Rare diseasesFrom recognition to treatment:

role of the AFM

EDITORIAL p 2

AFM – AN ORGANISATION IN THE FIGHTAGAINST NEUROMUSCULAR DISEASES p 3A patients’ association …… at the heart of rare disease issuesA general interest strategy …… accompanied by an innovative approach

FINDING A CURE p 6Developing tools and programmesuseful for rare diseasesDeveloping innovative treatments

IMPROVEMENT OF PATIENTS’ DAILY LIVES p 12Coming out from oblivionAttaining full citizenshipFighting misdiagnosis

CONCLUSION p 17

APPENDICES p 19

Translated by David Kerridge from the AFM document “Maladies rares – de la reconnaissance aux thérapeutiques : le rôle de l’AFM”.

For more information: AFM-BP 59- 91002 Evry Cedex – France Phone: +33 1 69 47 28 28 – www.afm-france.org -

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EDITORIAL

Because they affect nearly three million people in France today, rare diseases have become a real public health issue. Despite their wide diversity, they share many problems, and if these problems were tackled by the public authorities within an overall policy of research and treatment, it would allow nearly 5% of the population to come out from oblivion.

Thanks to French Telethon donations, it is now nearly 18 years since the AFM has been committed to an innovative policy of research and assistance for patients. Eighteen years of combat and initiatives for neuromuscular diseases through a general interest strategy which has resulted in outstanding advances all round, for rare genetic diseases as well as more common diseases. The AFM has come a long way: today, rare diseases are recognised as a real public health issue, and little by little research is being organised and new hopes for treatments are emerging. But we are still confronted with an obstacle course: misdiagnosis, insufficient research, difficulties with bearing medical costs, accumulation of exclusion factors etc. There is still a lot to be done and although the patients’ associations play a motor role, they cannot act alone. They must have the full support of the public authorities.

Now that a political will seems to be emerging to set up a national plan for rare diseases, we are redoubling our vigilance to ensure that this plan is both well-structured and financed for the long term.

At the AFM we have taken on the combat of patients affected by neuromuscular diseases, all of them rare and progressive, often seriously disabling and mortal. We are doing everything we can to ensure that this political will on behalf of the public authorities marks the beginning of a new era for these patients.

Laurence Tiennot HermentPresident of the AFM

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- AFM – AN ORGANISATION IN THE FIGHT AGAINST

NEUROMUSCULAR DISEASES

The AFM is born from a new generation of patients and patients’ relatives who have decided to take their destiny in hand and to put up a resistance to the disease on all fronts. Engaged in scientific research as well as in assistance to patients, it acts independently and is guided solely by the interest of the patient.

A PATIENTS’ ASSOCIATION …

Created in 1958 by patients and patients’ relatives, the AFM set itself a single aim: to conquer neuromuscular diseases. It is this refusal to accept fate and a determination to make every effort to fight against these rare, chronic, progressive and often fatal diseases which has determined the strategy of the Association since its founding. Faced with the isolation and distress of sick persons and their families, the AFM has developed an innovative strategy both in the field of research as well as in assistance to patients.

If the Association now figures among the major actors in research and health in France, it is because this strategy was rooted in values first laid down by its founder members and perpetuated since:

• against oblivion and ignorance: revolt – a founding value of the AFM is the revolt of relatives who refuse fate and resignation

• to make choices: will and conviction – since its creation, the AFM has made every effort to carry out its will and repeat its conviction that cure is possible

• to succeed: rigour and effectiveness – this is the golden rule that the AFM has always set itself as it works in highly complex fields with limited and unpredictable resources

• accountability: transparency – this is more than just a requirement, transparency is an ethic. Ever since the first Téléthon, the Association has always been committed to giving a faithful account of the use of its donations.

… AT THE HEART OF RARE DISEASE ISSUES

For a long time forgotten by science and medicine and ignored by the health system, neuromuscular diseases are at the heart of rare disease issues. In the 1960s, when the families first decided to group together within an association, every day they had to face up to a real obstacle course : misdiagnosis, a quasi-absence of competent consultation, a medical profession that had given up, and non-existent research or support for medical costs.

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Under the impetus of the AFM, research has emerged, specialised consultations exist, diagnosis has been refined and treatments have been developed. But even if the road to recovery is long and hard, the AFM’s action has demonstrated that it is possible to “do something.”

