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Rare genetic diseases: update on diagnosis, treatment and online resources
Drug Discovery Today Volume 00, Number 00 November 2017
Rare genetic diseases: update on diagnosis, treatment and online resources Q1
Robert E. Pogue1,z, Denise P. Cavalcanti4, Shreya Shanker5, Rosangela V. Andrade1, Lana R. Aguiar1, Juliana L. de Carvalho1,6 and Fabrício F. Costa1,2,3,z
1 Q2 2 Genomic Sciences and Biotechnology Program, Catholic University of Brasília, Distrito Federal, Brazil MATTER, Chicago, IL, USA 3 The Founder Institute, San Francisco, CA, USA 4 University of Campinas (UNICAMP), Sao Paulo, Brazil 5 Illinois Mathematics and Science Academy (IMSA), IL, USA 6 OneSkin Technologies, San Francisco, CA, USA
Rare genetic diseases collectively impact a significant portion of the world’s population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computeraided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how a collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases.
Introduction The terms ‘rare disease’ and ‘orphan disease’ are used to describe conditions that affect a small proportion of the population; in the USA they are described as affecting fewer than 200 000 people (http://www.fda.gov, May 2017), and in Europe as affecting fewer than one in 2000 (http://www.orpha.net/consor/cgi-bin/index. php, May 2017). Although the terms are often used interchangeably, orphan diseases are also defined as diseases that are underappreciated or ignored by the medical community and drug companies. The Orphanet portal for rare diseases and orphan drugs (http://www.orpha.net) lists 5856 diseases in its database (January 2017). Although individually rare, the statistics suggest that collectively these conditions affect up to 10% of the popula-
Corresponding authors: Pogue, R.E. ([email protected]), Costa, F.F. ([email protected]), ([email protected]) z
These two authors contributed equally in this review article.
1359-6446/ã 2017 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2017.11.002
tion (California Healthcare Institute: http://califesciences.org/). In this context, rare diseases represent a significant impact on health and, as such, it is important for healthcare professionals to be aware of the resources that exist to support their diagnosis, management and treatment. Q3 Many rare diseases are genetically inherited (Fig. 1a), and this fact can cause resistance among doctors owing to perceptions of genetic diseases as difficult and expensive to diagnose, and with few treatment options. Rare diseases can be stratified as lethal, severe but nonlethal, and not severe and manageable diseases, with effective treatment options (Fig. 1a). Also, with novel DNA sequencing technologies, diagnosis is less expensive and can contribute to prognosis determination, as well as to disease treatment, which can follow specific and/or nonspecific strategies (Fig. 1b). Because these diseases are uncommon, most doctors have no experience in diagnosing or treating them and there might only be a handful of physicians in the world who have
www.drugdiscoverytoday.com 1 Please cite this article in press as: Pogue, R.E. et al. Rare genetic diseases: update on diagnosis, treatment and online resources, Drug Discov Today (2017), https://doi.org/10.1016/j. drudis.2017.11.002
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DRUDIS 2119 1–9 Drug Discovery Today Volume 00, Number 00 November 2017
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(a)
Rare diseases Genetic
Lethal
Severe, but nonlethal
Nongenetic
Not severe
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(b)
Rare disease steps for evaluation Specific Diagnosis
Prognosis
Treatment Nonspecific
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FIGURE 1
Rare disease stratification and steps for evaluation. Rare diseases can be divided into genetically inherited and nongenetically inherited diseases, which can present different degrees of severity (a). The steps for rare disease diagnosis are essential, as with the diagnosis in hand, the healthcare professional can assess patient prognosis and treatment options, which might be specific for the disease being treated or unspecific, focusing on mitigating disease symptoms (b).
direct experience with a given condition [1]. These conditions are frequently further complicated by genetic and phenotypic heterogeneity. Compared with common and complex conditions that strike hundreds of millions of people such as diabetes, cancer, among others, rare diseases can lack similar levels of interest among the general public, medical and research communities, and pharmaceutical companies. Moreover, the fact that drug development in general is complicated, time-consuming and expensive, with extremely low success rates further complicates the situation [2]. In this context, orphan drugs are defined as compounds used for treating rare diseases [3]. The current review focuses on progress related to diagnosis, management and treatment of rare diseases that have a genetic origin, with emphasis on diagnostic tools, existing and in-development treatments, and the use of online and web-based resources for diagnosis, research and patient support.
