Predisposition
Severe disease is more common in babies and young children, and in contrast to many other infections, it is more common in children who are relatively well nourished. Other risk factors for severe disease include female sex, high body mass index, and viral load. While each serotype can cause the full spectrum of disease, virus strain is a risk factor. Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. The risk of severe disease from secondary infection increases if someone previously exposed to serotype DENV-1 contracts serotype DENV-2 or DENV-3, or if someone previously exposed to DENV-3 acquires DENV-2. Dengue can be life-threatening in people with chronic diseases such as diabetes and asthma.Polymorphisms (normal variations) in particular genes have been linked with an increased risk of severe dengue complications. Examples include the genes coding for the proteins TNFα, mannan-binding lectin, CTLA4, TGFβ, DC-SIGN, PLCE1, and particular forms of human leukocyte antigen from gene variations of HLA-B. A common genetic abnormality, especially in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk. Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection against severe disease in secondary dengue infection. Mechanism
When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquitos saliva. It binds to and enters white blood cells, and reproduces inside the cells while they move throughout the body.
Also, the accelerated approval of golodirsen has paved the way for the patients to have early access to the drug, at the same time, it shrouded with controversy over a number of issues. A double-blind placebo-controlled confirmatory trial (NCT02500381) is ongoing to resolve the issues. History
Golodirsen was developed by collaborative research led by Prof. Steve Wilton and Prof. Sue Fletcher in the Perron Institute and licensed to Sarepta Therapeutics by the University of Western Australia.In the pivotal clinical trial of golodirsen, dystrophin levels increased, on average, from 0.10% of normal at baseline to 1.02% of normal after 48 weeks of treatment with the drug or longer. The change was a surrogate endpoint and the trial did not establish clinical benefit of the drug, including changes to the subjects motor function.The pharmacological assessment of golodirsen did not include special population groups, e.g., pregnant and lactating women, the elderly, and patients with concurrent disease states. As DMD predominantly affects male children and young adults, and golodirsen is indicated for the treatment of pediatric patients, but primarily not for adult women, the elderly, and patients with comorbidity, it was not evaluated on them.The US Food and Drug Administration (FDA) approved golodirsen in December 2019, under the accelerated approval pathway. The application for golodirsen was granted fast track designation, priority review designation, orphan drug designation, and a rare pediatric disease priority review voucher. References
External links
"Golodirsen". Drug Information Portal. U.S. National Library of Medicine (NLM).