22 November 2014 print
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The final report on the first European Reference Networks conference is now available

According to Directive 2011/24/EU on the application of patients' rights in cross-border healthcare, the establishment of a system of European Reference Networks is crucial to provide expertise for high quality and affordable treatment to patients in Europe. The establishment of European Reference Networks is especially significant and momentous for rare disease patients across Europe as they will now have the possibility to access resources that may not be available within the confines of their countries. The establishment of ERNs also require a great deal of cooperative and collaborative effort across Europe. The legal framework was put into action on 27 May 2014 by the Commission, DG SANCO organised a conference on European Reference Network on 23rd of June in Brussels to address the organisation of these specialised networks where several eminent stakeholders gathered to devise, deliberate and prepare for the present and future of European Reference Networks and address the forthcoming call for European Reference Networks in 2015.

Whilst OrphaNews has previously reported on the highlights of the conference, the final version of conference report published by the Commission is now online.

The report outlines the central points made during the presentations of the Plenary session illustrating the importance of communication and networking for optimal healthcare outcomes. The roundtable on “Framework for the Establishment of ERNs” discussed in detail the current undertakings of the European Reference Networks and its future. The presenters also impressed upon the significance of collaboration and sharing of expertise, as well as to provide high quality healthcare for patients. During one of the Breakout sessions the views of stakeholders on European Reference Networks for rare and complex diseases was presented. The presenters provided crucial information that will assist in the appropriate organisation and harmonisation of European Reference Networks to provide access to expert resources for rare disease patients in Europe. Challenges and accomplishments of networking were shared by Expo-R-Net, E-PILEPSY Network and ENERCA.

From the conference it was clear that while sustainability and inclusiveness of European Reference Networks will be challenging, augmenting collaboration and cooperation among the European states will advance and synchronize healthcare standards for rare diseases, as intended by the cross-border healthcare directive. As expertise in highly specialised healthcare is scattered, a system coordinated at the European level, such as the European Reference Network is a fundamental necessity for rare disease patients and the way forward for European healthcare.
Read about the conference in OrphaNews
Read the conference report by the Commission

Spotlight on...
A combination of cysteamine and epigallocatechin gallate seems to restore the CFTR function in a mouse model of Cystic Fibrosis
Cystic fibrosis transmembrane conductance regulator (CFTR) repairing strategies are an emerging option in Cystic Fibrosis (CF) therapy as it addresses the primary cause of CF, namely the loss-of-function of CFTR. The authors of a study published in Autophagy investigated whether the oral administration of cysteamine and epigallocatechin gallate (EGCG), a green tea flavonoid – readily available compounds that the authors had anticipated would rescue CFTR function - in a mouse model of CF which has an F508del mutation in CFTR, would improve CF symptoms in these mice.

The authors demonstrated highly promising results in the mouse model and are testing the clinical efficacy of these compounds in CF patients homozygous for the F508del mutation. This endeavor has been an entirely academia driven exercise and may summon a new era of orphan drug discovery. OrphaNews spoke to the researchers who are involved in crafting this treatment approach

Member of the research team - Dr. Valeria Raia
Could you describe the Cystic fibrosis treatment approach that you have developed? We have developed and applied a totally new approach that restores the function of the most common disease causing mutation, the F508-CFTR by restoring defective autophagy in CF airways. This provides hope without hype.

How is it different from other therapies that are currently available for CF patients?
Current therapies for CF include digestive enzymes, mucolytics and antibiotics (to reduce the symptoms of CF lung disease) whereas new approaches target defective CFTR in a mutation specific manner. CFTR modulators include (1) channel potentiators to improve ion transport (class III mutations), (2) correctors to improve abnormal CFTR protein folding and its trafficking (class II mutations) and (3) stop codon mutation read-through drugs relevant for patients with premature stop codons (most class I mutations) as recently reviewed by Amaral (J Intern Med. 2014 29. doi: 10.1111/joim.12314). In total contrast, our approach focuses on rescuing CFTR function, by restoring the deranged intracellular environment of CF cells through which the defective mutated protein has to navigate to reach its correct location at the surface of the cell. Our approach sweeps the cell clean of its littered debris, left scattered by defective autophagy.
Member of the research team - Dr. Guido Kroemer
How did you discover this treatment?
We previously reported (Luciani et al Nat Cell Biol. 2010;12 (9):863-75. doi: 10.1038/ncb2090) that defective CFTR in the airways of CF patients induces upregulation firstly, of damaging free radicals ‘reactive oxygen species (or ROS) and secondly, a protein ‘spot-welder’ tissue transglutaminase (TG2). This, in turn, drives the crosslinking of an important regulatory protein beclin 1, leading to sequestration of a cell controller, phosphatidylinositol-3-kinase (PI(3)K) complex III, finally leading to defective autophagy and accumulation of p62 which normally regulates ‘aggresome’ formation (a cellular garbage bin). Our recent data demonstrate that a simple molecule known for decades (cystamine and/or its reduced form cysteamine), by inhibiting TG2, acts as a cell restorer (proteostasis regulator) and can rescue and stabilize ΔF508-CFTR at the plasma membrane, through restoring defective autophagy in CF airways (Luciani et al Autophagy. 2012;8(11):1657-72.; Villella et al Cell Death Differ. 2013;20(8):1101-15; Villella et al Autophagy. 2013;9(9):1431-4). Furthermore, we selected the green tea-derived flavonoid epigallocatechin gallate (EGCG) on the basis of its ability to modulate the activity of one particular Ser/Thr kinase, CSNK2, a "master protein kinase” involved in the proteolytic degradation of CFTR F508 at the plasma membrane (Venerando A et al, PLoS One. 2013 18;8(9); Tosoni K et al, Biochem J 2013 1;449(1):295-305). This combined radically alternative approach allows EGCG to sustain F508del-CFTR function beyond cysteamine washout as determined by many assays.
Member of the research team - Dr. Anil Mehta
Who does your multinational team consist of?
Pediatricians, cell biologists, pharmacologists, otorhinolaryngologists, immunologists, statisticians, engineers and biochemists.