Progress in molecular diagnosis of rare diseases Since 2010, the number of genes and mutations found per year has grown rapidly, thanks to improvements in DNA sequencing technologies and big data analysis [4,5]. Orphanet currently lists 3573 genes associated with rare diseases (May 2017). Many commercial and customizable gene-sequencing panels are available for relatively low-cost analysis of genes related to specific disorders or groups of diseases, and directories of diagnostic laboratories and the genetic tests that they offer can be found on sites such as Orphanet. For a more comprehensive analysis, exome sequencing has become technically feasible and more cost-effective, offering new opportunities for Mendelian disease diagnosis and research [4,6]. Exome sequencing limits sequencing mainly to the protein-coding regions of the human genome. These 180 000 2
exons constitute 2% of the whole genome but contain an estimated 85% of heritable Mendelian disease-causing mutations [4]. However, it must be remembered that variants affecting regulatory and noncoding DNA regions might be the cause of some cases of rare diseases [7]. Currently, the cost of sequencing an exome in the clinical setting is
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Treatment options: current and future therapies The issue of therapies for rare diseases goes hand-in-hand with the discussion of diagnosis, because in the end any patient being tested for a genetic disease (or any healthcare professional recommending a test) wants to know what treatments the results might indicate. The general public are now more aware of the availability of genetic tests, and so the expectation of effective therapies will increase. However, diagnosis, possibly leading to improved disease management, often does not lead to disease-modifying treatments [14,15]. For metabolic disorders, successful disease management frequently results in significant improvement in quality-of-life, because such diseases are often responsive to therapy that targets pathophysiological features, such as enzyme replacement and/or dietary therapy [14]. For instance, hypophosphatasia is an inborn error of metabolism with available enzyme replacement therapy. Since 2012, asfotase alfa, a chimeric recombinant protein with an alkaline phosphatase ectodomain, has provided clinical evidence for successful management of the disease [16]. Currently, asfotase alfa is approved for use in Japan, Canada, the EU and the USA. In the absence of afostase alfa, patient management reverts to supportive action [16]. In 2016, Tarailo-Graovac et al. [14] provided evidence that, at least for neurometabolic disorders, whole-exome sequencing combined with deep clinical phenotyping resulted in a 44% rate of change in treatment beyond genetic counseling for patients with
intellectual developmental disorders and unexplained metabolic phenotype. In other words, the combination of clinical and genetic information has led to customization of patient management, which included dietary changes for at least five probands, among other strategies. It has been estimated that such modifications resulted in increased quality-of-life. In addition to enzyme replacement and dietary therapy, gene and cellular therapy options are also increasingly available. For diseases such as severe combined immunodeficiency (SCID), cellular therapy based in bone marrow transplant is available over several years and is sufficient to cure patients [17]. Nevertheless, the underlying genetic defect is not reverted. Therefore, strategies available frequently fail to deal with the primary cause of rare diseases, which is the genetic alteration. Several countries have introduced an orphan legislation, with incentives to produce and increase access to appropriate treatments for some patients with rare diseases [18,19]. However, high costs and a lack of transparency remain an issue. A summary of rare genetic diseases, their estimated incidence according to the literature, genes associated, current treatments (and estimated costs), as well as companies providing treatments is provided in Table 1.