Today, neuromuscular diseases represent some 200 different diseases among the 6 to 7000 rare diseases. A disease is considered rare if it affects fewer than one person in 2000. Rare diseases are very diverse and the majority are of genetic origin. They are responsible for more than 10% of the mortality of young people (less than 15 years old). They can prevent movement (myopathies), sight (retinitis), hearing (deafness), breathing (cystic fibrosis), understanding (fragile X syndrome) etc. However, these diseases have certain things in common – there is no curative treatment, it is difficult to obtain diagnosis and treatment, there is an absence of research but social exclusion is common.A total of about 3 million French people and 20 to 30 million Europeans are concerned by rare diseases.

A GENERAL INTEREST STRATEGY …

In order to be more effective in its fight against neuromuscular diseases, the AFM has chosen to intervene beyond the simple neuromuscular disease level so as to take on the more comprehensive issues of genetic and rare diseases. In fact, it is by advancing our knowledge about the wider groups of pathologies to which neuromuscular diseases belong that the Association has the best chances of getting results.

Because neuromuscular diseases affect the muscle and the neurone, the AFM has set out to uphold myology (the science and medicine of the muscle) as a discipline in its own right, like cardiology, immunology etc.

Because neuromuscular diseases are of genetic origin, the AFM has developed general interest tools, means and know-how to speed up understanding of genetic diseases and open the way to treatments originating from genetic knowledge.

Because neuromuscular diseases belong to the group of rare diseases hitherto neglected by the public health system, the AFM has developed an overall strategy for the recognition of these patients who were excluded from support for medical costs and from social and economic life.

Because neuromuscular diseases are chronic and seriously disabling, the AFM – along with other associations – is fighting for the recognition of the right of each citizen to have the means at their disposal to compensate for their disabilities, whether they are physical, intellectual or sensorial.

… ACCOMPANIED BY AN INNOVATIVE APPROACH

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Faced with “dead-end” situations, the AFM positions its courses of action within a logic of innovation. Whether in the scientific or social field, its approach is the same: look for new solutions, develop them alone or in partnership, then – after validating them – encourage the State and institutional or industrial partners to take up the challenge and widen its benefits.

The role of the Association is not to be a substitute for the public authorities – even all the Telethon donations would not be sufficient for this – but to be an impetus, a pioneer and an incentive.

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FINDING A CURE

Every initiative of the AFM, from fundamental research into the muscle to the development of innovative treatments and including molecular biology, is undertaken with a single objective: cure. Because the disease can still be a killer, the AFM’s strategy aims to reach this objective as quickly as possible. Through its different forms of targeted action, the AFM is at the origin of a real medical revolution generated by a better understanding of genes. Thus it plays a pioneering role in areas where both State and industry are absent. It plays this role by supporting and encouraging both work of general interest in the field of drug development and in the research for innovative treatments.

DEVELOPING TOOLS AND PROGRAMMES USEFUL FOR RARE DISEASES

The integrative policy of the AFM has led it to support or take charge of the development of general interest tools and programmes that are of use to all rare genetic diseases, including neuromuscular diseases.

DNA and tissue banks: collecting and storing the raw material of researchLike 80% of rare diseases, the majority of neuromuscular diseases are of genetic origin. Finding the genetic anomaly responsible for a disease necessitates having the DNA of the members of the same family (as well as other families) in order to search for a link between the genome, the modifications and the disease.

Therefore, as early as in 1989 the AFM launched its first campaigns for samples aimed to collect the DNA of patients and their families. It contributed to the setting up of banks where the collected DNA could be preserved for research purposes. Today, 14 DNA banks have benefited from the support of the AFM – in metropolitan France, French overseas territories, Europe and North Africa. With more that 50 000 samples from nearly 20 000 families, the bank of the AFM laboratory, Généthon, figures among the largest in Europe. This bank contains DNA collections concerning 360 very different diseases. In 1996, in order to promote the physiological and physiopathological analysis of rare diseases, the AFM set up a Tissue Bank for Research (TBR) which is responsible for the collection, storage and distribution of tissue samples to research teams.

Genethon: from genes to treatmentsCreated in 1991 and financed by the AFM, the Généthon laboratory is unique in the world. A powerful catalyst to genetic research, it is capable of adapting itself to each new step along the way towards cure.

• Faced with a total absence of a national genetics policy, the AFM created Généthon with the aim of sharing and automating research into genes in order to accelerate their discovery and envisage treatments. Thus Généthon published the first genome maps in record time between 1992

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and 1996 and, on one hand, contributed to the discovery of the genetic origin of several hundred rare (or frequent) diseases and on the other, established the bases for the complete deciphering of the human genome.