What are the benefits of this international collaboration?
The research groups amalgamate leading experts with unique but complementary expertise in cell biology, autophagy, proteostasis regulation, biochemistry, immunology, statistics and clinical aspects of CF. This is a well-balanced group of research partners that provide the complementary expertise required to carry out the research goals. The partnership has been designed to use resources and strengths from each participating faculty providing the best research networking opportunities available, delivered by leaders in their fields, from both research and clinical academia. A perfect integration and sharing of know-how allowed each partner to brings their own solutions, techniques and experience and crucially, funding. These experts have already been involved in previous CF research efforts achieving noteworthy.

Can you mention some of the challenges you faced during the development of this treatment approach?
Our ambition aimed at translating our basic research into a pragmatic clinical approach. We wished to identify a new option for treatment of CF patients by a combinatory treatment targeting different disease-relevant pathogenic steps, allowing a bottom-up pathogenic-based drug discovery strategy for CF. We also targeted pathogenic-based biomarkers of efficacy of CF therapy, whilst assessing markers of autophagy, CFTR function and inflammatory cytokines in freshly isolated primary nasal cells in order to obtain a priceless practical tool to predict treatment efficacy in a given CF patient.
Member of the research team - Prof. Luigi Maiuri
In what way does your work impact Cystic fibrosis patients around the world?
We believe that since our experience is based on a pilot clinical trial we cannot give a definitive answer at the present time. However, we hypothesize that patients might have a better quality of life, given that this approach is not just symptomatic alleviation. In addition, the compounds we propose for such a new therapeutic approach are already commercially available. Thus, this combined treatment is not prohibitive in predicted costs, even for a developing nation. Rescuing and keeping CFTR protein function ‘alive’ could impact on the longer-term clinical effects contributing to ameliorating the quality of life of these patients.

Does your work contribute to the goals of IRDiRC? How?
Yes it does contribute to the goals of IRDiRC by boosting translational, preclinical and clinical research with a candidate therapy.

What advice would you provide to other researchers and pharmaceuticals who are working on developing treatments for rare disease patients?
We suggest to identify the molecular mechanisms that constitute the milestones of a clinical manifestation. Translational research needs, in addition, a cooperative group of several types of researchers with complementary skills. We strongly support the idea to start this experience with a small pilot clinical trial, having in this manner the possibility of efficiently harnessing the feedback from the patients in terms of acceptability safety and efficacy. Our patients are our teachers.
Consult the Pubmed abstract of their paper published in Autophagy


National & International Policy Developments
Other European news
Atlantic Bio GMP: the first pharmaceutical company to acquire public status in France
Atlantic Bio GMP (ABG) is a public based GMP facility dedicated to the manufacturing and the quality control of advanced therapy medicinal products (ATMPs) such as gene therapy and cell therapy. It is also now the first pharmaceutical company to obtain public status in France. Placed under the operational management of the French Blood Establishment (EFS) Pays de la Loire and under the common governance EFS, Inserm, the AFM Telethon and the University Hospital of Nantes, its goal is to offer research teams the ability to produce advanced therapy medicinal products for Phase I and II clinical trials by adhering to the highest quality and safety standards. They work in accordance with current regulations and cost constraints, which is consistent with the public service mission of the EFS. The authorisation of ABG as a public entity is a key step in its development, as it has been already working alongside French and European teams in research projects oriented towards gene and cell therapy to produce innovative medicines and are at the cutting edge of science. They are currently developing strategies to formulate gene therapies for genetic retinal disease, neuromuscular diseases and disorders affecting the central nervous system.
Visit the Atlantic Bio GMP website

Strategy paper published by Health Technology Assessment Network for EU

Health Technology Assessment (HTA), supported by the Joint Action EUnetHTA, provides evidence-based information and analysis, which can be instrumental in helping decision-makers achieve sustainable healthcare systems as well as promote innovative healthcare options to patients. A paper drafted by the Network, sets out the strategic vision of HTA, which highlights cooperation as the cornerstone for better assessment and reimbursement of healthcare in Europe. Also unveiled in the paper is the strategy to help HTA secure long-term sustainability. According to the paper, HTA fully appreciates and respects the autonomy of individual states but also impresses upon the importance of stakeholders to take an active collaborative role with regards to HTA activities in EU. The strategy delineates the importance of broad cooperation and considers that cooperation at EU level should encompass the full life cycle of health technologies from early scientific advice phase until the technology is more established. Along with pharmaceuticals and medical devices, the strategy hopes for cooperation on a wide range of technology that will enhance healthcare. The paper notes that for rare conditions, paediatric medicines or advanced therapies, the added value of EU cooperation is likely to be even greater. For better outcomes the paper calls upon HTA bodies to reuse joint work, synergise knowledge as well as acknowledge the importance of stakeholders’ involvement in HTA processes at European, national and regional level. HTA also addresses EU’s role in international cooperation by welcoming input from the WHO, and calls for the European Commission to include HTA as part of the “EU Health strategy for Developing Countries”.
Read the strategy paper

Other International News
Cancer Research Australia audit reveals rare cancer research has been short-changed
Cancer Research in Australia recently published a document that accounts for the funding that cancer research has received from 2006 to 2011, in Australia. This document reveals findings of an audit that the Australian government performed in order to understand how future demands for funding in cancer should be allotted. The audit showed that there is rare cancers do not receive adequate funding as compared to common cancers in Australia. This has also been highlighted in an article published in The Lancet. According to the audit, between 2006 and 2011 more than AUS$1 billion was allotted to researching the aetiology and treatment approaches for cancer, 91% of which was granted to researchers studying common cancers, even though the mortality rate for rare cancers was around 30% for patients suffering from rare cancers in 2012. However, it is believed that the governmental funding agencies will take this report into account while making future cancer research investment and refurbish its focus.
Read the report by Cancer Research Australia

