinical manifestations of chronic pancreatitis, the asymptomatic course and the initial detection of exo- and endocrine insufficiency lead to a later choice of the optimal treatment method and increase the risk of complications. The key to effective care for children with chronic pancreatitis is the staging and continuity in research and treatment. At the Center for the Treatment of Developmental Anomalies and Diseases of the Hepatopancreatobiliary System in Children on the basis of the Filatov Hospital, highly effective interventions are carried out for chronic pancreatitis in children, the purpose of which is to ensure an adequate outflow of pancreatic juice using longitudinal pancreaticojejunostomy, which, in addition to draining the pancreas, allows to achieve clinical remission and stop the progression pathological process, including diabetes mellitus. The article reflects the experience of diagnosis and treatment of chronic pancreatitis in children.

Is it necessary to correct the intestinal microbiota disorders in chronic pancreatitis?

The frequency of intestinal microbiota disorders in patients with chronic pancreatitis (CP) is extremely high and can reach 97%. The bacterial overgrowth syndrome (SIBO) and the syndrome of increased epithelial permeability (SPEP), developing against the background of excretory insufficiency of the pancreas, affect the severity of the clinical picture of the disease, reduce the effectiveness of enzyme replacement therapy and generally contribute to the further progression of CP.The article presents a modern view on the mechanisms of the formation of SIBO and SPEP in CP. There is their aggravating effect on the course of the disease and the aggravation of disorders of the digestive and absorption processes that accompany them is shown and analyzed in the article.For decontamination of conditionally pathogenic and pathogenic flora, increasing the number and metabolic activity of indigenous microflora in patients with CP, the use of a non-absorbable broad-spectrum antibiotic rifaximin is effective. In order to restore the barrier function of the gastrointestinal mucosa, the drug of choice is rebamipid, a universal cytoprotector that affects all three levels of epithelial tissue protection (preepithelial, epithelial and subepithelial).Conclusion. CP is characterized by the complexity of its etiology and pathogenesis. Bacterial factors, in particular, SIBO and SPEP, play an essential role in the development of inflammatory changes in the pancreas. In the complex therapy of CP, it is advisable to take measures aimed at correcting disorders of the intestinal microbiota.

Screening of Chimeric GAA Variants in a Preclinical Study of Pompe Disease Results in Candidate Vector for Hematopoietic Stem Cell Gene Therapy

Pompe disease is a rare genetic neuromuscular disorder caused by acid alpha-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy (ERT) is the current standard of care, which prolongs the quality of life for Pompe patients. However, ERT has limitations due to lack of enzyme penetration into the central nervous system (CNS) and skeletal muscles, immunogenicity against the recombinant enzyme, and requires life-long biweekly infusions. In a preclinical mouse model, a clinically relevant promoter to drive lentiviral vector-mediated expression of engineered GAA in autologous hematopoietic stem and progenitor cells (HSPC) was tested with nine unique human chimeric GAA coding sequences incorporating distinct peptide tags and codon-optimization iterations. Vectors including glycosylation independent lysosomal targeting (GILT) tags resulted in effective GAA enzyme delivery into key disease tissues with enhanced reduction of glycogen, myofiber and CNS vacuolation, compared to non-tagged GAA in Gaa knockout mice, a model of Pompe disease. Genetically modified microglial cells in brains were detected at low levels, but provided robust correction. Furthermore, an aminoacid substitution in the tag added to reduced capacity to induce insulin signaling and there was no evidence of off-target effects. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model providing a promising vector candidate for further investigation.

Enzyme Replacement Therapy with Idursulfase in Patients with Mucopolysaccharidosis Type II: Literature Review

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is X-linked hereditary disease from the group of lysosomal storage disease. Its prevalence is 3–7 cases per 1 million live-born boys. MPS II occurs due to the deficiency of iduronate-2-sulfatase enzyme because of pathological changes in the structure of the IDS gene. Enzyme deficiency leads to the accumulation of glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate, in lysosomes. This leads to the damage of various organs and systems in the body with further development of clinical picture of the disease: coarse face, recurrent infections of upper respiratory tract, hearing loss up to deafness, cardiovascular and respiratory systems pathologies, hepatosplenomegaly, musculoskeletal system abnormalities, low growth, central nervous system damage. Enzyme replacement therapy with idursulfase, that was introduced in clinical practice 15 years ago, has significantly changed the quality of life of these patients. Idursulfase is purified form of natural lysosomal enzyme iduronate-2-sulfatase obtained via human cell line. Exogenous enzyme entry promotes GAGs catabolism in cells. This article provides outcomes analysis of foreign and Russian studies on the efficacy and safety of this medication, and its effect on MPS II patients survivability.