New Drugs for Rare Diseases in Children.

Clin Ther. 2017 Feb;39(2):246-252

Authors: Rose K

Abstract
PURPOSE: United States (US) Pediatric Legislation (PL) was introduced in 1997 to improve children's health. The European Union PL (EUPL) has been in force since 2007. Both PLs facilitate additional pediatric research on primarily adult drugs. The EUPL declares that the forces of the market are not sufficient for children. Without a pediatric investigation plan, new drugs can no longer be registered with the European Union. New ways on how to facilitate drug development for rare pediatric diseases are being proposed.
METHODS: US PL, EUPL, and implications of modern labels for medical decision making are discussed.
FINDINGS: Modern drug labels constituted a step from eminence-based towards data-based medical decision making. However, approval by regulatory authorities did not replace knowledge transfer in medicine, which continued in university education, through conferences, consensus papers, and so on. Children were successfully treated with off-label drugs in pediatric oncology and in many other diseases. Describing children as "therapeutic orphans" reflected an overestimation of drug labels and an underestimation of nonregulatory systematic clinical testing. Therapeutic breakthroughs have occurred, for example, in acute myelogenous leukemia and cystic fibrosis. Rare diseases need new innovative drugs and therapeutic concepts for further breakthroughs.
IMPLICATIONS: The focus of PL on additional pediatric measures for predominantly adult new drugs reflects a tunnel view. Similar to the introduction of modern pharmaceutical legislation that triggered comparable laws in most countries worldwide after 1962, we currently need new worldwide steps to reward innovative treatment concepts for rare diseases-not against, but through the market. Created by philanthropy, parents, and other supporters, new therapeutic concepts should be rewarded upon meeting regulatory milestones. This market is limited today. It needs not only a boost by pioneers, but also acceptance, welcome, and re-thinking about drug development in academia, politics, and by the general public.

PMID: 28161117 [PubMed - indexed for MEDLINE]

Clinical trial network for the promotion of clinical research for rare diseases in Japan: muscular dystrophy clinical trial network.

BMC Health Serv Res. 2016 Jul 11;16:241

Authors: Shimizu R, Ogata K, Tamaura A, Kimura E, Ohata M, Takeshita E, Nakamura H, Takeda S, Komaki H

Abstract
BACKGROUND: Duchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely "orphan drugs", have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases.
METHODS: To accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation.
RESULTS: Thirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time.
CONCLUSION: Counting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to an improvement of neuromuscular disease treatment in Japan.

PMID: 27401940 [PubMed - indexed for MEDLINE]

Heparanase: a rainbow pharmacological target associated to multiple pathologies including rare diseases.

Future Med Chem. 2016 Apr;8(6):647-80

Authors: Rivara S, Milazzo FM, Giannini G

Abstract
In recent years, heparanase has attracted considerable attention as a promising target for innovative pharmacological applications. Heparanase is a multifaceted protein endowed with enzymatic activity, as an endo-β-D-glucuronidase, and nonenzymatic functions. It is responsible for the cleavage of heparan sulfate side chains of proteoglycans, resulting in structural alterations of the extracellular matrix. Heparanase appears to be involved in major human diseases, from the most studied tumors to chronic inflammation, diabetic nephropathy, bone osteolysis, thrombosis and atherosclerosis, in addition to more recent investigation in various rare diseases. The present review provides an overview on heparanase, its biological role, inhibitors and possible clinical applications, covering the latest findings in these areas.

PMID: 27057774 [PubMed - indexed for MEDLINE]

The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.

Kidney Int. 2017 May;91(5):1243-1255

Authors: Palazzo V, Provenzano A, Becherucci F, Sansavini G, Mazzinghi B, Orlandini V, Giunti L, Roperto RM, Pantaleo M, Artuso R, Andreucci E, Bargiacchi S, Traficante G, Stagi S, Murer L, Benetti E, Emma F, Giordano M, Rivieri F, Colussi G, Penco S, Manfredini E, Caruso MR, Garavelli L, Andrulli S, Vergine G, Miglietti N, Mancini E, Malaventura C, Percesepe A, Grosso E, Materassi M, Romagnani P, Giglio S

Abstract
Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.

PMID: 28233610 [PubMed - indexed for MEDLINE]

Should we 'open the kimono' to release the results of rare autosomal aneuploidies following noninvasive prenatal whole genome sequencing?