Access the article published in The Lancet

Guidance Documents and Recommendations
AL amyloidosis: guidelines on the diagnosis, investigation and management
Consult the Pubmed abstracts
To read more about "AL amyloidosis"

Br J Haematol. ; [Epub ahead of print] ; October 2014
Limb-girdle and distal dystrophies: guidelines on the diagnosis and treatment
Consult the Pubmed abstract
To read more about "Limb-girdle muscular dystrophy"
To read more about "Distal myopathy"
To read more about "Myofibrillar myopathy"

Neurology ; 83(16):1453-63 ; October 2014
Bioinformatics, Registries and Data Management
Genetic diagnoses for patients with neuromuscular disease is hard to come by in New Zealand

The New Zealand Neuromuscular Disease Registry (NZ NMD Registry) has published an article in the Journal of Clinical Neuroscience describing the levels and the rate of molecular diagnosis that patients suffering from neuromuscular disorders receive. NZ NMD Registry, supported by the Muscular Dystrophy Association of New Zealand and part of the TREAT NMD Alliance, enrols patients with all neuromuscular conditions. The registry provides relevant information to both researchers and patients by helping them recruit for clinical trials as well as find existing clinical trials respectively, thus providing a platform for furthering the development of new and cutting edge therapies for neuromuscular patients.

After a careful examination of the data of 456 patients in their registry the authors found an important, albeit disturbing information regarding rate of molecular diagnosis of NMD patients. According to them, only 51% of the patients enrolled have a confirmed molecular genetic diagnosis, where patients suffering from Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease had the lowest frequency of diagnosis while patients with spinocerebellar ataxia, Duchenne Muscular Dystrophy and Spinal Muscular Atrophy had more luck with diagnosis. The authors believe that, apart from the fact that the conditions that caused by multiple genes (such as limb girdle muscular dystrophy and Charcot-Marie-Tooth disease) is more difficult and expensive to diagnose, scarcity in diagnosis may also be because of the clinicians attitude towards testing. The authors believe that the clinicians may be unaware of tests or may not recommend it if there are no at-risk family members. The authors emphasise that following the current guildelines for testing in New Zealand, which recommend testing if there are at-risk family members or if it significantly alters the patient’s management or options but not for participation for research or clinical trials, makes it more complicated for patients to get a confirmed diagnosis. Finally the authors observe that “patient demand coupled with greater collaboration between geneticists and neurologists, as well as greater subspecialty expertise, is likely to promote confidence and an increase in genetic diagnosis”.
Consult the abstract

Screening and Testing
Universal tumor-screening for Lynch Syndrome influences patient follow-through
Genetics in Medicine has recently published an article describing how universal tumour screening (UTS) implementation for colorectal cancer patients, which can improve the identification of Lynch syndrome, is very efficient in influencing patient follow–through. The authors wanted to explore the challenges and facilitators to UTS adoption as well as develop a model to explain varying levels of patient follow-through with germ-line testing across institutions. From the results obtained the authors proposed a model for efficient patient follow through, recommending streamlined UTS procedures, a high level of involvement of genetic counsellors in various UTS procedures, and provided methods for overcoming barriers to patient contact and for facilitating follow-up. The current study provides compelling evidence that tumour-screening implementation influences patient follow-through.
Consult the Pubmed abstract

Lymphangioleiomyomatosis requires more stringent surveillance
A study published in Orphanet Journal of Rare Diseases attempted to understand the growth and incidence of bleeding in patients with sporadic Lymphangioleiomyomatosis (LAM) by examining the natural history of angiomyolipoma in a large cohort of patients, so as to develop better screening protocols for these tumours. They showed that angiomyolipomas are present in half of patients with sporadic LAM, can present at any time during the clinical course and are prone to growth and haemorrhage. The authors advocate all patients to be screened for angiomyolipoma at diagnosis of lung disease by MRI scanning and their tumours require continuous monitoring, which is an approach that is more stringent than what is recommended by the current guidelines.
Read the Open Access article


Ethical, Legal & Social Issues
Mothers of children with rare disease go online to combat their sorrow
Journal of Pediatric Nursing has published a study analysing how families affected by rare diseases use online communications to manage the extremely difficult and emotional journey. The authors note that the isolating nature of rare disease and the unfamiliarity of many healthcare providers complicate the management of the condition and psychosocial experiences make mothers, who are more likely to search the internet for health related information, use online support groups. In this study the authors interviewed mothers of children with Alagille syndrome to understand how they used online health communications to manage their chronic sorrow. They found that not only did online communication impact the emotional state of these mothers but also provided them knowledge to manage the disease and educate others, including healthcare providers. The authors report that the mothers appreciated being part of the online community and meeting others in similar circumstances but did acknowledge that it sometimes triggered unpleasant feelings or chronic sorrow and sometimes faced an information overload. Overall, the authors believe that it is important to understand how mothers seek online avenues to ease their sorrow, even though it was sometimes painful.
Consult the Pubmed abstract

BioPontis Alliance attempts to bring treatments for rare diseases by building collaborations

BioPontis Alliance is a philanthropic organisation that aims to help bring more treatments for rare diseases to the fore by serving to build profitable partnerships and collaborations between patient organisations and academic researchers to identify and help carry forward research that they believe has promise to become a treatment for rare disease patients. According to them, the candidate “treatment” could “be licensed, spun off for private investors or developed by BioPontis Alliance”. They are currently raising $2 million to develop a treatment for a rare neurological disease research project. Led by people with experience in industry, regulatory, research and patient organisation, the alliance is currently inviting corporate, private and foundation philanthropic support.
Go to the Biopontis Alliance


New Syndromes

Novel cohesinopathy affecting heart and gut rhythm termed CAID syndrome caused by SGOL1 mutation in 17 subjects
The authors described a new syndrome characterized by chronic atrial and intestinal dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Sweden. They showed that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome.
Consult the Pubmed abstract
Consult the blog article