• In 1997, following State takeover of genomic activities, the AFM reoriented the activities of Généthon towards the development of treatments. To begin with, in collaboration with the Harvard Medical School, the laboratory devoted itself to the construction and production of vectors designed to transport the gene-drug to the cell. From 1997 to 2003, the AFM led the GVPN (Gene Vector Production Network) bringing together both French and European laboratories. This network, financed solely by the AFM, supplied nearly 3000 batches of preclinical vectors to French or international teams, who thus learned how to use them and acquired know-how in the field of vector production. The objective of this incentivising policy was reached in 2003, and the AFM decided to put an end to the GVPN network. However, it has continued its support to certain laboratories (Nantes, Barcelona, Geneva) which remain vector production sites for the scientific community. The vectors supplied – retrovirus, lentvirus, adenovirus, adeno-associated virus and plasmids – have allowed work to continue on more than 80 diseases: genetic diseases (cystic fibrosis, haemophilia, Gaucher disease) cancers, auto-immune diseases, acquired degenerative diseases etc.

• Today, Généthon has made its entry into the era of therapeutic trials: setting up 4 strategic clinical projects for neuromuscular diseases and immune deficiency, collaboration in trials concerning adrenoleukodystrophy and epidermolysis bullosa etc and the opening in 2005 of a clinical vector production unit. Also Généthon is pursuing its research into emerging therapeutic leads, in particular exon skipping and stem cells.

Genopole: encouraging the crossover of fundamental to applied researchWith the success of Généthon came the birth of a political will and the State took over. The know-how of Généthon was transferred to the National Centres of Genotyping and Sequencing installed at the Genopole at Evry. This campus, created with the AFM’s support in 1998, is dedicated to genetics, genomics and biotechnologies and today heads an association of 25 public laboratories, 50 life-science high technology companies and university training courses.

Décrypthon: studying proteins and their interactionsAfter genomics, the AFM is now tackling proteomics (understanding of proteins and their interactions). Décrypthon was launched in 2001. By mobilising the calculating power of the computers of 75 000 netsurfers, this operation allowed the comparison of 550 000 proteins from the living world. Mapping was carried out and placed at the disposal of the scientific community. In 2003, the AFM launched an invitation to tender in order to support projects using this database. Four projects were accepted including one concerning X-linked adrenoleukodystrophy. At present, the Association is working on a second Décrypthon project which places powerful means of calculation at the disposal of researchers by associating university calculation centres.

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The Institute for Rare Diseases: developing fundamental research into rare diseasesIn 2000, the AFM – in association with Inserm and the Ministry of Research – launched a joint invitation to tender which led to the setting up of 32 pluridisciplinary research networks into rare diseases. Following this, in 2002 the AFM encouraged the creation of an Institute for Rare Diseases, associating the Ministries of Research, Industry and Health, Inserm, the CNRS, the CNAM, the Alliance for Rare Diseases and the AFM. Organised as a scientific interest group, the mission of the Institute for Rare Diseases is to stimulate, develop and coordinate research into these diseases. It has already financed 70 research networks and more than 100 projects through invitations to tender for such different diseases as Rett syndrome, amyotrophic lateral sclerosis, osteosarcoma, genodermatosis, Evans syndrome, cutis laxa, dystonia, metabolic diseases etc. It has also developed partnerships with the Mouse Clinic in Strasburg for the development of animal models and with the pharmaceutical industry for the provision of molecules likely to be of therapeutic interest for rare diseases. At present, the AFM remains the principal financial contributor to the Institute for Rare Diseases.

The Institute of Myology: improving knowledge of the muscleTo make progress in understanding the mechanisms of neuromuscular diseases due to different lesions, the AFM supports fundamental research into the physiopathology not only of the diseased muscle, but also of the injured or aging muscle. Each year, it finances several research teams through its “fundamental myology” calls for tender. In addition, to encourage the emergence of myology as a scientific and medical discipline in its own right, the AFM created the Institute of Myology in 1997. Today, situated in the heart of the Pitié-Salpêtrière Hospital Group, this international centre of expertise of the muscle is developing an original collaboration between researchers, physicians and patients as well as a national and international teaching programme in myology. It is also a first class clinical centre with 16 trials or studies at present under way concerning – as well as neuromuscular diseases – malignant hyperthermia, multiple sclerosis etc.

DEVELOPING INNOVATIVE TREATMENTS

Because traditional medicine offers no therapeutic solution to neuromuscular diseases, the AFM has been involved in the development of innovative treatments based on the understanding of genes and cells, particularly within the framework of its Great Attempt (1998-2002) and New Frontier (2002-2007) scientific programmes. The first results, obtained in 2000 and 2001 by French teams long-supported by the AFM, were for children affected with severe combined immune deficiency (bubble babies), heart failure or Huntington disease. They demonstrate the relevance of this strategy and the necessity of continuing along this path.

