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At least 19 recordsLinked to original sources
PubMed1999

Is orphan drug status beneficial to tropical disease control? Comparison of the American and future European orphan drug acts.

UNLABELLED: OBJECTIVES To quantify past outcomes of tropical pharmacology research and development (R & D) and to assess past benefits of the American orphan drug act and potential benefits of the future European orphan drug regulation on tropical diseases. METHODS: This paper presents two analyses: a 1983-97 retrospective study of the United States Orphan Drug Act concerning rare diseases and a prospective study of the European Proposal for a Regulation Concerning Orphan Drugs and its possible impact on tropical diseases. RESULTS: Different programmes have in the past tried to stimulate R & D in this area, but results remain limited. Of 1450 new chemical entities marketed between 1972 and 1997, 13 were specifically for tropical diseases and considered as essential drugs. Between 1983 & 1997, the US Orphan Drug Act approved 837 drugs and marketing of 152 new molecular entities (NMEs). Three NMEs have been designated for malaria and human African trypanosomiasis. Seven others, already commonly used in tropical diseases, received either orphan designation or an orphan approval for another indication. Pharmaceutical companies benefit from the US framework only when the US market exclusivity clause was applicable. Future European orphan drug regulation appears to be similar to the US Orphan Drug Act. CONCLUSION The orphan drug programmes relating to rare diseases have met with some success. Considering tropical diseases rare diseases seems inadequate to boost pharmaceutical R & D. However, some provisions of the European text may be relevant to tropical diseases, admitting the need for a more specific rule for evaluations of this kind of drug and recognizing the existence of 'diseases of exception'.

Europe↗
PubMed1998

A cross-national comparison of orphan drug policies: implications for the U.S. Orphan Drug Act.

Six countries--Canada, France, Japan, Sweden, the United Kingdom, and the United States--were studied to compare public policies affecting the development and marketing of pharmaceuticals for rare diseases (i.e., orphan drugs). Information was obtained from a variety of published and unpublished sources, including interviews with public policy and pharmaceutical experts in each country. This article presents different approaches to encouraging the development of orphan drugs while ensuring access by regulating their prices. Additionally, the article describes access to orphan drugs as promoted by special coverage for population subgroups, disease categories, and/or specific drugs. Not all efforts to increase access to orphan pharmaceuticals have been the result of government action, as illustrated by the proliferation of for-profit organizations that specialize in orphan drugs. The many policy options from other countries identified in this study are especially relevant, given increasing calls for reform of the U.S. Orphan Drug Act.

Canada↗
PubMedDate not supplied

[Orphan drugs and orphan diseases].

OBJECTIVES: To define the concepts of orphan drugs and diseases, the current situation of clinical investigation of them, the attitude of the pharmaceutical industry and aspects of health legislation, especially in the European Community. DEVELOPMENT: We review the history of orphan drugs, the name used for those drugs, apparatus, biological agents and dietetic preparations used to treat diseases so rare as to affect 650 1,000 persons per million inhabitants. Approximately 5,000 of such disease have been identified. Of these, 80% are genetic disorders which are very common in neuropaediatrics, since 50% appear in childhood. Half of these disorders affect the nervous system but in general there are no relative preventive and/or therapeutic methods. In view of the expense involved, the pharmaceutical industry is loath to develop products which are only used in rare diseases. Society cannot tolerate the fact that these patients do not have access to medical progress. For this reason organizations of affected persons (especially the National Organization for Rare Diseases) put pressure on the USA authorities leading to the Orphan Drug Act of 1983 which was subsequently copied by other countries. Since January 2000 there is a similar Regulation in the European Community. Orphan diseases need to be diagnosed early by specialists who have had patients referred to them by general practitioners. However, initial recognition of the disorder is often delayed and late diagnosis occurs in 45% of these rare diseases which make up 10% of human illnesses. Currently over 150 orphan drugs are being used for over seven million patients. CONCLUSION: The struggle to treat rare diseases must continue, since its true importance is shown when suffered personally.

Drug Therapy↗
PubMed1997

Multiple orphan nuclear receptors converge to regulate rat P450c17 gene transcription: novel mechanisms for orphan nuclear receptor action.

