Predictors of orphan drug approval in the European Union

Objective: To encourage the development of drugs for rare diseases, orphan drug legislation has been introduced in the USA (1983) and in the EU (2000). Recent literature discusses factors that may influence the development of new orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential orphan drugs in the EU. Methods: A comparison between randomly selected authorised and a matched sample of not-yet-authorised orphan drug designations has been performed. Determinants in the study included characteristics of the indication, of the product and of the sponsor. Data were collected from the public domain only. Results: Orphan drug approval was strongly associated with previous experience of the sponsor in obtaining approval for another orphan drug (OR=17.3, 95% CI=5.6-53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR=3.9, 95% CI=0.9-16.6). Conclusion: This study showed that experience of a company in developing orphan drugs is an important predictor for subsequent authorisation of other orphan drugs. The same applies for existing (synthetic) molecules, for which much knowledge is available. Further research should be directed towards studying the quality of the clinical development program of those designated orphan medicinal products not reaching approval status

Role of Fractalkine/CX3CR1 Interaction in Light-Induced Photoreceptor Degeneration through Regulating Retinal Microglial Activation and Migration

Background: Excessive exposure to light enhances the progression and severity of some human retinal degenerative diseases. While retinal microglia are likely to be important in neuron damage associated with these diseases, the relationship between photoreceptor damage and microglial activation remains poorly understood. Some recent studies have indicated that the chemokine fractalkine is involved in the pathogenesis of many neurodegenerative diseases. The present study was performed to investigate the cross-talk between injured photoreceptors and activated retinal microglia, focusing on the role of fractalkine and its receptor CX3CR1 in light-induced photoreceptor degeneration. Methodology/Principal Findings: Both in vivo and in vitro experiments were involved in the research. In vivo, Sprague– Dawley rats were exposed to blue light for 24 hours. In vitro, the co-culture of primary retinal microglia and a photoreceptor cell line (661W cell) was exposed to blue light for five hours. Some cultures were pretreated by the addition of anti-CX3CR1 neutralizing antibody or recombinant fractalkine. Expression of fractalkine/CX3CR1 and inflammatory cytokines was detected by immunofluorescence, real-time PCR, Western immunoblot analysis, and ELISA assay. TUNEL method was used to detect cell apoptosis. In addition, chemotaxis assay was performed to evaluate the impact of soluble fractalkine on microglial migration. Our results showed that the expression of fractalkine that was significantly upregulated after exposure to light, located mainly at the photoreceptors. The extent of photoreceptor degeneration and microglial migratio

Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study

BACKGROUND: Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury. We have now investigated the time course of EP1 and Cox-2 changes in injured human nerves and dorsal root ganglia (DRG), and the chronic constriction nerve injury (CCI) model in the rat. METHODS: Tissue sections were immunostained with specific antibodies to EP1, Cox-2, CD68 (human macrophage marker) or OX42 (rat microglial marker), and neurofilaments (NF), prior to image analysis, from the following: human brachial plexus nerves (21 to 196 days post-injury), painful neuromas (9 days to 12 years post-injury), avulsion injured DRG, control nerves and DRG, and rat CCI model tissues. EP1 and NF-immunoreactive nerve fibres were quantified by image analysis. RESULTS: EP1:NF ratio was significantly increased in human brachial plexus nerve fibres, both proximal and distal to injury, in comparison with uninjured nerves. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. While there was a rapid increase in EP1-fibres and CD-68 positive macrophages, Cox-2 increase was apparent later, but was persistent in human painful neuromas for years. A similar time-course of changes was found in the rat CCI model with the above markers, both in the injured nerves and ipsilateral dorsal spinal cord. CONCLUSION: Different stages of infiltration and activation of macrophages may be observed in the peripheral and central nervous system following peripheral nerve injury. EP1 receptor level increase in sensory neurones, and macrophage infiltration, appears to precede increased Cox-2 expression by macrophages. However, other methods for detecting Cox-2 levels and activity are required. EP1 antagonists may show therapeutic effects in acute and chronic neuropathic pain, in addition to inflammatory pain

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Transmission of attachment in a DMM perspective

Aim of this research is to investigate the relation between the pattern of mothers attachment and the one of their children at 12 months of age, using the Dynamic-Maturational Method (DMM) criteria for the first time in an Italian sample. It was hypothesized that mothers with secure (or balanced) pattern (B) - more sensitive and protective towards their offspring - should foster a B pattern in their children. On the contrary, insecure mothers - less sensitive, more anxious and more controlling - should promote the development of an insecure pattern in their children. A sample of 40 Italian mothers-child dyads was initially considered and 30 mothers (aged from 19 to 40 years) and their children met criteria for inclusion in the research. A final sample of 26 dyads completed the procedures. All mothers, at the 6th month of delivery, were subjected to the Adult Attachment Interview (AAI), and afterwards to the Strange Situation (SS) when their children were 12 months old. Both procedures were administered and codified in double blind by 2 reliable codifiers following DMM criteria. Results: 23.1% of mothers resulted balanced (B), 15.4% dismissing (A), 42.3% preoccupied (C), 11.5% dismissing/preoccupied (A/C) and 7.7% in course of reorganization (R). 34.6% of children resulted secure (B), 23.1% avoiding (A), 38.5% ambivalent (C) and 3.8% avoiding/ambivalent (A/C). This study confirmed the attachment transmission hypothesis revealing a modest correlation between mother\u2019s and child\u2019s secure attachment (B) (p < .05). However, a reversal pattern is evinced in a significant part of the insecure sample: children of insecure mother show an opposite pattern in respect to their mother (A versus C or C versus A). This \u201creversal trasmission of attachment\u201d is in line with others studies (Hautam\ue4ki el al., 2010a, 2010b; Shah, Fonagy, Strathearn, 2010) and is coherent with DMM theory

Attachment forerunners in fathers with preterm babies

Preterm birth is a stressful and potentially traumatic event for the family. In this critical situation, the psychological characteristics of the father are important for the protection of the family and for the child development. The paternal function is manifested not only by supporting and encouraging his partner to foster a good mother-child bond, but also directly in the relation with the child. Aim of this research was to study the influence of attachment forerunners and dyadic sensitivity of the father in the child development. A sample of 110 father-child couples, 55 with preterm born children (birth weight < 1500 g) and 55 with term born children were assessed from the first 6 months of corrected age. At 3 months of corrected age of the baby, all couples were subjected to CARE-Index, a video-recorded procedure of adult-child spontaneous interaction evaluating parental sensitivity and attachment forerunners. The child\u2019s psychomotor development was assessed at 6 months of corrected age by the Bayley Scales of Infant Development (BSID III). Fathers of preterm children, compared to controls, showed lower dyadic sensitivity scores (p < .01) and more frequent insecure attachment forerunners (p < .01). 75% of these \u201cpreterm\u201d fathers falls into the high risk category of the CARE-Index (requiring psychological and/or pharmacological treatment). These factors were associated with lower scores on the psychomotor development of the children at 6 months of corrected age (p < .01). The presence of insecure attachment forerunners and poor dyadic sensitivity \u2013 even in fathers with term children \u2013 seems to have a negative effect on the psychomotor development of child (p < .05). The results underlines the extreme importance of the quality of the relationship of the father with his baby from the first months of life. Poor parental sensitivity and insecure attachment forerunners influence negatively the psychomotor development of the newborn