Nat Genet. ; 46(11):1245-9 ; November 2014
Early onset hepatocellular carcinoma and genomic instability due to mutations in SPRTN in three patients
The authors identified biallelic germline mutations in SPRTN in three patients from two unrelated families. All three patients were affected by a new syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma.
Consult the Pubmed abstract

Nat Genet. ; 46(11):1239-44 ; November 2014
Undescribed autosomal recessive lethal fetal ciliopathy phenotype associated with biallelic inactivating mutations in KIF14 in one family
The authors identified an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction, severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not similar to any known condition. Novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype were identified.
Consult the Pubmed abstract

Clin Genet. ; 86(3):220-8 ; September 2014

New Genes

Laurin-Sandrow syndrome is associated with microduplications encompassing the Sonic hedgehog limb enhancer ZRS in three unrelated families
Consult the Pubmed abstract
To read more about "Laurin-Sandrow syndrome"

Clin Genet. ; 86(4):318-25 ; October 2014
Epileptic encephalopathy due to de novo mutations in KCNB1
Consult the Pubmed abstract
Ann Neurol. ; 76(4):529-40 ; October 2014
Autosomal recessive and autosomal dominant intellectual disability: ELP2 and ZNF238 confirmed as causal genes
Consult the Pubmed abstract
Ann Neurol. ; 76(4):473-83 ; October 2014
Familial amyotrophic lateral sclerosis associated with mutations in CHCHD10
Consult the Pubmed abstracts
To read more about "Amyotrophic lateral sclerosis"

Brain ; awu227. [Epub ahead of print] ; August 2014
Brain ; awu265. [Epub ahead of print] ; September 2014
Autosomal dominant mitochondrial myopathy due to a double-missense mutation in CHCHD10 in a Puerto Rican kindred
Consult the Pubmed abstract
To read more about "Mitochondrial myopathy"

Neurogenetics ; [Epub ahead of print] ; September 2014
Autosomal dominant Charcot-Marie-Tooth disease type 2 caused by a novel mutation in VCP in a family
Consult the Pubmed abstract
To read more about "Autosomal dominant Charcot-Marie-Tooth disease type 2"

Brain ; 137(Pt 11):2897-902 ; November 2014
Autosomal recessive axonal Charcot-Marie-Tooth disease type 2 associated with a homozygous missense mutation in HSJ1 in a family
Consult the Pubmed abstract
To read more about "Autosomal recessive axonal Charcot-Marie-Tooth disease type 2"

Neurology ; 83(19):1726-32 ; November 2014
Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations
Consult the Pubmed abstract
To read more about "Centronuclear myopathy"

Brain ; [Epub ahead of print] ; September 2014
Nemaline myopathy caused by homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families
Consult the Pubmed abstract
To read more about "Nemaline myopathy"

J Clin Invest. ; 124(11):4693-708 ; November 2014
X-linked syndromic disorder hallmarked by microcephaly, growth retardation and seizures associated with a novel missense mutation in RPL10 in a multigenerational pedigree
Consult the Pubmed abstract
Genetics ; 198(2):723-33 ; October 2014

Research in Action

Clinical Research
Amyotrophic lateral sclerosis: ceftriaxone, a β-lactam antibiotic, did not show clinical efficacy
Consult the Pubmed abstract
To read more about "Amyotrophic lateral sclerosis"

Lancet Neurol. ; 13(11):1083-91 ; November 2014
Friedreich ataxia: in patients with less severe disease, deferiprone 20mg/kg/day may reduce disease progression, whereas higher doses appear to worsen ataxia
Consult the Pubmed abstract

To read more about "Friedreich ataxia"

Ann Neurol. ; 76(4):509-21 ; October 2014
Friedreich ataxia: proof of concept for the development of an epigenetic therapy
Consult the Pubmed abstract
To read more about "Friedreich ataxia"

Ann Neurol. ; 76(4):489-508 ; October 2014
Duchenne/Becker muscular dystrophy: sildenafil, a phosphodiesterase 5 inhibitor, does not improve cardiomyopathy
Consult the Pubmed abstracts
To read more about "Duchenne and Becker muscular dystrophy"
To read more about "Duchenne muscular dystrophy"
To read more about "Becker muscular dystrophy"

Ann Neurol. ; 76(4):541-9, 550-7 ; October 2014
X-linked severe combined immunodeficiency: interim results of parallel trials in nine boys with SCID-X1 showed that a self-inactivating γ-retrovirus vector retained efficacy
Consult the Pubmed abstract
Consult this study on Orphanet
Consult this study on Orphanet

To read more about "T-B+ severe combined immunodeficiency due to gamma chain deficiency"

J Clin Endocrinol Metab. ; 99(10):3644-52 ; October 2014
Acute lymphoblastic leukemia: chimeric antigen receptor T cells (CTL019) associated with sustained remissions
Consult the Pubmed abstract
To read more about "Acute lymphoblastic leukemia"

N Engl J Med. ; 371(16):1507-17 ; October 2014
Stiff person syndrome: autologous hematopoietic stem cell transplantation as a novel therapy
Consult the Pubmed abstract
To read more about "Stiff person syndrome"

JAMA Neurol. ; 71(10):1296-9 ; October 2014
Therapeutic Approaches

Primary hyperoxaluria type 1: pharmacologic rescue of an enzyme-trafficking defect with dequalinium chloride in a cellular model system
Consult the Pubmed abstract
To read more about "Primary hyperoxaluria type 1"

Proc Natl Acad Sci U S A. ; 111(40):14406-11 ; October 2014
Mucopolysaccharidosis type IIIb: delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic
Consult the Pubmed abstract
To read more about "Mucopolysaccharidosis type 3"

Proc Natl Acad Sci U S A. ; 111(41):14870-5 ; October 2014
Mucopolysaccharidosis type I: liver-directed gene therapy corrects cardiovascular lesions in cats
Consult the Pubmed abstract
To read more about "Mucopolysaccharidosis type 1"