The orphan nuclear receptor steroidogenic factor-1 (SF-1) plays a key role in regulating the expression of the rat P450c17 gene in testicular Leydig and in adrenocortical cells. Other DNA sequences, not bound by SF-1, are also involved in transcriptional regulation of the rat P450c17 gene in both cell types. The region from -447/-399 or from -447/-419 increased both basal and cAMP-induced transcription, and the region from -418/-399 increased basal transcription to a greater extent than the intact -447/-399 DNA. The -447/-399 DNA sequence contains three imperfect copies of the orphan nuclear receptor-binding motif, AGGTCA, and at least three known orphan nuclear receptors, chicken ovalbumin upstream promoter transcription factor (COUP-TF), SF-1, and an early response gene induced by nerve growth factor (NGFI-B), bind to -447/-399 DNA. The AGGTCA triad is bound by one set of nuclear proteins when these three elements are colinear and is bound by a different set of proteins when these elements are separated. When the elements are separated, COUP-TF no longer binds, and the region -418/-399 is bound by a protein that greatly stimulates basal transcription. The region -447/-419 is bound by two different proteins that mediate both basal and cAMP-stimulated transcription. We call the protein binding to -418/-399 steroidogenic factor inducer of transcription-1 (StF-IT-1), and one of the proteins binding to -447/-419, StF-IT-2. SF-1 binds to a second AGGTCA element in the -447/-419 region. StF-IT-1 and StF-IT-2 are both found in Leydig and adrenal cells, and transcriptional regulation is similar in both cell types. SF-1 and NGF-IB may increase transcription by displacing COUP-TF (a transcriptional repressor) because these proteins share DNA-binding domains. However, neither SF-1 nor NGF-IB alone, binding as monomers, increases transcription. Rather, these proteins must interact with another DNA-binding protein, e.g. StF-IT-2, to increase transcription. StF-IT-2 also requires interaction with SF-1 (or NGF-IB) bound to DNA and cannot increase transcription by itself. This mechanism of action is different from the mechanism by which SF-1 regulates transcription from the -84/-55 region of the rat P450c17 gene. Thus, we have defined a novel mechanism of action for orphan nuclear receptors that bind to DNA as monomers.

Animals↗
PubMed1999

Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers.

Small heterodimer partner (SHP) is an orphan nuclear receptor that lacks a conventional DNA binding domain. It interacts with several other members of the nuclear receptor superfamily and inhibits receptor transactivation. In order to characterize the regulation of SHP expression, a number of receptors and other transcription factors were tested for effects on the SHP promoter. Among these, the orphan receptor steroidogenic factor-1 (SF-1) was found to potently transactivate the SHP promoter. Detailed footprinting studies show that the SHP promoter contains at least five SF-1 binding sites, and mutagenesis studies demonstrate each of the three strongest binding sites is required for SF-1 transactivation. SHP is coexpressed with SF-1 in adrenal glands, but is also expressed in tissues that lack SF-1, including liver. However, liver expresses a close relative of SF-1, the orphan fetoprotein transcription factor (FTF), and FTF can also transactivate the SHP promoter. These results suggest that alterations in the levels or activities of SF-1 or FTF could modulate SHP expression in appropriate tissues and thereby affect a variety of receptor dependent signaling pathways.

Binding Sites↗
PubMed2026

Identification and Classification of Expressed Orphan Genes, Spurious Orphan Genes, and Conserved Genes in the Human Gut Microbiome.

Orphan genes (OGs)-genes lacking detectable homologs outside a species-are widespread in microbial genomes and are thought to contribute to their adaptation and molecular innovation. However, not all predicted OGs may represent novel functional coding sequences. False positive OGs, also called spurious OGs, can arise from gene prediction errors. We reason that OGs lacking detectable expression are more likely to be spurious. To test this, we combined large-scale metatranscriptomic profiling of the human gut microbiome with machine learning to distinguish expressed OGs from spurious ones and compare them with conserved genes (CGs) found in multiple species. Using nearly 5,000 metatranscriptome libraries, we identified ∼218,000 OGs supported by expression evidence, while ∼330,000 predicted OGs lacked detectable expression and were classified as spurious. We extracted 154 features for sequence, structural, and evolutionary properties for each gene and trained XGBoost classifiers while accounting for genomic representation. The models achieved an area under the receiver operating characteristic curve (AUC) of 0.82 in distinguishing expressed OGs from spurious OGs and an AUC of 0.93 in distinguishing expressed OGs from CGs. Interpretation based on SHAP (SHapley Additive exPlanations) revealed clear biological signals. Particularly, expressed orphans were present in more genomes than spurious ones, and expressed OGs were shorter than CGs. This work improves OG discovery and suggests that expressed OGs differ systematically from CGs and spurious OGs in sequence composition, structural constraints, and evolutionary signals.