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Exploring all the emerging therapeutic leadsThe AFM has been involved in the development of treatments with the intention of following up all leads. It encourages all initiatives which emerge from laboratories, supports preclinical work and – when a promising new lead is confirmed – sets out to identify the rare diseases potentially candidate for this technique and supports the clinical trials on these “model” diseases.

Today, beyond the original concept of the gene-drug (transfer of a therapeutic gene to the nucleus of a cell), new leads are opening up which could have applications for very many rare diseases. In particular, they allow direct intervention on the gene or the “message” delivered by the gene to the cell. In this way:

- mixed oligonucleotides (an NRA a DNA hybridised together) are able to associate with a specific part of the genome (there where there is a mutation) and to cut the DNA in order to take out and replace the zone containing the mutation responsible for the disease. This technique has been studied in the animal for haemophilia B, Crigler-Naajjar syndrome and oculo-cutaneous albinism.

- exon skipping can allow the elimination of the mutated part of NRAm and make possible the production of a slightly different but functional protein. The first spectacular results concerning Duchenne myopathy were obtained at Généthon on the mouse. This technique also had a preclinical application to beta-thalassemia. In addition, other diseases where truncated proteins maintain their function are concerned, for example, haemophilia A or epidermolysis bullosa. In partnership with Genatlas database, the AFM has just launched a programme to identify for rare genetic diseases which will be able to benefit from this new technique.

- antisense oligonucleotides can adapt gene expression. In preclinical studies this technique is applied to dominant genetic diseases with triplet expansion, such as Steinert myotonia, fragile X syndrome, spinocerebellar ataxia, Friedreich ataxia or Huntington disease.

- reading through a stop codon allows the unblocking of a premature stop in the production of a protein for certain patients affected by Duchenne myopathy, cystic fibrosis or mucopolysaccharidosis type 1.

- stimulation of foetal or alternative gene expression using certain pharmacological products can compensate for the deficient protein. In particular, this technique would be applicable for spinal amyotrophies (SMN2 gene), Duchenne myopathy (utrophin gene), beta-thalassemia and drepanocytosis (foetal haemoglobin gene).

- recombinant proteins can be developed to compensate for deficiencies, as in Fabry and Gaucher diseases.

New leads are also emerging in cell therapy, in particular through stem cells. As they are capable of transforming themselves into different types of cells, these cells offer promising therapeutic prospects for the reconstruction of a damaged organ or tissue. As well as the transplants of myoblasts (muscle stem cells) applied in neuromuscular diseases (Duchenne myopathy, oculo-pharyngeal muscular dystrophy, facio-scapulo-humeral dystrophy), certain stem cells can be used in the degenerative diseases of the liver, the nervous system or immune deficiencies etc. With the support of the AFM, this work is being carried out in its Généthon laboratory, at the Cochin Institute and at the Institute of Biotherapy Research at Montpellier. Foetal stem cells can also be transplanted to compensate for damaged tissue in Huntington disease, for example.

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Finally, embryonic stem cell research was authorised with the revision of bioethics laws in August 2004, and this should lead to major therapeutic progress. In order to explore this lead, the AFM supported the opening of an embryonic stem cell study centre at Evry in 2005. This centre directed by Marc Peschanski has a dual objective: to cultivate cell lines and to study the differentiation process of these cells for the treatment of monogenic diseases.

Improving therapeutic tools and techniquesHuman trials have shown up obstacles that need to be overcome if the effectiveness of treatments is to be improved. This is why the AFM supports research programmes that aim to reduce these obstacles. The objectives are to:

- improve vectors: vectors are necessary tools for transporting therapeutics to the nucleus of cells (for example, by gene transfer for gene therapy or for gene surgery). This field was still new less than 10 years ago and knowledge is being refined. The AFM is pursuing its research at Généthon (Evry) for example, but also at Nantes, Geneva and Barcelona.

- transport the treatments more widely in the diseased tissue: in order to bring the drug to the largest possible number of cells, much work needs to be done on the transport methods of these treatments, in particular by systemic route, in other words, using the blood circulation to repair the maximum of damaged tissue. A new method of gene transfer (a plasmid) by intravenous injection has been developed with the support of the AFM by Prof John Wolf in the United States.

- control better the immune system: the mission of the immune system is to recognise and reject all elements foreign to the body. This of course raises a real barrier to gene transfer or cell transplants. It is therefore vital to understand better how the system functions. The know-how developed by Prof Brigitte Dreno at the University Hospital Centre at Nantes and supported by the AFM brings valuable understanding in this field.