Proc Natl Acad Sci U S A. ; 111(41):14894-9 ; October 2014
Duchenne muscular dystrophy: regulatory T cells suppress muscle inflammation and injury in mdx mice
Consult the Pubmed abstract
To read more about "Duchenne muscular dystrophy"

Sci Transl Med. ; 6(258):258ra142 ; October 2014
Autosomal dominant spastic paraplegia type 3: pharmacologic rescue of axon growth defects in a human induced pluripotent stem cells model
Consult the Pubmed abstract
To read more about "Autosomal dominant spastic paraplegia type 3"

Hum Mol Genet. ; 23(21):5638-48 ; November 2014
Diagnostic Approaches

Sickle cell anemia: density-based separation in multiphase system provides a simple method to identify the disease in low-resource areas
Consult the Pubmed abstract
To read more about "Sickle cell anemia"

Proc Natl Acad Sci U S A. ; 111(41):14864-9 ; October 2014

Patient Management and Therapy
Immunoglobulin A vasculitis in children: a review
Consult the Pubmed abstract
To read more about "Immunoglobulin A vasculitis"

Nat Rev Nephrol. ; 10(10):563-573 ; October 2014
Epilepsy surgery in children and adults: a review
Consult the Pubmed abstract
Lancet Neurol. ; 13(11):1114-1126 ; November 2014
Ovarian cancer: a review
Consult the Pubmed abstract
Lancet ; 384(9951):1376-88 ; October 2014
Ovarian teratoma-associated anti-NMDAR encephalitis: a systematic review of reported cases
Lire le résumé
To read more about "Limbic encephalitis with NMDA receptor antibodies"
To read more about "Malignant teratoma of ovary"

Orphanet J Rare Dis. ; 9(1):157 ; October 2014
Adult-onset mendelian progressive external ophthalmoplegia associated with mitochondrial disease: a review
Lire le résumé
To read more about "Autosomal dominant progressive external ophthalmoplegia"
To read more about "Autosomal recessive progressive external ophthalmoplegia"
To read more about "Mitochondrial disease with eye involvement"

J Neurol. ; 255(9):1384-91 ; September 2008
Cystic fibrosis: reviews on appetite stimulants, gastric acidity, airway clearance, antioxidant supplementation, self-management education and pneumococcal vaccines
Consult the Pubmed abstracts
To read more about "Cystic fibrosis"

Cochrane Database Syst Rev. ; 7:CD003424, 7:CD006842, 8:CD007020, 9:CD007641, 8:CD008865 ; July 2014, August 2014, September 2014
Osteogenesis imperfecta: updated review on bisphosphonate therapy
Consult the Pubmed abstract
To read more about "Osteogenesis imperfecta"

Cochrane Database Syst Rev. ; 7:CD005088 ; July 2014
Sickle cell anemia: two reviews on the treatment for avascular necrosis of bone and for inhaled bronchodilators for acute chest syndrome
Consult the Pubmed abstracts
To read more about "Sickle cell anemia"

Cochrane Database Syst Rev. ; 7:CD004344, 8:CD003733 ; July 2014, August 2014
High-grade glioma: review on antiangiogenic therapy
Consult the Pubmed abstract
To read more about "High-grade astrocytoma"
To read more about "Glioblastoma"

Cochrane Database Syst Rev. ; 9:CD008218 ; September 2014
Craniopharyngioma in children: updated review on intracystic bleomycin
Consult the Pubmed abstract
To read more about "Craniopharyngioma"

Cochrane Database Syst Rev. ; 9:CD008890 ; September 2014
Updated review on the evaluation of follow-up strategies for patients with epithelial ovarian cancer following completion of primary treatment
Consult the Pubmed abstract
Cochrane Database Syst Rev. ; 9:CD006119 ; September 2014
Rolandic epilepsy: comparison of antiepileptic drugs, no treatment, or placebo for children
Consult the Pubmed abstract
To read more about "Rolandic epilepsy"

Cochrane Database Syst Rev. ; 9:CD006779 ; September 2014
PFAPA syndrome: updated review on tonsillectomy
Consult the Pubmed abstract
To read more about "PFAPA syndrome"

Cochrane Database Syst Rev. ; 9:CD008669 ; September 2014
Guillain-Barré syndrome: review on intravenous immunoglobulin
Consult the Pubmed abstract
To read more about "Guillain-Barré syndrome"

Cochrane Database Syst Rev. ; 9:CD002063 ; September 2014
Behçet disease: review on interventions for the management of oral ulcers
Consult the Pubmed abstract
To read more about "Behçet disease"

Cochrane Database Syst Rev. ; 9:CD011018 ; September 2014
Graft versus host disease: review on mycophenolate mofetil versus methotrexate for prevention in people receiving allogeneic hematopoietic stem cell transplantation
Consult the Pubmed abstract
To read more about "Graft versus host disease"

Cochrane Database Syst Rev. ; 7:CD010280 ; July 2014

Orphan Drugs
A ray of sunlight for Erythropoietic Protoporphyria patients: Scenesse recommended by the CHMP
Scenesse has been recommended for marketing authorisation in Europe to protect patients with erythropoietic protoporphyria (EPP), against phototoxicity. EPP is a rare genetic condition where patients experience pain after exposure to sunlinght, which is sometimes so extreme that it adversely affects their quality of life to a great extent. Scenesse supposedly augments the production of eumelanin which in turn protects these patients against phototoxicity used by sunlight. The recommendation of Scenesse for marketing authorisation is a landmark decision as this is the first time patients were consulted during the CHMP benefit/risk assessment meetings for this medication. This is one of those exceptional circumstances where a medicinal product will be granted marketing authorisation even though robust efficacy data is unavailable due to placebo controlled trials being unfeasible as patients are unwilling to expose themselves to sunlight. However, 110 patients recruited under the compassionate use programs have found this product to be beneficial to them. Life of an EPP patient is that of extreme social deprivation, which is why the CHMP has recommended approval for Scenesse “on the condition that the applicant puts in place a robust risk management plan that ensures close surveillance of the safety and efficacy of the medicine”, which will be collected by the company through a registry.
Read the CHMP recommendation

