Rare Disease Research - A decade of progress

Elisabeth TOURNIER-LASSERVEDirector of GIS-Institut des Maladies Rares

Paris, France

Eurordis 2007

• Large number (6 000 to 8000)

• Genetic in 80 % of cases

• Low prevalence (< 1 out of 2000)

• Strong heterogeneity

Rare Diseases Main Features Rare Diseases Main Features

Identification of clinical phenotype

Genetic mapping SequencingCGH array

Identification of genetic basis

Pathophysiology

Clinical expertise Registries

Methods and Tools

Therapeutics

Expected outcome

Clinical criteria Cohorts

Diagnostic testsGenetic information

Animal modelsIn vitro models

Transcriptome, ProteomeMetabolom, Imaging

Biochemistry

Molecular pathwaysDisease course

Biomarkers

Animal modelsCellular models

Stem cellsGene

HTP ScreeningIndustry

Candidate « drugs »(Cell, gene, chemical

compounds)Preclinical testing

ToxicologyPharmacokinetics

CURE +++Clinical trials

Rare Disease Research: steps, tools and expected resultsRare Disease Research: steps, tools and expected results

• Gene identification was very tedious until 2000

• Human genome sequence and annotation +++

• Mouse mutants identified through large scale mutagenesis

• New tools: CGH and SNP arrays

• > 1500 Rare Disease genes identified since 1990

Rare Disease Genes IdentificationRare Disease Genes IdentificationAn enormous progress since 1997An enormous progress since 1997

Crow et al, 2006

Identification of Aicardi-Goutières genes in 2006Importance of human and yeast genomes sequencing and annotation

• 1984: Aicardi-Goutières Syndrome, a progressive familial encephalopathy in infancy with calcifications and chronic cerebrospinal fluid lymphocytosis• 2006: 4 AGS genes encoding 3 RNaseH2 subunits and TREX, a DNA exonuclease

RnaseH2B RnaseH2ARnaseH2C TREX

Skin features observed in Familial Chilblain Lupus in a family segregating an heterozygous TREX mutation

Skin features seen in a child with Aicardi Goutières Syndrome due to a de novo heterozygous D200N TREX1 mutation.

TREX mutations are also involved in Familial Chilblain LupusImportance of clinical expertise and clinicians / geneticists networks

Crow et al, 2007

Col4A1 mutations and strokeImportance of mouse large scale mutagenesis and phenotyping

Col4A1 mutation in a human family with stroke, leukoencephalopathy and

retinal vessel tortuosities

Vahedi et al, 2003 / Gould et al, 2005 / Gould et al, 2006

Col4A1 mutation in a mouse ENU mutant with hemorrhagic stroke

• CGH, Oligos and SNP arrays: New tools allowing detection of copy number variations +++

• Importance for mental retardation with and without dysmorphic features, developmental anomalies and most likely many other rare disease conditions in which no gene has been identified yet

Recurrent microdeletion in 17q21 in mental retardation Importance of CGH and SNP microarrays platforms

Shaw-Smith, Carter NP et al, 2006

• A huge number of mouse but also fish, drosophila and C-elegans models of rare diseases created and analyzed +++

• Development of “Systems” approaches: transcriptomes, interactomes, …

• Importance of easy to use and reliable platforms / Bio informatics

• Link with multifactorial disorders

Pathophysiological Pathophysiological Mechanisms Mechanisms A decade of progress A decade of progress

Vidal et al, 2005

Systematic mapping of protein-protein interactionsLarge scale interactomes in animal models and man

High throughput yeast 2 hybrid screeningTo identify protein-protein interactions

Interactome involving 121 Rare Disease associated proteins

• Diversity +++ depending of the disease, gain or loss nature of mutations,available knowledge on mechanisms …

• Gene transfer: tremendous work on viral vectors in the past ten years / Gene transfer in immune deficiencies +++

• Substitutive treatments (enzymopathies): Gaucher disease

•“Conventional” drugs: On going trials of losartan in Marfan disease

• Novel approaches in animal models: RNAi, Ribozymes …

Clinical and Preclinical Therapeutics ResearchClinical and Preclinical Therapeutics ResearchA decade of tremendous work A decade of tremendous work

Rare Disease research1997-2007: A decade of progress

2007-2017: A number of challenges

• To characterize the numerous novel rare diseases identified eachyear and identify their molecular basis

• To identify the genes involved in > 1500 familial rare diseases without any known molecular basis

• The challenge raised by very rare, heterogeneous, and incomplete penetrance rare diseases

• New tools +++/ Platforms +++ / Cost +++

• Important not only for rare diseases but also for the understanding of normal biological pathways and common diseases +++

EpidemiologyEpidemiology,, NosologyNosology, Natural history, Molecular basis , Natural history, Molecular basis Research ChallengesResearch Challenges

• To elucidate the mechanisms of most of the 1800 rare diseases whose genes have already been identified

• Important not only for rare diseases but also for the understanding of normal biological pathways and common diseases +++

Pathophysiological Pathophysiological Mechanisms Research ChallengesMechanisms Research Challenges

• Need to improve efficacy and safety of gene transfer

• Need to identify molecules active on rare disease “druggable”genes / High throughput screening platforms / Libraries of molecules / need for academic/companies partnerships

• Somatic stem cell therapy

• Embryonic stem cell therapy

• Practical organization of clinical trials for rare diseases / rarity of patients / need for very efficient and available diagnostic tests to set up cohorts …

Therapeutics ResearchTherapeutics ResearchComing challengesComing challenges

How toHow to meet these meet these challengeschallenges at the European levelat the European level

1. Transnational calls for proposals2. No « a priori » selection of organ specific rare diseases3. Financial support for academic teams (networks)4. Financial support for existing platforms to help

specifically Rare Diseases research projectsGenotyping, sequencing, microarrays, bioinformatics, Transcriptome, proteomeMouse facilities, phenotyping including imaging platforms