Gene therapy Gene therapies are strategies for permanent treatment of genetic diseases. Gene therapies seek to correct the DNA alterations responsible for any given genetic disease, either by replacing the defective gene or by inserting normal copies of such genes in the genome. Despite the simple rationale, successful gene therapy requires correct and efficient delivery of new genetic information into a relevant percentage of target cells, which must survive and proliferate in the host to sustain the beneficial effects without eliciting negative responses [20]. Initially developed focusing on cancer treatment, gene therapy has expanded its application from cancer toward monogenic, rare diseases, aiming to benefit from reduced development risk when dealing with diseases with very clear and defined genetic etiology. Also, the possibility of receiving orphan status is an important attraction factor. Therefore, the first clinical trials for gene therapy were in the rare disease field (for a comprehensive review, see Ref. [21]). Initiated by the success of recent clinical trials, the field is now developing T cell and oncolytic viral therapies focused in other areas [22]. Initially, ex vivo transfection was the main strategy for gene therapy and, owing to ease of cell isolation, initial efforts focused on blood disorders [23–25]. Later in vivo trials showed limited success, and suffered the setback of the 1999 death of a patient in a trial based on adenovirus-mediated correction of ornithine transcarbamylase deficiency [26]. Also, the lack of efficiency in other trials fed a gradual decline in interest. More recently, viruses including lentiviruses and g-retroviruses have been improved regarding genotoxicity and integration [21], emerging as vehicles for hematopoietic stem cell transduction and treatment of disorders such as adenosine deaminase deficiency, SCID [27,28], b-thalassemia [29], X-linked adrenoleukodystrophy [30] and Wiskott–Aldrich syndrome [31]. Positive results have also been reported using adeno-associated virus (AAV) [22] in the treatment of familial lipoprotein lipase deficiency, a rare disorder that results in childhood-onset severe
www.drugdiscoverytoday.com 3 Please cite this article in press as: Pogue, R.E. et al. Rare genetic diseases: update on diagnosis, treatment and online resources, Drug Discov Today (2017), https://doi.org/10.1016/j. drudis.2017.11.002
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of CNVs being benign [10]. More recently, DNA sequencing on the genomic scale, using paired-end and split-read approaches, has become a viable option for cytogenetic analysis [11]. The problem arises in the interpretation of CNVs and the determination as to which are pathological and which are benign. Although data such as population frequency can help in the determination of probable pathogenicity, many CNVs end up being classified as ‘of unknown clinical significance’ [10]. The rare nature of many pathological CNVs makes their interpretation difficult owing to lack of other patients for comparison [12,13]. For this reason, deposition of data in clinical structural variant databases is an important process. The European Cytogenetics Association Register of Unbalanced Chromosome Aberrations (ECARUCA) is fed mainly by a network of European cytogenetics researchers focused on identifying chromosomal anomalies in rare diseases. The database contains data from >5000 patients, listing almost 7000 chromosomal anomalies with 2713 distinct CNVs. More than 50% of the listed anomalies are deletions, and the most frequent structural anomalies apart from deletions are duplications, followed by rings, triplications and uniparental disomy. The Decipher database (https://decipher.sanger.ac.uk) is a repository for genomic variants (mainly CNVs) that has collected >30 000 CNVs from >21 000 patients with rare diseases. Equally important in the evaluation of molecular cytogenetic profiles in patients with rare diseases are databases of normal genomic variation, the most important being the Database of Genomic Variants (DGV; http://dgv.tcag.ca/). DGV contains data regarding structural variation in normal samples, and as such is an important negative screening tool, because a CNV listed in DGV is less likely to be responsible for a rare disease.
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TABLE 1