Prenat Diagn. 2017 Feb;37(2):123-125

Authors: Bianchi DW

Abstract
The metaphor 'open kimono' has been applied in the business world to connote transparency via the release of all available data to an external party. Here, the author uses this term to discuss the relative advantages and disadvantages of reporting on the presence of rare autosomal aneuploidies detected by massively parallel sequencing of placental cell-free DNA in the plasma of pregnant women. Newly presented data sets from multiple laboratories suggest that autosomal aneuploidies such as trisomies 7, 15, 16, 22, and 8 are easily detectable and are potentially associated with fetal growth restriction, pregnancy loss, and maternal preeclampsia. Furthermore, they may explain false positive results for the common autosomal trisomies (13, 18, and 21) as well as test failures. Thus, release of this information may result in improved clinical utility. At the present time, however, professional societies in various parts of the world differ in their recommendations as to whether or not to release expanded autosomal aneuploidy results beyond the common trisomies. © 2016 John Wiley & Sons, Ltd.

PMID: 28010042 [PubMed - indexed for MEDLINE]

A case of multiple gastrointestinal stromal tumors caused by a germline KIT gene mutation (p.Leu576Pro).

Fam Cancer. 2017 Apr;16(2):267-270

Authors: Vale Rodrigues R, Santos F, Pereira da Silva J, Francisco I, Claro I, Albuquerque C, Lemos MM, Limbert M, Dias Pereira A

Abstract
Multiple gastrointestinal stromal tumors (GISTs) caused by germline KIT gene mutations are an extremely rare autosomal dominant disorder. We report a case of a 21-year-old woman who presented to the emergency department with a 2-week history of asthenia, palpitations and upper gastrointestinal bleeding. After further clinical evaluation one gastric and two small bowel GISTs were diagnosed, which were surgically resected after neoadjuvant therapy with Imatinib. Diffuse hyperplasia of the interstitial cells of Cajal was also seen in the background gastric and small intestinal walls. Somatic mutational analysis of the KIT gene revealed a substitution at codon 576 in exon 11 (p.Leu576Pro) in all tumors and normal ileal mucosa. The germline nature of this mutation was confirmed by mutation analysis in peripheral blood leukocytes. However, she had no familial history of GISTs and her parents did not carry the respective germline mutation.

PMID: 27771813 [PubMed - indexed for MEDLINE]

Alveolar Rhabdomyosarcoma of the foot metastasizing to the Iris: report of a rare case.

BMC Cancer. 2016 Jul 11;16:447

Authors: Fabian ID, Hildebrand GD, Wilson S, Foord T, Sagoo MS

Abstract
BACKGROUND: Intraocular iris rhabdomyosarcoma is extremely rare, and in the 3 cases reported to date occurred as the primary site of tumour growth. We report a case of rhabdomyosarcoma of the foot metastasizing to the iris.
CASE PRESENTATION: An 18-year-old white female was referred to the London Ocular Oncology Service for management of a metastatic rhabdomyosarcomatous deposit in the iris, a metastasis from alveolar rhabdomyosarcoma of the foot. She was diagnosed nearly 2 years earlier with the primary sarcoma with extensive systemic spread and treated by resection of the foot lesion and chemotherapy, and achieved a partial remission. The left iris deposit was noted while she was receiving systemic chemotherapy, heralding a relapse. However, anterior uveitis and raised intraocular pressure developed and she was referred to our service for further management. A left iris secondary rhabdomyosarcoma deposit was noticed and in addition a lacrimal gland mass, as indicated by ultrasound B scan of the eye and orbit. The patient was treated with external beam radiotherapy to the globe and orbit, but died 2 months after treatment completion.
CONCLUSION: Rhabdomyosarcoma of the iris is very rare and was previously documented only as a primary malignancy in this location. We report that secondary spread to the iris can also occur, in this case as the first sign of widely disseminated systemic relapse.

PMID: 27401166 [PubMed - indexed for MEDLINE]

Controversies and research agenda in nephropathic cystinosis: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

Kidney Int. 2016 Jun;89(6):1192-203

Authors: Langman CB, Barshop BA, Deschênes G, Emma F, Goodyer P, Lipkin G, Midgley JP, Ottolenghi C, Servais A, Soliman NA, Thoene JG, Levtchenko EN, Conference Participants

Abstract
Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

PMID: 27181776 [PubMed - indexed for MEDLINE]

Implementing the single institutional review board model in the undiagnosed diseases network.

Clin Transl Sci. 2017 Sep 25;:

Authors: Splinter K, Hull SC, Holm IA, McDonough TL, Wise AL, Ramoni RB, Members of the Undiagnosed Diseases Network

PMID: 28945957 [PubMed - as supplied by publisher]

Monogenic Hashimoto thyroiditis associated with a variant in the thyroglobulin (TG) gene.