- evaluate the effectiveness of therapeutic solutions: a treatment cannot be validated if it has not been suitably evaluated. In this case, it is a question of designing or improving tools capable of following the effects of new therapies in the human body. In particular, the AFM supports access to and improvement of imaging techniques.

Encouraging human trialsAs cure remains its objective, the AFM encourages human applications of new therapeutic strategies as early as possible. In 2001, it was associated with the Italian Comitate Telethon in launching a joint invitation to tender with the aim of associating French and Italian teams in the setting up of clinical trials for rare diseases. In total, the financing of about 15 gene or cell therapy trials on “model” rare diseases has been planned within the New Frontier programme between 2002 and 2007. These trials will allow the validation of the therapeutic effectiveness of a particular strategy before envisaging its transfer to other diseases presenting similar problems.

Thus, as well as trials concerning muscular diseases, the AFM gives its support to the following current or future clinical trials:

- Gene therapy for chromosome X-linked severe combined immune deficiency (A. Fischer)

- Gene therapy in non-lethal Junctional Epidermolysis Bullosa (JEB) (M. de Luca, JP Ortonne)

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- Cell therapy for Huntington disease by transplantation of foetal neurones (M. Pechanski)

- Cell therapy for transplant rejection in the transplant of haematopoeitic stem cells (M. Cavazzana-Calvo)

- Gene therapy for cerebral forms of X-linked adrenoleukodystrophy in the child (P. Aubourg)

- Gene therapy for auto-immune diseases complicated by myelodysplasia/secondary leukaemia (phase I/II) (D. Klatzmann)

- Gene therapy for severe combined immune deficiency linked to a deficiency in the Adenosine Deaminase enzyme (M.G. Roncarollo)

- Gene therapy for drepanocytosis and thalassemia (E. Gluckman)- Gene therapy for Wiskott-Aldrich disease (Généthon)

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IMPROVEMENT OF PATIENTS’ DAILY LIVES

For a long time ignored by science, medicine and public authorities, persons affected by neuromuscular diseases had to face up to an exclusion that limited any life projects. Then, through the AFM, patients took their destiny into their own hands and developed innovative solutions to fight against these progressive and seriously disabling diseases. The majority of these initiatives are applicable not only to neuromuscular diseases, but to other rare pathologies.

COMING OUT FROM OBLIVION

Changing opinionsBeyond its fund-raising operation that allows the AFM to finance its projects, one of the effects of the French Telethon has been to mobilise a whole population around little-known diseases. By giving them the opportunity to express themselves, to describe their daily lives, their expectations and hopes, it has brought to light persons whose disease or handicap had relegated to the outskirts of society. It is a powerful vector of sensitisation which has changed public opinion and highlighted long-ignored diseases. Thus, through such different diseases as pigmentary retinitis, epidermolysis bullosa, cutis laxa, amytrophic lateral sclerosis, Usher syndrome, infantile axonal neurodystrophy and many others, the Telethon has led to public understanding and media coverage of the term “rare disease.” Today, during the Telethon, it’s a whole population which participates in the fight against the disease and contributes to developing the medicine of tomorrow.

Existing through representation by an associationConvinced that association is the most effective way of bringing patients’ claims to public attention, the AFM has supported the creation and development of association structures dedicated to rare diseases, in particular by ensuring a large share of their financing.

In 1997, the AFM – with the VLM (French association for cystic fibrosis), the National League against Cancer and the AIDES National Federation – contributed to the creation of EURODIS. EURODIS is a European federation of associations of rare diseases whose main mission was to see through the elaboration of European regulations on orphan diseases, adopted in December 1999. Today, with more than 200 member-associations, EURODIS is a widely-consulted and respected interlocutor at a European level. In this capacity, it contributes to developing access to treatments, information, mutual assistance services for persons affected with rare diseases and also encourages the development of patient-centred research. EURODIS participates in the COMP (Orphan Drugs Committee) and in different work groups within the European Drug Agency.

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In 2000, the AFM supported the creation of the Alliance for Rare Diseases in France, with the aim of making the issue of rare diseases better recognised in our country. The Alliance is a collective of associations whose main missions are to raise awareness of the problems posed by these diseases, to improve the quality of life of the affected persons, to promote the hope of cure by research and to act as the spokesperson of the associations and patients. Financed to a level of 80% by the AFM, the Alliance groups together more than 130 associations representing more than 1000 diseases and more than a million patients. Today it is a recognised interlocutor which represents and defends the specificities of rare diseases in numerous official organisations.

