Edition of 15 October 2013

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Editorial

ECRIN funds clinical trials to augment rare disease research

The European Clinical Research Infrastructures Network (ECRIN) is a non-profit organisation that supports multinational academic clinical research projects in Europe which is "hampered by the fragmentation of health and legislative systems in Europe". ECRIN provides information, consulting and services to investigators and sponsors in the preparation and in the conduct of multinational clinical studies, for any category of clinical research and in any disease area. This is particularly relevant for investigator-initiated or academic clinical trials, and for clinical research on rare diseases where international cooperation is a key success factor. ECRIN is based on the connection of coordinating centres for national networks of clinical research centres and clinical trials units, able to provide support and services to multinational clinical research.

Recently, ECRIN organised a call for applications to allow multinational extension of trials already funded in the coordinating country in three specific areas: Nutrition, Medical Devices and Rare Diseases. Trials were proposed by public or private non-profit institutions, and to address important clinical questions. The evaluation process was based on the possible impact on the health of European citizens, the scientific merit and excellence, and the feasibility of each proposed trial. Project selection was carried-out by the ECRIN IA Scientific Board (which also includes patients representatives), supported by external peer-reviewers, each assessing one clinical trial in his/her specific field of competence, and three methodologists, each assessing all the trials pertaining to one of the clinical areas considered by the call. The ECRIN European Correspondents provided the Board with an estimation of the logistical feasibility and cost of the trials. Eight clinical trials, involving a total of 21 European countries, were recommended for free access to ECRIN services after selection by the ECRIN-IA Scientific Board convened in Milan on June 20-21, 2013 : Four of the trials chosen are in the field of rare disease research. Below are the details of the trials to be funded involved in rare disease research:
Prospective multicenter study (phase III) to evaluate clinical efficacy and safety of anti-Pseudomonas antibodies (IgY) in prevention of P. aeruginosa infection in CF patients PsAerIgY – Trial Germany 4.0 Clobazam or steroids for ESES syndrome: a European, multicenter, randomized, controlled clinical trial

Clobazam or steroids for ESES syndrome: a European, multicenter, randomized, controlled clinical trial

Very early FDG-PET/CT-response adapted therapy for advanced stage Hodgkin Lymphoma, a randomized phase III noninferiority study

Endoscopic versus Laparoscopic Myotomy for Treatment of Idiopathic Achalasia: A Randomized, Controlled Trial

Spotlight on...

Interview

IRDiRC: What is the main problem that you will tackle?
Liz Donohue: Many new developments in the diagnosis and treatment of human disease rely on research that involves the collection and analysis of data, but research into rare diseases is challenging due to a lack of information, the low numbers and geographic spread of individuals affected by rare disease, and data collected and stored in separate databases. There is a compelling need for the creation of a centralized resource of contact and clinical data on patients diagnosed with a rare disease.

IRDiRC: What is the concrete solution that you have selected? What are the steps? At what stage are you today?
Liz Donohue: To help address these challenges and advance research into rare diseases, we have established a central rare disease patient registry for all rare diseases, working with patient groups that want to start a general rare disease patient registry or a disease-specific patient registry. We will be accepting applications from researchers to access data in the coming months.

IRDiRC: What can the patients, the clinicians or other stakeholders expect at the end of the project?
Liz Donohue: At the end of the project, patients would be able to contribute to basic contact and clinical data after providing informed consent. They may indicate if they would like to be contacted about research opportunities in the future and how they would like their information to be shared.
Researchers with Institutional Review Board (IRB) approval (or corresponding approval in their country) may apply for access to de-identified data into CoRDS database. Researchers would also be allowed to request CoRDS staff members to contact patients on their behalf.
Providers with IRB approval may apply for access to de-identified data into CoRDS database. Providers would also be allowed to request CoRDS staff members to contact patients on their behalf.

IRDiRC: How is your project contributing to reaching the goals of IRDiRC by 2020?
Liz Donohue: CoRDS is contributing to reaching the goals of IRDiRC by 2020 by:
Creating a central registry for rare diseases which will help establishing and providing access to harmonized data and samples Gathering natural history of diseases by updating and overseeing the registry data which will help performing the molecular and clinical characterization of rare diseases
Facilitating the translational, preclinical and clinical research in the future, by building a rare disease biobank which will become operational in late 2013.
Providing feedback on issues pertaining to informed consent which will help streamlining ethical and regulatory procedures.