J Autoimmun. 2017 Sep 21;:

Authors: Lo MS, Towne M, VanNoy GE, Brownstein CA, Lane AA, Chatila TA, Agrawal PB

Abstract
BACKGROUND: Risk of autoimmune thyroid disease (AITD) is strongly heritable. Multiple genes confer increased risk for AITD, but a monogenic origin has not yet been described. We studied a family with apparent autosomal dominant, early onset Hashimoto thyroiditis.
METHODS: The family was enrolled in an IRB-approved protocol. Whole exome sequencing was used to study the proband and an affected sibling. The identified variant was studied in other family members by Sanger sequencing.
RESULTS: We identified a previously unreported splice site variant in the thyroglobulin gene (TG c.1076-1G > C). This variant was confirmed in all affected family members who underwent testing, and also noted in one unaffected child. The variant is associated with exon 9 skipping, resulting in a novel in-frame variant transcript of TG.
CONCLUSION: We discovered a monogenic form of AITD associated with a splice site variant in the thyroglobulin gene. This finding raises questions about the origins of thyroid autoimmunity; possible explanations include increased immunogenicity of the mutated protein or thyroid toxicity with secondary development of anti-thyroid antibodies. Further study into the effects of this variant on thyroid function and thyroid autoimmunity are warranted.

PMID: 28942902 [PubMed - as supplied by publisher]

The Use of Social Media in Orphan Drug Development.

Clin Ther. 2017 Sep 20;:

Authors: Milne CP, Ni W

Abstract
Social media has transformed how people interact with one another through the Internet, and it has the potential to do the same for orphan drug development. Currently, social media influences the orphan drug development process in the following three ways: assisting the study of orphan diseases, increasing the awareness of orphan disease, and playing a vital role in clinical trials. However, there are some caveats to the utilization of social media, such as the need to protect patient privacy by adequately de-identifying personal health information, assuring consistent quality and representativeness of the data, and preventing the unblinding of patient group assignments. Social media has both potential for improving orphan drug development and pitfalls, but with proper oversight on the part of companies, support and participation of patients and their advocacy groups, and timely guidance from regulatory authorities, the positives outweigh the negatives for this powerful and patient-centric tool.

PMID: 28942336 [PubMed - as supplied by publisher]

Direct-to-Consumer Genetic Testing and Orphan Drug Development.

Genet Test Mol Biomarkers. 2017 Aug;21(8):456-463

Authors: Mason M, Levenson J, Quillin J

Abstract
Since the introduction of the Orphan Drug Act (ODA) in 1983, orphan drug approvals in the United States have jumped from <100 per decade to over 200 per year. This growth is widely attributed to the financial incentives the ODA gives to companies that develop these medicines, and it is likely to continue for a unique reason: partnerships between pharmaceutical firms and direct-to-consumer (DTC) genetic testing companies. This emerging trend is the subject of this article, which begins by considering how rare-disease drugs are regulated and the rising interest in nonclinical genetic testing. It then outlines how DTC companies analyze DNA and how their techniques benefit researchers and drug developers. Then, after an overview of the current partnerships between DTCs and drug developers, it examines concerns about privacy and cost brought up by these partnerships. The article concludes by contrasting the enormous positive potential of DTC-pharma relationships and their concomitant dangers, especially to consumer privacy and cost to the healthcare system.

PMID: 28696792 [PubMed - indexed for MEDLINE]

[Neuroendocrine prostate cancer: Natural history, molecular features, therapeutic management and future directions].

Bull Cancer. 2017 Sep;104(9):789-799

Authors: Campedel L, Kossaï M, Blanc-Durand P, Rouprêt M, Seisen T, Compérat E, Spano JP, Malouf G

Abstract
Neuroendocrine prostate cancer is a rare malignancy with a an adverse prognostic. Histologically, It can be pure (small cells or large cells neuroendocrine carcinoma) or mixed with a adenocarcinoma component. Rarely diagnosed de novo, neuroendocrine prostate cancer is generally associated with advanced stage disease resistant to castration. As such, this histological subtype could represent an aggressive evolution of prostatic adenocarcinoma, through the epithelio-neuroendocrine transdifferentiation mechanism (phenomenon of lineage plasticity). Nonetheless, neuroendocrine prostate cancer is a heterogeneous malignancy with multiple histopathological variants showing distinct clinical features. The broad variety of molecular analyses could help to understand the ontogeny of this histological subtype and its signaling pathways. This may also allow identifying diagnostic and prognostic biomarkers as well as potential molecular targets. However, treatment options are currently limited and consist only in platinium-based chemotherapy for advanced stage disease.

PMID: 28673439 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/09/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Alzheimer's disease from Auguste Deter to the present : Progress, disappointments and open questions].