Humans↗
PubMed1992

Creating the costliest orphan. The Orphan Drug Act in the development of Ceredase.

The FDA recently approved Ceredase, a new treatment for Gaucher's disease, under the provisions of the Orphan Drug Act. Ceredase is unusually expensive, but there are no satisfactory alternative therapies. It appears likely that Ceredase would not have become available without the protection of the Orphan Drug Act, but its expense and the lack of information about its long-term effects on health raise questions about whether the ODA provides appropriate incentives to develop cost-effective technologies.

Adolescent↗
PubMed2001

Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner.

The orphan nuclear hormone receptor liver receptor homologous protein-1 (LRH-1; NR5A2, also known as FTF), an unusual receptor that binds DNA as a monomer, is an essential regulator of expression of a rate-limiting enzyme in bile acid formation, cholesterol 7-alpha-hydroxylase. In a classic negative feedback loop that is a crucial component of the complex regulation of cholesterol metabolism, cholesterol 7-alpha-hydroxylase expression is decreased when bile acid levels are high. This repression is thought to be based on the bile acid-dependent induction of expression of the orphan receptor small heterodimer partner (SHP) NR0B2, which inhibits the activity of LRH-1. We have explored the molecular basis for this important regulatory effect by characterizing the mechanisms by which mouse and human SHP inhibit LRH-1-mediated transactivation. Both SHP proteins specifically interact with the AF-2 transactivation domain of LRH-1 both in vivo and in vitro. This domain is a common target for coactivator interaction, and the SHP proteins can compete with p160 coactivators for binding to LRH-1. In addition to the N-terminal receptor interaction domain, SHP includes a C-terminal domain with autonomous repression function. Neither a deletion nor a point mutation specifically affecting this domain blocked the ability to interact with LRH-1 to compete for coactivator binding or to repress LRH-1 transactivation. However, the relative ability of these mutants to inhibit LRH-1-mediated transactivation was markedly decreased. We conclude that the proposed central role of SHP in cholesterol metabolism is based on a two-step mechanism that is dependent on both coactivator competition and direct transcriptional repression.

Animals↗
PubMed2001

Differential regulation of the orphan nuclear receptor small heterodimer partner (SHP) gene promoter by orphan nuclear receptor ERR isoforms.

The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHP promoter is also activated by the estrogen receptor-related receptor gamma (ERRgamma) but not the related ERRalpha and ERRbeta isoforms. SHP and ERRgamma mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRgamma transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRalpha and ERRbeta activity on this element indicating that the lack of activity of ERRalpha and -beta may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRgamma transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRgamma and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRgamma activity. Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs.

Base Sequence↗
PubMed2002

Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha.

The Rev-erb and retinoic acid-related orphan receptors (ROR) are two related families of orphan nuclear receptors that recognize similar response elements but have opposite effects on transcription. Recently, the Rev-erbalpha gene promoter has been characterized and shown to harbor a functional Rev-erbalpha-binding site known as Rev-DR2, responsible for negative feedback down-regulation of promoter activity by Rev-erbalpha itself. The present study aimed to investigate whether Rev-erbalpha gene expression is regulated by RORalpha. Gel shift analysis demonstrated that in vitro translated hRORalpha1 protein binds to the Rev-DR2 site, both as monomer and dimer. Chromatin immunoprecipitation assays demonstrated that binding of RORalpha to this site also occurred in vivo in human hepatoma HepG2 cells. The Rev-DR2 site was further shown to be functional as it conferred hRORalpha1 responsiveness to a heterologous promoter and to the natural human Rev-erbalpha gene promoter in these cells. Mutation of this site in the context of the natural Rev-erbalpha gene promoter abolished its activation by RORalpha, indicating that this site plays a key role in hRORalpha1 action. Finally, adenoviral overexpression of hRORalpha1 in HepG2 cells led to enhanced hRev-erbalpha mRNA accumulation, further confirming the physiological importance of RORalpha1 in the regulation of Rev-erbalpha expression.