FDA approves new treatment for rare form of haemophilia

In related news FDA has approved Obizur for the treatment of bleeding episodes in adults with acquired haemophilia A (acquired Factor VIII [FVIII] deficiency). Acquired haemophilia A, unlike inherited haemophilia, is not a genetic disorder but is a rare and potentially life threatening, bleeding disorder. It is caused by the development of antibodies directed against the body’s own FVIII, a protein necessary for blood clotting. Both males and females can be affected by this condition and the severity of the bleeding can make treatment challenging. Obizur contains a recombinant analogue of porcine FVIII which is similar to human FVIII but has the reduced likelihood to be affected by the antibodies against human FVIII that are present in people with acquired haemophilia A. The trial consisting of 29 adults demonstrated the safety and efficacy of Obizur in the treatment of bleeding episodes.
Read the FDA approval

The 5 most expensive drugs are orphan drugs in the United States
An article in The Motley Fool describes the top 5 most expensive drugs in the world, all of which are orphan drugs. The article names Acthar Gel, Cinryze, Kalydeco, Naglazyme, Soliris, in ascending order of price. While these drugs have life-altering properties for rare-disease patients, the article argues that, in the US, the exorbitant price could drive insurers to opt out of offering these drugs in their approved drugs list. This could be disastrous for both the pharmaceutical companies and patients.
Read the Motley Fool article

Evaluate Pharma publishes the second editions of its orphan drug report
EvaluatePharma has recently published the second edition of the Orphan Drug Report, which provides an insightful review of the Orphan drug market. Although the report largely focuses on the market in US, they also provide some perceptive information regarding the European and Japanese market.

The report predicts that the orphan drug market will be worth a total of $176bn, with a market share of 19.1% of the worldwide prescription market sales by 2020, which is especially beneficial for orphan drug developers since, according to the report, Phase III development for orphan drugs costs half of that of a non-orphan drug. The report highlights that the return on investment for orphan drugs is considerably high, almost double the investment during phase III, compared to the investment on non-orphans.

While the drug Soliris gathers the highest revenue in the US, the report envisages Revlimid to be the no. 1 orphan drug in 2020. The report also predicts that the pharmaceutical company Bristol-Myers Squibb will be the number one seller of orphan drugs in 2020, even though they currently are not in the top 10 list. The report forecasts the Cystic Fibrosis drug Ivacaftor to be the most promising drug in 2020.

While orphan designations offered by FDA hit a record high, designations in EU and Japan saw a slump in the year 2013. According to the report, granting of orphan designations by FDA and EU has steadily increased, while Japan has not made much inroads in terms of granting orphan designations. However, the report notes that FDA has provided fewer marketing authorisation for orphan drugs in 2013 compared to 2012. While Non-Hodgkin Lymphoma (NHL) is the indication with most filed orphan drug designations in EU, it was also noted that a considerable number of orphan designations (18.7%) were given to products being developed for ultra rare conditions in EU.
Download the Orphan Drug Report

Regulatory News
Cost-effectiveness argument for reimbursement decisions fail rare disease patients
An opinion piece published in Q J Med examines the sensitive subject of funding of expensive treatments for rare diseases. The authors believe that viewing reimbursement of orphan drugs with the lens of cost-effectiveness is a flawed approach. They remark that financing decisions by health economic/technology assessments (HTAs) solely depends on how many people benefit from the drug and the extent to which it will improve the quality of life, rare disease patients will be greatly deprived. Thus, the authors maintain that cost-effectiveness should play a limited role in reimbursement decisions for orphan drugs. The article decribes in detail some of the exchangeable limitations of the cost-effectiveness formulae, as well as some unalterable limitations. The authors note that applying comparative-effectiveness research can improve the cost-efficiency equation without sacrificing the needs of rare disease patients. The authors believe that while "orphan drugs fare poorly on ‘efficiency’ or health economic measures, such as the quality-adjusted life years, because of high cost and frequently poor gains in quality of life and survival", by funding these disease we will in essence providing a fair society in which patients, who walk a rough road because of their debilitating or life-threatening disease, will not be deprived of necessary medications.
Consult the Pubmed abstract

Transparency in drug reimbursement decision making in four European countries
A related article published in Health Policy gauges the significance of disease-severity in drug reimbursement decision making in Belgium, France, The Netherlands and Sweden. The authors investigated scientific literature and policy documents and conducted three interviews in each country with persons involved in drug reimbursement, with at least one person with an economic background and one person with a medical or pharmaceutical background to ascertain if disease-severity is critical to drug reimbursement decisions in these countries.

The analysis revealed that the decision-making process for drug reimbursement is often not transparent and differs between countries in Europe. The authors observed that France and Belgium not only explicitly express the role of disease-severity in drug reimbursement, but also demarcates the percentage of cost the society is willing to reimburse for a specific treatment targeting a more or less severe condition. In contrast, in The Netherlands and Sweden disease-severity serves an important function in reimbursement decisions, but the extent to which it is depended on, is ambiguous. The authors believe that improving the transparency of the reimbursement procedure, especially revealing the actual importance of disease-severity relative to the other criteria in the decision-making process is essential.
Consult the abstract

Pricing of drugs for paediatric rare diseases in the United States will not affect patients
While Europe has been dealing with drug reimbursement, the United States is now beginning to grapple with issues relating to reimbursement for orphan drugs after the adoption of its universal healthcare policy - the Affordable Care Act.