Z Gerontol Geriatr. 2017 Sep 18;:

Authors: Pantel J

Abstract
AIM: The present article aims to provide a short overview of the discovery history, conceptual development, as well as on current neurobiological and pharmacological research questions in the field of Alzheimer's disease (AD). In view of the long hoped for but so far unachieved therapeutic breakthrough, this also includes a critical reflection of current research paradigms.
MATERIAL AND METHODS: Starting from the first case report described by Alois Alzheimer in 1906, the historical impact of his seminal discovery is reconstructed. Neurobiological research paradigms central to AD are discussed with respect to their relevance for modern biomarker-based diagnostic approaches as well as to the development of innovative disease-modifying drug therapies.
RESULTS: Originally conceived as a rare presenile form of dementia it was not until the 1970s that AD was granted an orphan disease status. The biomedical deconstruction of senility and the introduction of new research methods enabled the nosological unification of AD with the concept of senile dementia which, in turn led to a global flowering of AD research. In the 1990s the amyloid cascade hypothesis was introduced as the leading research paradigm of AD. In the following years this stimulated the development of a huge variety of innovative biomarker-based diagnostic and disease-modifying pharmacological approaches.
CONCLUSION: Against the background of the recent failures of many clinical drug trials, the relevance of the amyloid cascade hypothesis to explain the etiology of sporadic AD is increasingly being questioned. On the one hand, this leaves the question of the central etiological paradigm unresolved and on the other hand it stimulated a debate on alternative etiological models which might lead to fruitful consequences for future research strategies.

PMID: 28924872 [PubMed - as supplied by publisher]

Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.

Lancet Oncol. 2017 Aug;18(8):1022-1039

Authors: Gatta G, Capocaccia R, Botta L, Mallone S, De Angelis R, Ardanaz E, Comber H, Dimitrova N, Leinonen MK, Siesling S, van der Zwan JM, Van Eycken L, Visser O, Žakelj MP, Anderson LA, Bella F, Kaire I, Otter R, Stiller CA, Trama A, RARECAREnet working group

Abstract
BACKGROUND: Rare cancers pose challenges for diagnosis, treatments, and clinical decision making. Information about rare cancers is scant. The RARECARE project defined rare cancers as those with an annual incidence of less than six per 100 000 people in European Union (EU). We updated the estimates of the burden of rare cancers in Europe, their time trends in incidence and survival, and provide information about centralisation of treatments in seven European countries.
METHODS: We analysed data from 94 cancer registries for more than 2 million rare cancer diagnoses, to estimate European incidence and survival in 2000-07 and the corresponding time trends during 1995-2007. Incidence was calculated as the number of new cases divided by the corresponding total person-years in the population. 5-year relative survival was calculated by the Ederer-2 method. Seven registries (Belgium, Bulgaria, Finland, Ireland, the Netherlands, Slovenia, and the Navarra region in Spain) provided additional data for hospitals treating about 220 000 cases diagnosed in 2000-07. We also calculated hospital volume admission as the number of treatments provided by each hospital rare cancer group sharing the same referral pattern.
FINDINGS: Rare cancers accounted for 24% of all cancers diagnosed in the EU during 2000-07. The overall incidence rose annually by 0.5% (99·8% CI 0·3-0·8). 5-year relative survival for all rare cancers was 48·5% (95% CI 48·4 to 48·6), compared with 63·4% (95% CI 63·3 to 63·4) for all common cancers. 5-year relative survival increased (overall 2·9%, 95% CI 2·7 to 3·2), from 1999-2001 to 2007-09, and for most rare cancers, with the largest increases for haematological tumours and sarcomas. The amount of centralisation of rare cancer treatment varied widely between cancers and between countries. The Netherlands and Slovenia had the highest treatment volumes.
INTERPRETATION: Our study benefits from the largest pool of population-based registries to estimate incidence and survival of about 200 rare cancers. Incidence trends can be explained by changes in known risk factors, improved diagnosis, and registration problems. Survival could be improved by early diagnosis, new treatments, and improved case management. The centralisation of treatment could be improved in the seven European countries we studied.
FUNDING: The European Commission (Chafea).

PMID: 28687376 [PubMed - indexed for MEDLINE]

Congenital inverse Duane's retraction syndrome: A rare presentation.

Indian J Ophthalmol. 2017 May;65(5):422-423

Authors: Agarkar S, Kaduskar A

Abstract
A 12-year-old girl presented with esotropia and face turn since birth. Ocular motility examination showed restricted abduction associated with down shoot and retraction on attempted abduction characteristic of inverse Duane's retraction syndrome. To the best of our knowledge, this is one of the very few reported cases of congenital inverse Duane's retraction syndrome.

PMID: 28574005 [PubMed - indexed for MEDLINE]

A case report on a very rare variant of popliteal artery entrapment syndrome due to an enlarged fabella associated with severe knee osteoarthritis.

J Orthop Sci. 2017 Jan;22(1):164-168

Authors: Ando Y, Miyamoto Y, Tokimura F, Nakazawa T, Hamaji H, Kanetaka M, Koshiishi A, Hirabayashi K, Anamizu Y, Miyazaki T

PMID: 26740435 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/09/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/09/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.