Adenoviridae↗
PubMedDate not supplied

The Orphan Drug Act and the Federal Government's Orphan Products Development Program.

Through the combined efforts of agencies and organizations in the public and private sector, drugs have been made available that would not have been at hand without a specific focus on the orphan drug issue. It is anticipated that these cooperative efforts will continue beyond the first enthusiastic burst engendered by the inception of new and interesting activities.

Drug Industry↗
PubMed1999

Are orphans at increased risk of malnutrition in Malawi?

The objective of this study was to compare the nutritional status and health problems of village orphans, non-orphans and orphanage children, and to identify factors associated with undernutrition. A cross-sectional study was conducted in three orphanages and two villages near Blantyre, Malawi. Seventy-six orphanage children, 137 village orphans and 80 village non-orphans were recruited. Anthropometric measurement was done and guardians were interviewed. In the group of children aged < 5 years, the prevalence of undernutrition in orphanage children was 54.8% compared with 33.3% and 30% of village orphans and non-orphans, respectively. Sixty-four per cent of young orphanage children were stunted compared with 50% of village orphans and 46.4% of non-orphans. The mean (SD) Z-score of height/age was significantly lower in the orphanage group, -2.75 (1.29) compared with -2.20 (1.51) and -1.61 (1.57) in the village orphan and non-orphan groups (p < 0.05). Conversely, older orphanage children (> or = 5 years) were less stunted and wasted than orphans and non-orphans in villages. Illness of children in the last month was reported to be higher in the non-orphan group, especially diarrhoeal disease, which occurred in 30% compared with 10.8% of village orphans and 6.6% of orphanage children. More than three children in a family being cared for by guardians was significantly associated with undernutrition. Orphanage girls were more likely to be malnourished than orphanage boys. Children who had been admitted to an orphanage for more than a year were less malnourished. In village orphans, there was no association between undernutrition and duration of stay in extended families. Age and education of guardians were not associated with the nutritional status of children. We conclude that young orphanage children are more likely to be undernourished and more stunted than village children. Older orphanage children seem to have better nutrition than village orphans. There was no significant difference in nutritional status between village orphans and non-orphans.

Adolescent↗
PubMed1997

The US orphan drug programme 1983-1995.

The Orphan Drug Act has become a staple of food and drug law in the US. The experience with the US programme continues to serve as a useful reference point as interest in orphan drug incentive programmes expands globally. This article first reviews details of the legislation and orphan drug regulations, and then provides a 13-year overview (1983-1995) of orphan drug activity in the US, including descriptive data on the designated and approved orphan drugs, their indications and sponsors. In light of a recent challenge to the Food and Drug Administration's (FDA's) authority under the Act, we also examine the interplay between the exclusivity provision of the Act and the orphan drug regulations that define when 2 drugs will be considered the 'same' for the purposes of the Act. A recent court decision affirming the FDA's interpretation of the clinical superiority provisions of the regulations suggests that orphan exclusivity may be less predictable and less certain than it has been in the past. Finally, we consider the usefulness to orphan drug sponsors of other initiatives such as FDA's early access and fast-track approval programmes, and the extent to which the FDA's discretion to waive, defer and reduce prescription drug user fees has worked to the benefit of orphan drug sponsors. Over the 13-year analysis period, the FDA granted 631 orphan designations involving 450 different drugs, for which 121 FDA marketing approvals have been granted. Those with both treatment investigational drug designation and fast-track approval status appeared to benefit substantially from shorter development times. The indications targeted by the orphan drugs fall into 8 categories, with 40% of all orphan indications involving cancer and genetic diseases. Evident in the latter part of the analysis period is the increasing share of orphan activity attributable to biotechnology firms. Even though the Prescription Drug User Fee Act of 1992 did not recognise orphan status for the purpose of waiving or reducing the amount of fees payable, almost one-third (32%) of the $US 8,531,550 in user fee revenue foregone through waivers and reductions was attributable to orphan drugs.

Drug Approval↗