A position statement published in Orphanet Journal of Rare Diseases describes the current climate of cost-containment in the United States. The authors claim that the attention and antagonism that expensive drugs draw in political and policy discussions, is “particularly worrisome in the case of rare diseases that affect children, where high drug pricing, broad political support, and favorable regulatory attitudes have long been the bedrock of the economic “deal” between industry, government, and researchers underlying the development of therapies for previously untreatable “orphan” diseases”. To comprehend the current climate towards cost-containment in the US, the article discusses the recent 340b court case, which may have hinted at an attempt to corrode away at the orphan drug act, but court verdict was in favour of the pharmaceutical companies, the authors see no indication of a desire to create price pressure on drugs used for “real” orphan designations. The authors also address another threat, which is the willingness and ability of payers to continue to provide reimbursement at the very high (> $100,000/year) costs that is required to make these drugs economically viable for their developers. They believe that rare diseases with not many treatment options are reimbursed fairly well, and rare paediatric patients are a specialised population who are protected legislatively, due to which the patients can afford these medications.

The authors try to dispel the perception that the number of these expensive drugs is increasing, by illustrating that although there has been an increase in the number of drugs applying for orphan designations, drug approvals for these drugs have been essential flat since 2006. They state that there is a real need for innovative therapies for rare conditions and other recent legislative changes should provide additional support for the development of therapies for rare paediatric diseases.

Finally the authors add that “cost pressures are undoubtedly a serious risk for the drug discovery and development industry, but the drugs used to treat rare paediatric diseases will likely remain a special, protected class, well insulated from the general climate” and should remain so.
Read the Open Access article

Political and Scientific News
Outcomes measures used in Huntington Disease Pharmacological Trials
An article published in Journal of Huntington’s Disease, details the outcome measures that have been commonly used in Huntington Disease (HD) trials. This is an important article as the identification of the gene mutation causing the symptoms of HD has raised hopes for new treatments leading to an increased drive towards designing efficient clinical trials which in turn has increased the importance of identifying optimal outcome measures. While the National Institute of Neurological Disorders and Stroke (NINDS) has published recommendations for measurement selection in HD, many of the recommended measures have little published data in HD. According to the authors, clinical outcomes assessments generally fall into one of three categories: “patient-reported outcome (PRO) assessment, observer reported outcome assessment (ObsRO), or clinical-reported outcome (ClinRO) assessment”. The authors conducted a systematic review of the literature to identify the frequency of the usage of these outcome measures.

They found that ClinRO measures are used most commonly in HD drug studies (which included motor functioning measures, functional limitations measures as well as emotional/behavioral functioning measures), and there are psychometric data to support the use of at least a few of these measures as COAs in HD clinical research. However, the authors did not find many studies using PROs, in fact the only PRO used in more than a single study was the Beck Depression Inventory, while practically no studies used ObsRO. The authors believe that much work still needs to be done before specific recommendations for HD PROs and ObsRO measures are made.
Read the Open Access article



Research on Eosinophil Associated Disorders (R01) and (R21)
These two NIH grants are open to non-US entities. Areas of interest include, but are not limited to, the following topics
Research on the fundamental immuno-biologic and mechanistic roles of human eosinophils in Eosinophil-Associated Disorders
Development of predictive biomarkers and clinical outcomes for Eosinophil-Associated Disorders Development of novel therapeutic targets for use in Eosinophil-Associated Disorders
Preclinical evaluation of existing therapeutic agents for use in Eosinophil-Associated Disorders
Identification and improvement of novel invasive and non-invasive techniques for the diagnosis and clinical monitoring of Eosinophil-Associated Disorders
Improvement of diagnostic criteria that delineate differential phenotypes within Eosinophil- Associated Disorders
Development of novel animal models with improved predictive value for human Eosinophilic- Associated Disorders
Earliest Submission Date for the R01 grant : 5 January 2015
Earliest Submission Date for the R21 grant : 16 January 2015

For further details on the R01 grant
For further details on the R21 grant


Courses & Educational Initiatives

III International EPIRARE workshop: rare disease and orphan drug registries
Date: 24-25 November, 2014
Venue: Rome, Italy

Participants will be able to exchange experiences and present scientific results, in an effort to foster international collaboration.
For further information

ESH-ENERCA Training course on haemoglobin disorders: laboratory diagnosis and clinical management
Date: 23-24 January, 2015
Venue: Barcelona, Spain

The course will cover the following topics: Epidemiology in practice, Clinical aspects of thalassaemia, Trends in biological aspects of thalassaemia, Abnormal haemoglobins and Complications and treatments of thalassaemia and sickle cell disease.
Participants are encouraged to submit clinical cases or abstracts for presentation and discussion during the meeting. Submit your detailed clinical case(s) online
Deadline for clinical cases and abstracts: 24 November, 2014
For further information

European Advanced Postgraduate Course in Classical and Molecular Cytogenetics
Date: February/March of each year
Venue: Nimes, France

It is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification.
For further information


What's on Where?

radiz Symposium 2014
Date: 1 December, 2014
Venue: Zürich, Switzerland

Presentations of radiz project leaders and project managers as well as to short lectures young researchers to gather information on the first two years of research in radiz.
For further information in German

Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base
Date: 2-3 December, 2014
Venue: Maryland, USA

This meeting will explore the use of nutritional interventions in primary mitochondrial disorders.
For further information in German

Epigenomics and Health Care Policy: Challenges and Opportunities
Date: 1-3 December, 2014
Venue: Milan, Italy

Semm promotes training and research within emerging sectors of biomedicine, such as genomics, molecular medicine, nanotechnologies and bioethics.
For further information in German

22nd René Touraine Foundation for Dermatology Scientific Meeting
Date: 5 December, 2014
Venue: Paris, France

Every year, the Scientific Meetings go over any acquired knowledge on one skin cell. Mornings are reserved for fundamental approaches, while afternoons are devoted to approaches applied to physiopathology, pharmacology and therapeutic. These are multi-subject meetings. Each presentation starts with a general overview of the terminology used, and continues with the speaker’s own research.
For further information

From Targets to Treatments: Bridging Autoimmune Research to Advance Understanding of Alopecia Areata
Date: 4 - 5 December, 2014
Venue: Maryland, USA

The conference aims to create an engaging agenda that will bring seasoned experts and bright new minds together to distill learning from recent advances in autoimmune, skin, hair and related disease research and chart the path forward.
For further information