Finally, the AFM wished to reinforce its action and the visibility of its structures by grouping them within a Platform for Rare Diseases. Since 2001, the main associations and public organisations working in the field of rare diseases have been accommodated at the same place. They are: the Alliance for Rare Diseases, EURODIS, the Institute for Rare Diseases, the Rare Diseases Information Service and Orphanet.

Rare diseases – the question of recognitionBecause being taken into account in a health system involves political recognition, the AFM has long lobbied for rare diseases to be recognised as a public heath issue. In October 2001, the ex-president of the AFM, Bernard Barataud published a study for the Social and Economic Council outlining the state of play and possible leads for action. The law of 9 August 2004 relating to public health policy marks an important stage in the strategy of recognition and taking into account of rare diseases. Thanks to the AFM, the notion of rare diseases figured in the statute books for the first time in France. Moreover, rare diseases are recognised as one of the five major public health priorities for the next five years. In order to implement this strategic axis, a national plan for rare diseases has been launched by French government in november 2004. Another strong sign of this political recognition is the Finance Bill for 2005 for research which places rare diseases as one of the first thematic priorities due to “their diagnostic difficulties and limited availability of treatments.”

Defending patients’ rightsIt was to further highlight patients’ interests that the AFM joined the Inter-association Collective for Health which, since 1996, groups together the main national associations of sick or disabled persons, consumers and families. On behalf of patients, it intervenes on essential subjects such as the bill for patients’ rights, modernisation of the health system or reform of sickness benefits.

ATTAINING FULL CITIZENSHIP

Restoring equality of opportunityAttaining full citizenship means being able to devise a life project and benefit from a social life without being prevented by disease or its consequences. With this always in mind, the AFM defends the right to compensation. This principle aims to restore equality of opportunity by opening up access to all forms of assistance necessary to the autonomy of each disabled person (technical and human assistance, specially-equipped accommodation etc).

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Also, the Association set out to have the right to compensation included in the Social Modernisation law of 17 June 2002. Equally, it wants to ensure that this implementation by the law of the equality of rights, opportunities, citizenship and participation of disabled persons remains true to the principle of the law. While awaiting the implementation of this right and the financial means necessary for its application, the AFM is pursuing its assistance through the acquisition of technical aids through the Personalised Aid Fund. As well as neuromuscular diseases, the AFM has endowed the APF (French Paralysis Association) with a similar fund for all persons affected by a motor handicap, whatever the origin.

Compensating disabilitiesIn the field of technical aids, the AFM has for many years supported the development of innovative technical aids which allows the restoration of movements interrupted by disease: manipulation robot, electric wheelchair, mini-arm for driving, page-turner etc. It encourages technological innovation by financing innovative research projects and contributing to the design then evaluation of prototypes. Finally, it participates in the publishing of information about the means of compensation available in Europe.

Choosing where you liveYoung adults naturally wish to choose where they live. In proposing an alternative to the family home or an institution, the AFM began an experimental research programme in 1991 about the conditions necessary for completely dependent tracheotomised persons to lead their lives at home. The results of this work came in 1997 with the construction of the “Gâte-Argent” in Angers: 10 apartments integrated into a social housing programme with a special provision of services guaranteeing tenants maximum security.The evaluation of this experimental programme should in the long run lead to an ongoing and reproducible solution, particularly for other situations of dependence.

Encouraging social participationIn order to respond to the specificities of neuromuscular diseases, the AFM set up a new profession in 1988. These professionals would intervene at the request of families in the realisation of a life project. Acting as an interface between health and social services, they help sick persons and their families find solutions to problems posed by the disease on an everyday basis as well as at each stage of its progression: diagnosis, treatment, means of compensation, schooling, work etc. Today, the AFM would like to prolong this initiative and has begun experiments to validate the relevance and usefulness of this new profession for other progressive and disabling diseases.Since 2002, four experiments have thus been carried out in different organisations:

- departmental association for Down’s syndrome persons (GEIST 21, Bordeaux)

- specialised team for autonomous home life (ESVAD of the APF, Lille) - service of adaptation for persons affected with progressive neurological

diseases (CHU of Tours)- institutions in the service of multihandicapped persons (site pour la vie

autonome, Nancy)

Finally, in Luxembourg and in partnership with the local association for neuromuscular diseases, the AFM supports the placing of one of these

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professionals who could also intervene in cases of persons affected with rare diseases.

The first evaluations of these experiments confirm the social usefulness of this new profession and indicate that its expansion can serve the general interest as it conforms to current developments in public policy. The AFM is working in this direction through a representative dedicated to the recognition of this innovative profession and the organisation of a conference on the support and caring professions in 2005.