IRDiRC: Where does this project position itself in this particular field at the international level?
Liz Donohue: Currently, individuals from all around the world are allowed to enrol to CoRDS registry, as long as they speak and understand English. The software used does support other languages, and CoRDS hopes to translate documents into other languages in the future. Researchers from all around the world can access the Registry as long as they have IRB approval (or corresponding approval in their country).

Liz Donohue, on behalf of CoRDS, USA
Visit CoRDS website for more information
Visit the IRDiRC website

National & International Policy Developments

Other European news

Other International News

A good year for rare disease research as multiple projects are awarded by NIH

In a recent press release, the National Institutes of Health (NIH) have announced $6,865,689 to the National Disease Research Interchange (NDRI) to continue funding the recovery and distribution of human organs and tissues for medical research. This five-year award funds the Research Resource for Human Tissues and Organs (RRHTO) Cooperative Agreement which provides biomedical investigators with donated normal and diseased human tissues and organs, recovered using customised procurement, processing, preservation and distribution protocols from a diverse donor pool. A unique element of NDRI’s work supported through this agreement is the provision and distribution of human tissue for rare disease research. The Office of Rare Diseases Research within NCATS provides funds for outreach to rare disease patients and advocates, and to their medical and research communities, for the collection and distribution of rare disease biospecimens.

In related news, the Therapeutics for Rare and Neglected Diseases program at the NIH’s National Center for Advancing Translational Sciences is funding four new preclinical drug development projects targeting several rare diseases. Two of the projects focus on development of a treatment for retinitis pigmentosa, which is a severe form of hereditary blindness, and the third project involves investigation of a potential treatment for hypoparathyroidism. The fourth project targets a potential treatment for hypertrophic cardiomyopathy associated with LEOPARD syndrome, an extremely rare genetic disease that affects many areas of the body. These projects also represent the first time the program has used stem cells and marks its first collaboration with a large pharmaceutical company, Eli Lilly, to jointly develop treatment for a rare disease, according to the press release.
Visit the NIH website for more information on the projects
Visit the NCATS website

Guidance Documents and Recommendations

Bioinformatics, Registries and Data Management

Screening and Testing

Ethical, Legal & Social Issues

New Syndromes

New Genes

Research in Action

Clinical Research

Gene Therapy

Therapeutic Approaches

Diagnostic Approaches

Patient Management and Therapy

Orphan Drugs

Political and Scientific News

The treatment of neuronal ceroid lipofuscinosis - a focus on clinical trial development

The neuronal ceroid lipofuscinoses constitute one of many groups of rare childhood diseases for which disease-modifying treatments are nonexistent. An article published in Journal of Child Neurology, describe disease-specific barriers to therapeutic success, which include incomplete understanding of disease pathophysiology and limitations of treatments that cannot adequately cross the blood-brain barrier to access the central nervous system. The authors state that the therapeutic development in the neuronal ceroid lipofuscinoses shares many challenges with other rare diseases, such as incomplete understanding of natural history to inform trial design, need for alternatives to the randomized controlled clinical trial, requirement for more sensitive outcome measures to quantify disease, limited access to resources required to mount a clinical trial, and difficulties of recruiting a small sample to participation. The authors state that solutions to these barriers will require multicenter collaboration, partnership with patient organisations, training a new generation of researchers interested in rare diseases, and leveraging existing resources.

Although experimental therapeutics for rare disorders faces many challenges, there have been several recent accomplishments in the neuronal ceroid lipofuscinoses, including initial development of disease-specific rating scales, funding to further develop outcome measures for juvenile neuronal ceroid lipofuscinosis, and several ongoing clinical trials. The article describes continuing to improve our understanding of animal model phenotypes, disease pathophysiology, and natural history, to improve the existing quantitative measures and to hone a patient-centered approach as some of the future priorities. Other significant measures included in the paper are continued efforts to build clinical trial design expertise and infrastructure and efforts toward research prioritisation will support the future directions of therapeutic development in the neuronal ceroid lipofuscinoses.
Consult the PubMed abstract

Grants

Courses & Educational Initiatives

What's on Where?

