New Therapies to Correct the Cystic Fibrosis Basic Defect

Rare diseases affect 400 million individuals worldwide and cause significant morbidity and mortality. Finding solutions for rare diseases can be very challenging for physicians and researchers. Cystic fibrosis (CF), a genetic, autosomal recessive, multisystemic, life-limiting disease does not escape this sad reality. Despite phenomenal progress in our understanding of this disease, treatment remains difficult. Until recently, therapies for CF individuals were focused on symptom management. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its product, a protein present at the apical surface of epithelial cells regulating ion transport, allowed the scientific community to learn about the basic defect in CF and to study potential therapies targeting the dysfunctional protein. In the past few years, promising therapies with the goal to restore CFTR function became available and changed the lives of several CF patients. These medications, called CFTR modulators, aim to correct, potentialize, stabilize or amplify CFTR function. Furthermore, research is ongoing to develop other targeted therapies that could be more efficient and benefit a larger proportion of the CF community. The purpose of this review is to summarize our current knowledge of CF genetics and therapies restoring CFTR function, particularly CFTR modulators and gene therapy.

Cystic Fibrosis: New Insights into Therapeutic Approaches

Since the identification of Cystic Fibrosis (CF) as a disease in 1938 until 2012, only therapies to treat symptoms rather than etiological therapies have been used to treat the disease. Over the last few years, new technologies have been developed, and gene editing strategies are now moving toward a one-time cure. This review will summarize recent advances in etiological therapies that target the basic defect in the CF Transmembrane Receptor (CFTR), the protein that is mutated in CF. We will discuss how newly identified compounds can directly target mutated CFTR to improve its function. Moreover, we will discuss how proteostasis regulators can modify the environment in which the mutant CFTR protein is synthesized and decayed, thus restoring CFTR function. The future of CF therapies lies in combinatory therapies that may be personalized for each CF patient.

Multi-Annual Planning of Public Budgets as a Way of Rationalising Public Expenditure

Multi-annual planning is an essential tool in public finance law for the efficient management of public funds. The management by one-year budget should be accompanied by future planning exceeding one calendar year. Such planning is being made at the present time to a certain extent; however, the fulfilment of long-term plans, which cannot be enforced, can be perceived as the basic defect, which means that long-term plans are not obligatory for the next calendar year. The aim of this article is to determine whether, and if so, how it affects the rationalisation of public expenditure, a process that should lead to the efficient and economical use of public funds.

Cystic fibrosis

Cystic fibrosis is the most common lethal autosomal recessive disorder in Caucasians. There is no known survival advantage of the heterozygote carrier state. Chronic progressive pulmonary infection and bronchiectasis are the major causes of morbidity and mortality. The disease affects all ductal systems where the basic defect is manifest, including the pancreas, gastrointestinal tract, sinuses, hepatobiliary system, and male reproductive system, and has significant effects on nutrition and growth.

Lymphedema

Chapter 7 covers Cholestasis-Lymphedema Syndrome, Distichiasis and Lymphedema, and Hereditary Lymphedema. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Urticaria

Chapter 8 covers Familial Cold Urticaria, Hereditary Angioedema, Melkersson-Rosenthal Syndrome, Muckle-Wells Syndrome, NOMID/CINCA, and Urticaria Pigmentosa. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Disorders of Subcutaneous Tissue

Chapter 6 covers Cerebrotendinous Xanthomatosis, Familial Multiple Lipomatosis, Familial Symmetric Lipomatosis, Fibrodysplasia Ossificans Progressiva, Lipogranulomatosis, Partial Lipodystrophy, and Berardinelli-Seip Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Other Disorders

Chapter 9 covers Congenital Erosive and Vesicular Dermatosis, Erythermalgia, Michelin Tire Baby, and Stiff Skin. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Premature Aging

Chapter 12 covers Cockayne Syndrome, De Barsy Syndrome, Hallermann-Streiff Syndrome, Hutchinson-Gilford Progeria, and Werner Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.