Nerve biology and inherited peripheral neuropathy. From biology to therapy
Date: 11-12 December, 2014
Venue: Madrid, Spain

This International Symposium focuses on current research and development on hereditary neuropathies which are a group of inherited disorders affecting the peripheral nervous system. The symposium boasts of top level researchers and rare disease stakeholders presenting their views.
For further information

European Forum for Good Clinical Practice Annual Conference 2015
Date: 27-28 January, 2015
Venue: Brussels, Belgium

“How do we improve health without betraying confidentiality within current and upcoming EU Regulations?” will debate the tensions between confidentiality and transparency in health research.
For further information

6th International Meeting on Pulmonary Rare Diseases and Orphan Drugs
Date: 27-28 February, 2015
Venue: Milan, Italy

The International Meeting on Pulmonary Rare Diseases and Orphan Drugs is the only European event dedicated to different types of rare pulmonary diseases affecting both parenchymal and vascular structures. The meeting will be an opportunity to exchange and disseminate knowledge among experts in different areas of clinical and basic research in respiratory medicine, in efforts to provide new insights into science and clinical care, thus helping patients and supporting doctors.
For further information

3rd Asia-Pacific Prader-Willi Syndrome Conference 2015: “From Better Start to Better Living”
Date: 11-12 April, 2015
Venue: Melbourne, Australia

For further information

3Gb-TEST course on NGS: “Next-generation sequencing in a diagnostic setting
Date: 20-23 April, 2015
Venue: Prague, Czech Republic

A 4-day course on Next Generation Sequencing in Prague - Czech Republic in the period of 20-23th April 2015. The focus of the course is on clinical diagnostics using exome/genome sequences, variant identification and analysis including afternoon practicals (limited places). The course will also include an evening symposium co-organised by Milan Macek; “Genotranslation: Interpretation of genome data in diagnostics”
For further information

2nd International GENCODYS Conference on Integrative Networks in Intellectual Disabilities
Date: 27-29 April, 2015
Venue: Crete, Greece

European funded research consortium GENCODYS exploits a multilevel approach to resolve the integrative networks in intellectual disabilities. The conference will bring together about 150 top researchers, medical doctors and patient representatives in the field of Cognitive Research and related activities.
Talks and submissions for talks have to be related to studies of cognitive dysfunction but can include other fields, namely genetics, cellular, molecular and physiological studies, genomics and epigenomics and bioinformatics.
For further information

Trisomy 21 Research Society (T21RS) International Conference
Date: 4-6 June, 2015
Venue: Paris, France

T21RS promotes research on Down syndrome and stimulates collaboration between researchers worldwide. The first edition of the T21RS International Conference will be held at the site of the Hôpital de la Pitié-Salpêtrière in Paris. More details will be announced in due course.
For further information

Tourette Syndrome Congress 2015
Date: 24-26 June, 2015
Venue: London, UK

The 1st World Congress on Tourette Syndrome and Tic Disorders is designed for linicians, researchers , post-doctoral fellows, medical residents and allied healthcare professionslas with an interest in current research, diagnosis and treatment of these and related conditions.
For further information

7th International Conference on Children’s Bone Health
Date: 27-30 June, 2015
Venue: Salzburg, Austria

The International Conference on Children’s Bone Health (ICCBH) meetings provide an international forum for the presentation and discussion of current basic and clinical science in the field of bone metabolism and bone mass in children, adolescents and young adults.
The call for abstracts opens in September 2014.
Abstract deadline: 6 February 2015.
For further information

The First Russian Congenital Aniridia Conference
Date: 3-4 July, 2015
Venue: Salzburg, Austria

The conference will aim at sharing knowledge and experience about Congenital Aniridia by increasing the dialogue between patients and doctors about the problems of congenital aniridia.
For further information

2nd International Primary Immunodeficiencies Congress (IPIC)
Date: 5-6 November, 2015
Venue: Budapest, Hungary

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the Second International Primary Immunodeficiencies Congress (IPIC). This event will build on the successful outcomes of the first IPIC, attended by 400 participants. The congress will consist of a two-day programme and is open to all stakeholders with an interest in clinical management of primary immunodeficiencies (PIDs).
For further information

13th International Congress of Human Genetics (ICHG) 2016
Date: 3-7 April, 2016
Venue: Kyoto, Japan

Hosted by the East-Asian Union of Human Genetic Societies (EAUHGS) and the Japan Society of Human Genetics, the 13th ICHG will focus on progress in genome analysis technologies and big data in order to explore disease mechanisms and treatment opportunities.
Registrations open in 2015.
For further information


Commercial events

Pharma Pricing and Market Access Congress 2015
Date: 24-26 February, 2015
Venue: London, UK

The conference provides information on the latest policies affecting market access from payers, HTA authorities and leading industry experts.
For further information

World Orphan Drug Congress USA 2015
Date: 3-7 April, 2016
Venue: Washington D.C, USA

For further information

World Orphan Drug Congress Asia 2015
Date: 3-4 June, 2015
Venue: Singapore

For further information


OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01)
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Divya Unni
Editors for Scientific Content: Catherine Pouzat, Sophie Höhn
Contact Us
Editorial Board: Ségolène Aymé, Paul Boom, Anna Bucsics, Kate Bushby, Barbara Cagniard, Lorenzo Dagna, Adam Heathfield, Lilian Lau, Yann Le Cam, Jordi Llinares-Garcia, Antoni Monserrat, Charlotte Rodwell, Gerhard Steffes, Till Voigtländer, Jaroslaw Waligora

Orphanet Partner Country Representatives: Kristine Hovhannesyan (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Riitta Salonen (Finland), Joerg Schmidtke (Germany), Helen Michelakakis (Greece), Eileen Treacy (Ireland), Annick Raas-Rothschild (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Vaidutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Jorge Sequeiros (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Borut Peterlin (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Ugur Ozbek (Turkey), Dian Donnai (UK)
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