Orphanews International, the newsletter of the European Union Committee of Experts on Rare Diseases
Orphanews International 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
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Editorial Board: Ségolène Aymé, Kate Bushby, Catherine Berens, Barbara Cagniard, Virginie Hivert, Helena Kaariainen, Odile Kremp, Yann Le Cam, Jordi Llinares-Garcia, Antoni Montserrat, Charlotte Rodwell, Jaroslaw Waligora

INTERNATIONAL CORRESPONDENTS
EUCERD Country Representatives: Helmut Hintner (Austria), Pol Gerits (Belgium), Rumen Stefanov (Bulgaria), Ivo Baric (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek Jr. (Czech Republic), Marianne Jespersen (Denmark), Inna Vabamae (Estonia), Helena Kaariainen (Finland), Alain Garcia (France), Birgit Schnieders (Germany), Christos Katamis (Greece), Janos Sandor (Hungary), Thor Thorarinsson (Iceland) , John Devlin (Ireland), Bruno Dallapiccola (Italy), Antra Valdmane (Latvia), Romalda Baranauskiene (Lithuania) , Yolande Wagener (Luxembourg), Miriam Dalmas (Malta), Jolande Huizer (Netherlands), Stein Are Aksnes (Norway), To be nominated (Poland), Alexandre Diniz (Portugal), Emilia Severin (Romania), Borut Peterlin (Slovenia), Frantisek Cisareik (Slovak Republic), Isabel Pena-Rey (Spain), To be nominated (Sweden) , Sabina Gallati (Switzerland), Edmund Jessop (UK)
EUCERD ECDC Representative: Andrew Amato
EUCERD Patient Organisation Representatives: Dorica Dan, Yann Le Cam, Christel Nourissier, Bianca Pizzera
EUCERD Pharmaceutical Industry Representatives: Wills Hughes-Wilson, Kevin William Loth, Samantha Parker, Barbara Valenta
EUCERD Rare Disease Projects under Health Programmes Representatives: Ségolène Aymé, Jean Donadieu, Ester Garne, Domenica Taruscio, Joan Luis Vives Corrons, Thomas Wagner, Susan Webb
EUCERD Rare Diseases Research Projects under Framework Programmes for Research and Technological Development Representatives: Jean-Yves Blay, Kate Bushby, Marc de Baets, Olaf Hiort, Gerard Wagemaker
EUCERD European Commission Participants: Catherine Berens, Iiro Eerola, Jordi Llinares-Garcia (EMA), Georgios Margetidis, Jaroslaw Waligora, Antoni Montserrat Moliner, Michael Huebel, Bruno Sepodes (EMA-COMP)

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), Zsuzsanna Lengyel (Hungary), Andrew Green (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)
For more information on the European Union Committee of Experts on Rare Diseases
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Editorial

ECRIN funds clinical trials to augment rare disease research

Spotlight on...

Coordination of Rare Diseases at Sanford (CoRDS) – Q&A with Liz Donohue

Interview

National & International Policy Developments

Draft NIH Genomic Data Sharing Policy Request for Public Comments

Other European news

Is it too early for mitochondrial replacement therapy to see the light of day?

Eurogentest survey to assess requirements of professionals working in a genetic center

Other International News

A good year for rare disease research as multiple projects are awarded by NIH

Australian Department of Health sets up Post-Market review of their Life Saving Drugs Program

ISPOR (International Society for Pharmacoeconomics and Outcomes Research) is implementing a rare disease Special Interest Group (SIG)

Guidance Documents and Recommendations

Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion

Bioinformatics, Registries and Data Management

Novel post-approval registry for Canakinumab

Screening and Testing

Prenatal screening: Experience of a Prenatal Diagnosis Center in Italy

Concerted efforts in Turkey to reduce incidence of hereditary rare diseases

Clinical management of rare renal disease in the absence of scientific evidence to support clinical practice

Ethical, Legal & Social Issues

What is the kind of assistance caregivers of patients with Juvenile Huntington’s Disease looking for?

New Syndromes

New syndrome featuring severe dermatitis, multiple allergies and metabolic wasting caused by homozygous mutations in DSG1

Novel syndrome characterized by hypopituitarism, post-natal microcephaly, visual and renal abnormalities due to an ARNT2 mutation

Previously unreported condition of intellectual disability, unusual facial morphology and hand anomalies

A new form of severe spondyloepimetaphyseal dysplasia described in two patients

Ataxia, intellectual disability, and ocular apraxia with cerebellar cysts in seven children

New Genes

Acute lymphoblastic leukemia: identification of PAX5 and TP53 as susceptibility genes

Intermediate form of autosomal-recessive Charcot-Marie-Tooth disease due to two homozygous mutations in PLEKHG5 in two consanguineous families

Chronic pancreatitis: variants in CPA1 are strongly associated with early-onset disease

Dyschromatosis universalis due to mutations in ABCB6 in a five-generation Chinese family and in two additional cases

Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS

West syndrome: SCN2A mutations identified in one case, and in seven cases with Ohtahara syndrome evolving to West syndrome

Hereditary spastic paraplegia type 43 is due to a homozygous missense mutation in C19orf12

