Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, explain the incentives and procedures, and touch on the role of patient organisations in the process.
The RNA exosome has a key role in RNA decays and RNA quality control. In 2012, two human Mendelian diseases: syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) and Ponto-cerebellar hypoplasia type 1(PCH1) were linked to the RNA exosome or its cofactor's defect. SD/THE's main features are an intractable diarrhea of infancy associated with hair abnormalities, facial dysmorphism, intra uterine growth restriction and immune deficiency. SD/THE is caused by a defect of the SKI complex (TTC37 and SKIV2L), the cytoplasmic co-factor of the RNA exosome for mRNA degradation. PCH1's main features are atrophy of the pons and of the cerebellum, a progressive microcephaly with developmental delay and muscle atrophy secondary to spinal anterior horn cell loss. In 30-40% of patients, PCH1 is caused by a defect in EXOSC3 which encodes RRP40, a protein of the cap of the RNA exosome. Thanks to knowledge about other forms of PCH it could be assumed that the altered substrates are probably transfer RNA However, as there exists no patient with two null mutations, residual RNA exosome functionality is probably required to preserve viability. Thus, to date two very different human Mendelian diseases have been related to the dysfunctioning of the RNA exosome. It illustrates the versatility of the RNA exosome function and substrate.
Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that plays an important role in the mineralization of the matrix in mature osteoblasts. However, understanding of the regulatory mechanism of IFITM5 expression is limited. Emerging evidence indicates that microRNAs (miRNAs) act as pivotal regulators in various biological processes including osteoblast proliferation and differentiation. This study aimed to investigate the impact of miRNAs on IFITM5 expression. Bioinformatic analyses predicted that miR-762 would be a potential regulator of IFITM5. A Dual-Luciferase Reporter Assay System indicated that miR-762 could bond with the 3'untranslated region (3'UTR) of IFITM5via wild-type or mutant recombinant vectors and Western blotting verified that miR-762 negatively regulated IFITM5 expression. Collectively, these data indicate that miR-762 is a novel regulator of IFITM5 and that it suppresses the expression of IFITM5 in Saos-2 cells.
Kartagner's syndrome is a rare autosomal recessive disorder characterized by sinusitis, bronchiectasis and situs inversus. Otitis media is seen in 95% of the individuals with this syndrome due to recurrent respiratory infections and dysfunctional cilia in the middle ear. Earlier research reported the presence of structural and functional deficits in the auditory brainstem following long standing otitis media. However, no such findings have been reported in individuals with this syndrome. Thus, the present case report highlights the results of various audiological tests with special emphasis on investigating the auditory processing abilities in a known case of Kartagner's syndrome. In order to accomplish the aim, the audiological test battery was carried out on a 42 year old male patient diagnosed as having Kartagner's syndrome. The basic audiological tests, including immittance audiometry, pure tone audiometry, otoacoustic emission and auditory brainstem response (using click stimulus) results indicated the presence of mild to moderate mixed hearing loss in both ears. However, results of the auditory brainstem response (using speech stimulus) pointed toward abnormal speech processing skills. Thus, the behavioral test battery approach (including speech perception in noise test, gap detection test, temporal modulation transfer function test and duration pattern test) was followed and the findings suggested presence of auditory closure and temporal processing deficit. The outcome of the case study recommends that a complete test battery approach involving psychoacoustic tests should be used to assess such cases and auditory rehabilitation should be suggested accordingly.
Reported here are 2 patients with connective tissue disease who developed pulmonary nocardiosis. Case 1 involved a 73-year-old man with malignant rheumatoid arthritis treated with prednisolone 25 mg/day. Chest X-rays revealed a pulmonary cavity and bronchoscopy detected Nocardia species. The patient was successfully treated with trimethoprim/sulfamethoxazole. Case 2 involved a 41-year-old woman with systemic lupus erythematosus. The patient received remission induction therapy with 50 mg/day of prednisolone and tacrolimus. Six weeks later, a chest CT scan revealed a pulmonary cavity; bronchoscopy resulted in a diagnosis of pulmonary nocardiosis. The patient had difficulty tolerating trimethoprim/sulfamethoxazole, so she was switched to and successfully treated with imipenem/cilastatin and amikacin.
Takayasu arteritis (TA) is a rare and idiopathic large-vessel arteritis typically affecting young women which has important morbidity and mortality. There are no animal models of TA and pathogenesis is still mysterious. Clinical assessment lacks accurate activity indexes and is based on the integration of clinical, laboratory and radiological data. TA rarity has hampered randomized clinical trials and the achievement of high-quality evidence to guide clinical activity. Prevention of vascular progression, with progressive vessel wall remodelling and hyperplasia, is the main therapeutic goal. Medical therapy remains the mainstay of management and comprises traditional immunosuppressive agents and anti-inflammatory drugs, such as steroids and blockers of pivotal cytokines, TNF-α and IL-6. These strategies however only partially limit vascular progression, indicating that local molecular events are involved. Here we discuss recent data suggesting that selected cellular components of TA lesions should be evaluated as novel therapeutic targets.