FIGHTING MISDIAGNOSIS

As well as lack of knowledge and social recognition, the main difficulty still too often faced by patients remains misdiagnosis. Today, out of 6000 rare diseases, only 1600 genetic anomalies have so far been identified. This means that for 75% of rare diseases of genetic origin, there are few genetic elements at our disposal, making diagnostic possibilities more or less non-existent. The persons concerned do not have access to adequate health care and are “deprived” of any therapeutic prospects. Yet the ignorance surrounding these diseases can be at the origin of real catastrophes: inappropriate patient management with occasionally very serious consequences, multiple births of handicapped children, deaths etc. Faced with this problem which affects above all those unable to construct a daily life or make future plans, the AFM has set up initiatives to reduce the lead-time from first symptoms to diagnosis.

Facilitating access to informationConscious of the lack of information from health professionals about these diseases, the AFM began to develop information tools in 1995, when it created Allo-Gènes, a genetic diseases information service. Since 2002, the “Maladies rares info services” took over and developed the work of Allo-Gènes. This service is for individuals – patients and their families – as well as health professionals and is accessible at the number 0 810 63 19 20.Simultaneously, the AFM supported the setting up of Orphanet in 1996 in collaboration with Inserm. Orphanet is a database of rare diseases and orphan drugs and can be consulted on internet. It collects information on current research programmes, diagnosis laboratories, patients’ associations and specialised consultations etc.Today, the information from Orphanet covers 20 European countries. In order to place the latest news about research and patient management at the disposal of everybody concerned, the AFM finances the “Orphanews” newsletter, distributed to several thousand readers.

Setting up networks of competenceBecause accurate and precise diagnosis is the determining factor in the management of each disease, the AFM has supported the setting up of pluridisciplinary consultations for neuromuscular diseases throughout France. They guarantee patients a certain quality of treatment and management by the different relevant specialists in the same place. In the light of its experience, in 2002 the Association participated in the ministerial work-group which drew up the specifications for pluridisciplinary consultations which could be quality-labelled “centres of reference for rare diseases.” The labelling in 2004 of the first

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centres of reference for groups of rare pathologies should improve access to diagnosis and adapted treatment.

Concerning diagnosis, the AFM defended the possibility for families affected by serious and mortal diseases to have access to pre-implantation diagnosis, as provided for in the law of July 1994. This technique, available in three centres in France (Paris, Montpellier and Strasbourg), has opened the possibilities for couples to envisage new pregnancies in cases of rare diseases such as cystic fibrosis, fragile X syndrome, Tay-Sachs disease and Von Recklinghausen disease. Finally, in 2003, under the impetus of associations, molecular biology laboratories dealing with diagnosis received supplementary State finance through an invitation to tender from the Ministry of Health. These additional means should contribute to the improvement of the quality and reliability of diagnoses of particularly complex diseases.

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CONCLUSION

The public health law adopted in 2004 recognised rare diseases as one of the five major national priorities for the next five years. However, it is vital that this political will is accompanied by concrete, coherent and well-designed measures that are led and financed for the long term. In the discussions for the elaboration of a “rare diseases” national plan, the AFM made eight priority proposals for the measures taken to have a real impact on the patients concerned.

1) Creating a real DNA field of activity- By organising and systematising the DNA collection of persons concerned and their families, an indispensable precondition to any research- By ensuring ongoing financing and institutional stability to guarantee the security of samples, their temporal stability and regulation of their use- By intensifying genotyping

2) Reorganising the system of treatment to limit misdiagnosis- By creating quality-labelled centres of expertise, bridgeheads of local treatment networks and reference centres for good practices- By ensuring them a financing strategy which also encourages research development- By giving them authority to bear medical costs with regard to health insurance and socio-medical structures.

3) Stimulating and coordinating research- By encouraging the networking of laboratories and research teams in France as well as in Europe- By widening access to modern research tools to all the teams working in isolation and with limited means- By considerably increasing public financing of research into rare diseases

4) Training and informing- By developing physicians’ faculty of critical doubt, continuing training initiatives and expert diagnostic assistance systems- By improving how emergency situations are managed, particularly through standardised official “patient cards” giving first aid care information- By continuing and developing telephony tools both for professionals and sick persons- By reinforcing online databases- By standardising information documents about the diseases, particularly those from patients’ associations

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5) Developing epidemiology- By planning and financing studies on the natural history of each disease, with watchdog organisations, registries and diagnosis review campaigns to keep up to date with research advances

6) Facilitating access to treatments and individualising support of medical costs- By guaranteeing to bear medical costs for all medical and para-medical treatments on the basis of protocols validated by centres of reference - By systematising the reimbursement of travel expenses to centres of reference without complicated procedures of prior agreement