Idiopathic bronchiectasis: identification of two missense variants in SLC26A9 in heterozygous patients that could trigger the pathogenic role of a single CFTR mutation

A case of paroxysmal nocturnal hemoglobinuria caused by a heterozygous germline splice site mutation and a somatic deletion in PIGT

Mosaic variegated aneuploidy syndrome: identification of haploinsufficiency or heterozygous mutations in BUB1 and BUB3

Primary sclerosing cholangitis: genome-wide association analysis identified risk loci at GPR35 and TCF4

Spondyloepimetaphyseal dysplasia with multiple dislocations-like phenotype due to homozygous missense mutations in NIN and POLE2, with mutant NIN most likely causative

Primary ovarian failure associated with a heterozygous stop codon in elF4ENIF1 in nine women in three consecutive generations

Isolated cytochrome C oxidase deficiency: novel heterozygous mutations in SCO1 in one patient with fatal encephalopathy but without hepatopathy or hypertrophic cardiomyopathy

Autosomal recessive congenital ichthyosis caused by a homozygous missense mutation in CERS3 which reveals the importance of ceramide acyl chain length

Research in Action

Clinical Research

Schnitzler syndrome: monthly 150 mg canakinumab injection was effective and well-tolerated in a 9 months study

Familial amyloid polyneuropathy: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and non-mutant forms of transthyretin

Uveal melanoma: durable responses to ipilimumab and manageable toxicity in 39 patients

Neurofibromatosis type 1: chemotherapy for the treatment of malignant peripheral nerve sheath tumors did not seem to reduce mortality in a retrospective review

Cholesteryl ester storage disease: sebelipase alfa is well tolerated, rapidly decreases serum transaminases, and improves serum lipid profile on the long-term

Biliary atresia: endoscopic therapy appears to be well tolerated and greatly reduces the risk of variceal bleeding in children, although continued endoscopic surveillance is needed

Therapies in development for mucopolysaccharidosis type 3

Behçet’s disease: potential for using gevokizumab for the treatment of uveitis

Gene therapy for Wiskott-Aldrich syndrome

Cystic fibrosis gene therapy is moving forward

Acute myeloid leukemia: vascular-targeting with an F16 antibody fused to IL-2, associated with cytarabine, significantly reduced AML lesions in a patient with disseminated disease

Mild and moderately severe hemophilia A: F8 genotyping facilitates the identification of patients at high-risk of developing inhibitor

Rare mitochondrial DNA mutations probably account for more than 7.4% of patients with respiratory chain deficiency

Limbic encephalitis with NMDA receptor antibodies is associated with functional and structural brain changes despite normal findings in routine clinical MRI

Gene Therapy

FKRP-related muscular dystrophies: significant improvement in pathology, serum creatine kinase levels and muscle function with AAV9-mediated FKRP gene therapy in model mice

Limb girdle muscular dystrophy type 2A: a new AAV vector with CAPN3 expression restricted to skeletal muscle prevents cardiac toxicity and corrects pathology in a murine model

Mucopolysaccharidosis type IIIB: targeting both the systemic and central nervous system early in life appears to be the most efficacious approach in model mice

Mucopolysaccharidosis type IIIA: evidence of neurological disease correction using autologous myeloid driven lentiviral-hematopoietic stem cells gene therapy in model mice

Acute neonatal citrullinemia type I: adeno-associated virus-mediated rescue of neonatal lethality in argininosuccinate synthetase-deficient mice

Autosomal-recessive infantile malignant osteopetrosis: lentiviral gene transfer of TCIRG1 into peripheral blood CD34+ cells restores osteoclast function

Development of gene therapy for blood disorders: an update

Therapeutic Approaches

Huntington disease: glutathione peroxidase activity is neuroprotective in yeast, mammalian cells and Drosophila models

Young adult-onset Parkinsonism: both ursocholanic acid and ursodeoxycholic acid rescue mitochondrial function in LRRK2G2019s mutant fibroblasts

Methylmalonic acidemia type cblB: pharmacological chaperones as a potential therapeutic option

Heritable pulmonary arterial hypertension with BMPR2 mutation or deficiency: chloroquine as a potential therapeutic approach through the restoration of cell surface BMPR-2

Spinal muscular atrophy: the Dcps inhibitor RG3039 improves motor function and survival in model mice

Amyotrophic lateral sclerosis: treatment of model mice with anti-miR-155 significantly extended survival by 10 days and disease duration by 15 days

Diagnostic Approaches

Pseudotumor cerebri syndrome: revised diagnostic criteria in adults and children