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Molecular Therapy. Nucleic Acids Sep 2023The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules... (Review)
Review
The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules through complementary base-pairing. A systematic review of published and ongoing clinical trials was performed. Web of Science, PubMed, and Embase were searched from January 1, 1998, to December 30, 2022 for clinical trials using RNAi. Following inclusion, data from the articles were extracted according to a predefined protocol. A total of 90 trials published in 81 articles were included. In addition, ongoing clinical trials were retrieved from ClinicalTrials.gov, resulting in the inclusion of 48 trials. We investigated how maturation of RNAi-based therapeutics and developments in delivery platforms, administration routes, and potential targets shape the current landscape of clinically applied RNAi. Notably, most contemporary clinical trials used either -acetylgalactosamine delivery and subcutaneous administration or lipid nanoparticle delivery and intravenous administration. In conclusion, RNAi therapeutics have gained great momentum during the past decade, resulting in five approved therapeutics targeting the liver for treatment of severe diseases, and the trajectory depicted by the ongoing trials emphasizes that even more RNAi-based medicines also targeting extra-hepatic tissues are likely to be available in the years to come.
PubMed: 37583575
DOI: 10.1016/j.omtn.2023.07.018 -
Journal of Personalized Medicine Aug 2022Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by gene mutations causing...
Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were -0.260, -0.102, -0.182, -0.360, -0.408, -0.587, -0.293, -0.311, and -0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.
PubMed: 36013287
DOI: 10.3390/jpm12081338 -
The Cochrane Database of Systematic... Sep 2021Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is a rare genetic disorder caused by the deficiency of arylsulphatase B. The resultant accumulation of... (Review)
Review
BACKGROUND
Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is a rare genetic disorder caused by the deficiency of arylsulphatase B. The resultant accumulation of dermatan sulphate causes lysosomal damage. The clinical symptoms are related to skeletal dysplasia (i.e. short stature and degenerative joint disease). Other manifestations include cardiac disease, impaired pulmonary function, ophthalmological complications, hepatosplenomegaly, sinusitis, otitis, hearing loss and sleep apnea. Intellectual impairment is generally absent. Clinical manifestation is typically by two or three years of age; however, slowly progressive cases may not present until adulthood. Enzyme replacement therapy (ERT) with galsulfase is considered a new approach for treating MPS VI.
OBJECTIVES
To evaluate the effectiveness and safety of treating MPS VI by ERT with galsulfase compared to other interventions, placebo or no intervention.
SEARCH METHODS
Eletronic searches were performed on the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Date of the latest search: 09 June 2021. Further searches of the following databases were also performed: CENTRAL, MEDLINE, LILACS, the Journal of Inherited Metabolic Disease, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Date of the latest search: 20 August 2021.
SELECTION CRITERIA
Randomized and quasi-randomized controlled clinical studies of ERT with galsulfase compared to other interventions or placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently screened the studies, assessed the risk of bias, extracted data and assessed the certainty of the the evidence using the GRADE criteria.
MAIN RESULTS
One study was included involving 39 participants who received either ERT with galsulfase (recombinant human arylsulphatase B) or placebo. This small study was considered overall to have an unclear risk of bias in relation to the design and implementation of the study, since the authors did not report how both the allocation generation and concealment were performed. Given the very low certainty of the evidence, we are uncertain whether at 24 weeks there was a difference between groups in relation to the 12-minute walk test, mean difference (MD) of 92.00 meters (95% confidence interval (CI) 11.00 to 172.00), or the three-minute stair climb, MD 5.70 (95% CI -0.10 to 11.50). In relation to respiratory tests, we are uncertain whether galsulfase makes any difference as compared to placebo in forced vital capacity in litres (FVC (L) (absolute change in baseline), given the very low certainty of the evidence. Cardiac function was not reported in the included study. We found that galsulfase, as compared to placebo, may decrease urinary glycosaminoglycan levels at 24 weeks, MD -227.00 (95% CI -264.00 to -190.00) (low-certainty evidence). We are uncertain whether there are differences between the galsulfase and placebo groups in relation to adverse events (very low-certainty evidence). In general, the dose of galsulfase was well tolerated and there were no differences between groups. These events include drug-related adverse events, serious and severe adverse events, those during infusion, drug-related adverse events during infusion, and deaths. More infusion-related reactions were observed in the galsulfase group and were managed with interruption or slowing of infusion rate or administration of antihistamines or corticosteroids drugs. No deaths occurred during the study. AUTHORS' CONCLUSIONS: The results of this review are based only on one small study (a 24-week randomised phase of the study and prior to the open-label extension). We are uncertain whether galsulfase is more effective than placebo, for treating people with MPS VI, in relation to the 12-minute walk test or the three-minute stair climb, as the certainty of the evidence has been assessed as very low. We found that galsulfase may reduce urinary glycosaminoglycans levels. We are also uncertain whether there are any differences between treatment groups in relation to cardiac or pulmonary functions, liver or spleen volume, overnight apnea-hypopnea, height and weight, quality of life and adverse effects. Further studies are needed to obtain more information on the long-term effectiveness and safety of ERT with galsulfase.
Topics: Adult; Enzyme Replacement Therapy; Humans; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase; Quality of Life; Recombinant Proteins
PubMed: 34533215
DOI: 10.1002/14651858.CD009806.pub3