Q7 Partial list of rare genetic diseases, incidence in populations, genes associated, treatment costs, drugs and pharmaceutical and Q8
biotechnology industries commercializing the drugs
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Disease (OMIM)
Incidence
Genes associated
Treatment costs in US$ (per patient per year)
Drugs
Companies
Cystic fibrosis (CF) (#219700)
1:2500
CFTR
US$200 000
Kalydeco1
Vertex Pharmaceuticals (VRTX)
Fabry disease (#301500)
1:50 000
a-Galactosidase A (a-GAL)
US$200 000–300 000
Replagal Fabrazyme1
Shire Pharmaceuticals (SHPG) Sanofi-Genzyme (SNY-GENZ)
Gaucher disease (Types I and II) (#230800)
1:50 000 (general population) 1:1000 (Ashkenazi Jewish)
GBA (b-glucocerebrosidase)
US$300 000
Elelypso Cerezyme1
Pfizer (PFE) Sanofi-Genzyme (SNY-GENZ)
Hemolytic uremic syndrome (aHUS) (#609536)
1: 100 000 to 1: 1 000 000
C5
US$400 000–500 000
Soliris1
Alexion Pharmaceuticals (ALXN)
Hereditary angioedema (#106100)
1:30–50 000
C1NH, SERPING1
US$300 000
Cinryze1
ViroPharma (acquired by Shire Pharmaceuticals SHPG)
MPS I or Hurler syndrome (#607014)
1:100 000
GNS, HGSNAT, NAGLU and SGSH
US$365 000
Elaprase1
Shire Pharmaceuticals (SHPG)
MPS IV or Moreteauz– Lame disease (#253010)
1:100 000
GALNS and GLB1
US$500 000
Naglazyme1
Shire Pharmaceuticals (SHPG) Biomarin (BMRN)
Nieman–Pick, type C (#257220)
1:150 000
NPC1, NPC2
US$100 000
Zavesca1 (Miglustat)
Actelion Pharmaceuticals (ALIOF)
Pompe disease (#232300)
1:40 000
GAA
US$298 000
MyozymeTM
Sanofi-Genzyme (SNY-GENZ)
Progeria (#176670)
1:3 000 000
LMNA
US$250 000
Lonafarnib
Merck Corporation (MRK)
Hypophosphatasia (HPP) (#146300)
1:100 000
ALP (TNSALP)
US$285 000
Strensiq1
Alexion Pharmaceuticals (ALXN)
hypertriglyceridemia [22,32]. Other clinical trials at different stages of development are: Leber’s congenital amaurosis type 2 (NCT00999609), cystic fibrosis (NCT00004533), choroideremia (NCT01461213), muscular dystrophy (NCT00428935) and a1antitrypsin deficiency ( NCT00377416) (https://clinicaltrials. gov/). The most recent developments in gene therapy have seen the appearance of gene-editing tools, such as zinc finger nucleases (ZFNs), transcription-activator-like effector nucleases (TALENs) and, more recently, clustered regularly interspaced short palindromic repeat-associated systems (CRISPR-Cas), placing gene therapy on the brink of a revolution [33]. The main advantage of such tools is the possibility of specifically targeting and correcting disease-causing mutations. Following several proof-of-concept assays, ZFNs have been tested clinically since the late 2000s (NCT02800369, NCT00842634, NCT02388594, NCT01252641, NCT01044654, NCT02500849, NCT02225665, NCT02695160, NCT02702115). The first clinical trials are also underway using CRISPR to delete PD-1 in cancer patients (NCT02793856, NCT02867345, NCT02863913, NCT02867332). Although not yet recruiting, these trials will be important in the future for rare diseases. Recently, RNAi has been tested clinically to silence defective genes by knockdown of target mRNAs. As of September 2016, 35 trials were registered at clinicaltrials.gov. Despite scarce available data, therapeutic effects have been registered in some of these trials [33]. Nevertheless, RNAi application is restricted to diseases 4
in which gene knockdown, although not complete, is of interest. The idea of modifying the DNA sequence of patients with a genetic disease recently became more attainable with the discovery and adaptation of the CRISPR-Cas9 system [34–36]. This mechanism was discovered in bacteria as an adaptive immune defense, but has since been used for editing DNA in several species, including humans [35]. The most recent iterations of the technology permit precise cutting and replacement of DNA sequences, creating the potential for repair of mutations [36,37]. In June 2016, the first clinical trial using CRISPR received provisional approval in the USA [38]. The trial, developed by the University of Pennsylvania, is focused on cancer immunotherapy, and will use CRISPR-modified T cells from cancer patients for tumor targeting [38]. Another trial is underway in China, with the objective of knocking out the PD-1 gene in T cells of patients with non-small-cell lung cancer [39]. No trials have yet started for a specific rare genetic disease, but we believe that this technology could be a game changer in the rare diseases field.