7) Recognising and developing specific care needs- By setting up and financing professionals specialised in the care of persons affected with rare diseases

8) Creating an ongoing and structured road map for an overall policy in favour of rare diseases- Taking into account issues of research, information and medical costs- Following up the implementation of the “rare diseases” plan- Issuing the quality labelling for the centres of reference and leading their network functioning

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APPENDICES

RESEARCH PROGRAMMES ON RARE DISEASES DIRECTLY SUBSIDISED BY AFM*

Acyl-CoA dehydrogenase, medium chain deficiencyAdenomatous polyposisAdrenoleukodystrophyAlport syndromeAmyloidosis, hereditaryAmyotrophic lateral sclerosisAngelman‚s syndromeAngioedema, hereditaryAtaxia telangiectasiaAtaxia, hereditaryAtherosclerosisAutismAutoimmune diseasesBeckwith-Wiedemann syndromeBone diseases/Osteogenesis imperfectaBreast cancer, familialByler disease/Alagille syndromeCardiac malformations, congenitalCardiomyopathy, dilatedCardiomyopathy, hypertrophicCardiomyopathy, idiopathicCerebellar ataxiaChediak-Higashi syndromeChondrodysplasiaChromosomal micro-rearrangementsChromosomal rearrangement with holoprosencephalyChronic pulmonary hypertensionColonic polyposisColorectal cancerConvulsions, benign neonatalCraniostenosisCrigler-Najjar syndromeCrohn’s diseaseCutis laxaCystic FibrosisCystinosisDeafness with ear aplasiaDeafness, congenitalDegenerative disease of the cerebellum and the spinal cordDiGeorge’s syndromeDown‚s syndromeDwarfismsEAEEctrodactylyEpidermolysis bullosaEpilepsy, idiopathicEpilepsy, myoclonic

Erythrocyte hereditary diseasesFamilial hematuriaFamilial Mediterranean feverFanconi’s anemiaFebrile convulsionsFragile X syndromeFriedreich ataxiaGenodermatosisGlanzmann’s thrombastheniaGlaucoma, familial hereditaryGlycogen storage disease type 1a and 2bGorlin’s syndromeHaemophilia BHemachromatosisHirschsprung‚s diseaseHolt-Oram syndromeHuntington‚s diseaseHydrocephalus, X-linkedHyperchlosterolemia, familialImmune deficienciesIncontinentia pigmentiKallmanns syndromeLaurence-Moon and Bardet-Biedl syndromesLeukemiaLeukoencephalopathyLissencephalyLiver cancer, primaryLong QT syndromeLysosomal diseasesMalonyl CoA mutase deficiencyMarfan’s syndromeMeckel’s syndromeMeningiomaMental retardationsMethemoglobinemia, congenitalMucopolysaccharidosis type 2Multiple sclerosisMuscular lipidosisNephronophtisisNeurofibromatosisOlivopontocerebellar atrophyOndine syndromePancreatitis, chronic familialParathormone resistanceParkinson’s diseasePelizaeus-Metzbacher diseasePeroxisomal diseasesPersistent Mullerian duct syndromePhenylketonuriaPolyarthritis rheumatoid

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PolyendocrinopathyPorphyria, acutePrader-Willi syndromeprogeriaPseudohypoaldosteronismRendu-Osler diseaseRestrictive dermopathyRetinal dystrophyRetinitis pigmentosaRetinochoroidopathy, BirdshotRett syndromeSchizophreniaSickle-cell diseaseSpastic paraplegiaStrümpell-lorrain syndromeSinus dysfunctionTay-Sachs diseaseThrombosisThymic epitheliumTrichothiodystrophyTuberous sclerosisTurner‚s syndromeUveitis’ chronicVon Hippel-Lindau diseaseWerner’s syndromeWillebrand diseaseWiscott-Aldrich syndromeXeroderma pigmentosumX-linked adrenoleukodystrophyX-linked mental deficiency

*This list does not take into account the diseases stored in the cell and DNA bank of Généthon, nor those stored in the AFM‚s Tissue Bank for Research, nor the diseases concerned by the Calls for Proposals of the Rare Diseases Institute financed by the AFM.

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AFM INVESTMENTS IN RARE DISEASES BETWEEN 1999 AND 2003

1999 33,1 M¤

2000 32,9 M¤

2001 36,2 M¤

2002 39,9 M¤

2003 35,7 M¤

TOTAL 177,8 M¤

This table does not include AFM investments in general interest actions (15,3 M¤)

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