Stem cell therapy Stem cells used for therapy can be either allogeneic or autologous, if the genetic correction of the mutations is performed before therapy. Currently, the former is the more common option. This strategy has provided impressive results, especially for SCID – the first disease to be successfully treated by hematopoietic stem cell therapy >45 years ago [40,17]. Osteogenesis imperfecta (OI), caused by defective type I collagen, and characterized by painful
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fractures, skeletal deformities and retarded bone growth from fetal life, has also shown strong response to treatment [41–43]. In addition to pharmacological treatments, treating OI with mesenchymal stem cells (MSCs) has delivered exciting results. In 2002, six infants who received systemic MSC infusions responded positively to therapy with accelerated growth velocity of bone during the first 6 months post infusion [43]. Because the treatment was shown to be promising and safe, in utero MSC infusions were also tested, with the first report published in 2005 [44]. This child received MSC infusions prenatally (at week 24) as well as at 4 and 8 years of age, and showed important improvements in several aspects. Another patient identified with the same mutation, who did not receive cellular therapy, succumbed at 5 months of age, despite pharmacological treatment [41,42]. Since this first prenatal study with MSC therapy for OI, other children have been treated with positive results. Stem cells are being tested in several other rare diseases, such as rare retinopathies using embryonic stem cells (ESCs) [45] and induced pluripotent stem cells (iPSCs), as well as in Myasthenia gravis [46], inborn errors of the metabolism [47], cystic fibrosis, mitochondrial disorders (NCT02427178), rare degenerative diseases such as Tay–Sachs disease, among others. Cell therapy is at different stages of development for each of these disorders and only a small fraction of rare diseases is currently under clinical trials, according to clinicaltrials.gov (rare retinopathies: NCT01344993, NCT01469832 and NCT01345006; inborn errors of metabolism: NCT00176904; cystic fibrosis: NCT01916577; Myasthenia gravis: NCT00424489; mitochondrial disorders: NCT02427178; other immune primary immunodeficiency disorders: NCT00579137, NCT01652092). iPSCs also have an important role in rare disease research owing to their potential for modeling of diseases in vitro. Through the collection of blood [48], skin [49] or even urine [50] from patients, it is possible to produce iPSCs and to differentiate these cells with high efficiency into most cell types of interest [50–53]. This means that it is possible to generate virtually endless material for research and to study the effects of any mutation detected in patients over the phenotype of several cells. Before this technology, tissue-specific cell lines from rare disease patients were not easily obtainable, owing to the frequent difficulty of performing biopsies. These cell lines have already proven useful in several contexts. For instance, iPS cell lines derived from Hutchinson–Gilford progeria syndrome (HGPS) patients were established in 2011 [54]. HGPS-iPSCs were shown to faithfully mimic the disease; and, when differentiated into smooth muscle cells, showed premature senescence phenotypes associated with vascular ageing — a hallmark of progeria. iPSCs have been generated from Xeroderma pigmentosum (XP), the first known rare autosomal recessive genetic disorder associated with defective repair of damaged DNA [55]. Although the genetic mutations associated with the disease are already known and an XP mouse model has already been obtained, XP mice fail to reproduce the neurological abnormalities observed in humans, with the result that the underlying mechanisms of such neurological observations have not yet been clarified. By producing XP-iPSCs it was possible to generate neurons and neural stem cells, the latter showing hypersensitivity to DNA-damage-induced apoptosis. XP-iPSCs provided the
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first molecular clues underlying the neurodegeneration observed in XP patients [55]. It is expected that information provided by in vitro models of disease will be increasingly important not only for acquiring knowledge regarding disease etiology but also for disease management, through personalized toxicity, diagnosis and response screening assays [56,57]. These publications are excellent references regarding the ever-growing list of genetic disorders already modeled by iPS cell lines and the use of ‘trials on a dish’. Combined with tissue engineering and other strategies to achieve complex organs and bodies in vitro, these technologies will change research approaches, not only for rare diseases but also for other genetic disorders.
Resources for researchers, healthcare professionals and patients It is important that tools and platforms exist to support patients, their relatives, as well as healthcare professionals and researchers in the search for information to help in the diagnosis and selection of specific treatments available or even ongoing clinical trials for specific diseases. For the physician, investigating a suspected rare disease the Online Mendelian Inheritance in Man (OMIM) and Orphanet databases are an important starting point. OMIM (http://www.omim.org/) is an online catalog describing genetic syndromes and genes. It provides the research history, phenotypic information, as well as data regarding mode of inheritance genetic heterogeneity (Table 2). Orphanet [58] is a more recently developed resource that focuses on providing descriptions of rare diseases (including genes and clinical characteristics), as well as providing a diagnostic assistance tool and information regarding pharmacological compounds available for rare diseases (orphan drugs). These and other databases are interlinked to facilitate access to complementary data (Table 2). Other tools are aimed at guiding molecular analysis. For example, FindZebra (http:// www.findzebra.com/) is a search engine that specializes in rare diseases, and has proven as helpful and relevant as basic Google searches [59]. Whereas Google’s ranking algorithm attempts to rank search results based on the popularity of the articles, FindZebra’s algorithm is solely concerned with the number of times the specified query appears in the article [59]. As a result, FindZebra can be an important web-based tool for healthcare professionals trying to learn more about rare diseases (Table 2, Fig. 2), as well as for patients seeking information. Masino et al. [60] developed an algorithm that uses semantic similarity to clinical descriptor terms to prioritize genes for analysis based on associations between genes and groups of terms according to existing databases and the published literature. The GeneReviews1 website (https://www.ncbi.nlm.nih.gov/books/NBK1116/ ) is another useful tool for information regarding genetic diseases, including gene-testing resources and clinical management. Other important resources are Human Phenotype Ontology and MeSH, which classify and annotate clinical terms relating to human syndromes to standardize vocabulary for database searching, and for reporting findings. The number of genetic diseases for which the causative gene(s) is not yet known is steadily decreasing, and these diseases are increasingly rare. Because it is difficult to convincingly propose a causative gene based on one case or family alone, and because a
www.drugdiscoverytoday.com 5 Please cite this article in press as: Pogue, R.E. et al. Rare genetic diseases: update on diagnosis, treatment and online resources, Drug Discov Today (2017), https://doi.org/10.1016/j. drudis.2017.11.002
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Drug Discovery Today Volume 00, Number 00 November 2017
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TABLE 2
Q9 List of web-based and computer-aided tools available to help in diagnosing and managing rare genetic diseases Resource
Link to resource
Purpose of the resource
CORD
https://www.raredisorders.ca
CORD provides a strong common voice to advocate for health policy and a healthcare system that works for those with rare disorders in Canada
DataGenno
https://www.datagenno.com
DataGenno is a clinical rare disorder database that also contains areas for information exchange and sharing of biomedical news
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Eurordis
https://www.eurordis.org
Provide information about specific rare genetic disorders
FindZebra
http://www.findzebra.com/
FindZebra is a search engine that uses freely available information to suggest diagnoses for rare diseases
GeneReviews1
https://www.ncbi.nlm.nih.gov/ books/NBK1116/
Tool to learn about a given genetic disease and to learn about genetic testing and clinical management
genepeeks
https://www.genepeeks.com
Catalog of genetic profiles from egg and sperm bank donations, enabling couples to choose or to decline a gamete based on whether recessive mutations for rare genetic diseases are in the same genes as in the fertile partner
Google
https://www.google.com
Google is a search engine in the internet that uses an algorithm to search results based on a ranking system
NORD
https://rarediseases.org/
Created with the goal of supporting patients and families with orphan and rare diseases, with a view to advocating for research into and development of treatments for rare diseases
OMIM
https://www.omim.org/
Public online catalog describing genetic syndromes and genes. Provides research history, phenotypic information, as well as data regarding mode of inheritance of genetic heterogeneity
Orphanet
http://www.orpha.net/consor/ cgi-bin/index.php
Provides descriptions of rare diseases as well as providing a diagnostic assistance tool and information regarding pharmacological compounds available for these diseases
PatientsLikeMe
https://www.patientslikeme.com/
Offers a forum for patients with different disorders to share their experiences and find help for themselves
Phenome Central
https://phenomecentral.org/
The objective of this resource is to connect researchers working on similar cases that might have the same genetic etiology combining genotypic and phenotypic information
PubMed
https://www.ncbi.nlm.nih.gov/pubmed
Database of biomedical literature meant to provide citations for biomedicine and molecular biology resources
research group will be unlikely to encounter more than one single case, resources such as Phenome Central (https://www. phenomecentral.org/; part of the Matchmaker Exchange) [61,62] could be used. The objective of this resource is to connect researchers working on cases that might have the same genetic etiology. By securely entering phenotypic and/or genotypic information, a researcher can find options for collaboration with the objective of producing more-robust data. Patients and families are becoming increasingly involved in the management of their conditions, and the internet contains many resources aimed at providing information to patients, and involving them in their medical care (Table 2) [63,64]. In a review of participant-centered initiatives, Kaye et al. [65] described the concept of digital platforms including social media as a tool for empowering patients, as well as mutual benefits such as increased trust on the part of the patients, and increased recruitment for research and epidemiological studies. Online platforms such as DataGenno help to strengthen connections and initiate interactions between people with similar interests [66,67]. Another interesting concept is the genepeeks company which promises to catalog genetic profiles of egg and sperm bank donations, enabling couples to accept or decline a gamete based on whether recessive mutations are in the same genes as in the fertile partner [68]. 6
The National Organization for Rare Disorders (NORD; https:// rarediseases.org/) was created in the 1980s with the goal of supporting patients and families with orphan diseases – to advocate for research into and development of treatments for rare diseases. Similar groups exist in Europe: Eurordis (https://www.eurordis. org/), and in Canada: Canadian Organization for Rare Disorders (CORD; https://www.raredisorders.ca). As well as providing excellent general information regarding rare diseases, these platforms are a starting point for those seeking support and information from patient organizations devoted to specific disorders (Table 2). There are important issues, however, with the use of social networking in this context. Whereas easy access to information is important, the implications for the privacy of patients is a valid concern [64] (https://www2.deloitte.com/content/dam/Deloitte/ mx/Documents/life-sciences-health-care/mx (esmx)Social% 20Networking%20in%20Life%20Sciences_2010.pdf). Therefore, Q4 those who collect information such as big data must make clear the policies regarding the privacy and the consent of the individuals sharing information [69]. When privacy concerns are minimized, more people are willing to take action through websites like PatientsLikeMe (Table 2) – a social network where individuals share stories about their experiences to communities of patients with the same disease [70]. Data sharing and open communication are key to maximizing the diagnostic potential of available resources.
www.drugdiscoverytoday.com Please cite this article in press as: Pogue, R.E. et al. Rare genetic diseases: update on diagnosis, treatment and online resources, Drug Discov Today (2017), https://doi.org/10.1016/j. drudis.2017.11.002
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Problems
Challenges
Google
for the average patient to get diagnosed in the USA
Clinical and phenotypic evaluation
It takes
PubMed
8 physicians for the average patient to get proper diagnosis The average patient receives
2 or 3 misdiagnoses before being properly diagnosed Only
45% of patients
Rare disease misdaignosis takes a great toll on patients′ physical emotional and economical health
Less than suspected for a disease receive a satisfactory molecular diagnosis
A database of biomedical literature for professional and amateur interest
PatientsLikeMe A forum for average patients with different diseases to share information about themselves
FindZebra A search engine for physicians that offers possible rare disease diagnoses
have all their costs covered by insurance providers
50% of patients
A search engine that uses an algorithm to search results based on a ranking system
Genetic and genomic analyses
DataGenno A rare disease database that offers interactive access to updated information Drug Discovery Today
FIGURE 2
Problems, challenges and solutions for rare disease management. Rare diseases demand a great amount of time, effort and resources to reach a diagnosis. This depiction shows the main problems in diagnosing rare diseases, the challenges posed and describes some of the web-based and online solutions that can significantly contribute to facilitating patient diagnosis, ascertaining the right treatment and providing patient support.
The P6 concept in helping disease diagnosis and treatment P6 is defined by six words: predictive, preventive, personalized, participatory, psycho-cognitive and public – aspects that empower patients with information [71,72]. Predictive medicine involves the use of DNA-sequencing technologies to identify the genetic causes of possible diseases before they manifest themselves with dangerous symptoms. Preventive medicine encourages the prevention of diseases before any true harm can occur. Personalized medicine is based upon an understanding that different individuals respond differently to similar treatments, rather than treating patients as a collective group. Participatory medicine involves a medical environment where patients and physicians interact in many ways to share information [5]. Psycho-cognitive aspects must be considered to empower the patient and their relatives with information and data, increase his or her quality-of-life and transform them from passive recipients into active decision makers. Finally, public dissemination of information through web-based resources is creating a new paradigm where patients can gain information and support, and in turn provide the same to others. Big data will be a definite driver toward the P6 medicine approach, and it will simultaneously bring benefits to other areas of the life sciences field, especially for patients with rare genetic disorders [5]. Thus, using these tools, the patient will be empow-
ered to facilitate their own diagnosis and make decisions on the treatment together with the healthcare professionals.
Concluding remarks and future perspectives In recent years, medicine has taken advantage of the information age. Mobile technologies, sensors, genome sequencing and advances in predictive analytics software make it possible to capture vast amounts of information about our individual makeup and the environment [67,73]. The sum of this information could transform medicine, turning a field aimed at treating the average patient into one that is customized to each person [1,4,5,14]. Data collection is changing the role of patients, offering them a chance to play a central part in their own care [73]. This kind of information will be useful and interesting for anyone, but it can become essential for millions living with chronic conditions like diabetes, heart disease and depression. It will also be important in diagnosing and treating rare genetic diseases (the so-called orphan diseases); however, it is important for patients to be able to put information in the correct context or perspective with the input of a knowledgeable healthcare professional [1,64]. The main responsibility remains with the healthcare professionals, who must keep themselves informed and up-to-date; however, patients and their relatives are taking actions to facilitate diagnosis and the correct treatment for rare genetic diseases.
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It takes
7.6 years
Web-based solutions
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Conflicts of interest
Acknowledgments
The authors declare that there are no conflicts of interest related to this review article.
The authors are supported by FAPDF, CNPq and CAPES. F.F.C. was supported by The Maeve MacNicholas Memorial Foundation.
References
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Drug Discovery Today Volume 00, Number 00 November 2017
Rare genetic diseases: update on diagnosis, treatment and online resources Q1
Robert E. Pogue1,z, Denise P. Cavalcanti4, Shreya Shanker5, Rosangela V. Andrade1, Lana R. Aguiar1, Juliana L. de Carvalho1,6 and Fabrício F. Costa1,2,3,z
1 Q2 2 Genomic Sciences and Biotechnology Program, Catholic University of Brasília, Distrito Federal, Brazil MATTER, Chicago, IL, USA 3 The Founder Institute, San Francisco, CA, USA 4 University of Campinas (UNICAMP), Sao Paulo, Brazil 5 Illinois Mathematics and Science Academy (IMSA), IL, USA 6 OneSkin Technologies, San Francisco, CA, USA
Rare genetic diseases collectively impact a significant portion of the world’s population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computeraided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how a collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases.
Introduction The terms ‘rare disease’ and ‘orphan disease’ are used to describe conditions that affect a small proportion of the population; in the USA they are described as affecting fewer than 200 000 people (http://www.fda.gov, May 2017), and in Europe as affecting fewer than one in 2000 (http://www.orpha.net/consor/cgi-bin/index. php, May 2017). Although the terms are often used interchangeably, orphan diseases are also defined as diseases that are underappreciated or ignored by the medical community and drug companies. The Orphanet portal for rare diseases and orphan drugs (http://www.orpha.net) lists 5856 diseases in its database (January 2017). Although individually rare, the statistics suggest that collectively these conditions affect up to 10% of the popula-
Corresponding authors: Pogue, R.E. ([email protected]), Costa, F.F. ([email protected]), ([email protected]) z
These two authors contributed equally in this review article.
1359-6446/ã 2017 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2017.11.002
tion (California Healthcare Institute: http://califesciences.org/). In this context, rare diseases represent a significant impact on health and, as such, it is important for healthcare professionals to be aware of the resources that exist to support their diagnosis, management and treatment. Q3 Many rare diseases are genetically inherited (Fig. 1a), and this fact can cause resistance among doctors owing to perceptions of genetic diseases as difficult and expensive to diagnose, and with few treatment options. Rare diseases can be stratified as lethal, severe but nonlethal, and not severe and manageable diseases, with effective treatment options (Fig. 1a). Also, with novel DNA sequencing technologies, diagnosis is less expensive and can contribute to prognosis determination, as well as to disease treatment, which can follow specific and/or nonspecific strategies (Fig. 1b). Because these diseases are uncommon, most doctors have no experience in diagnosing or treating them and there might only be a handful of physicians in the world who have
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(a)
Rare diseases Genetic
Lethal
Severe, but nonlethal
Nongenetic
Not severe
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(b)
Rare disease steps for evaluation Specific Diagnosis
Prognosis
Treatment Nonspecific
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FIGURE 1
Rare disease stratification and steps for evaluation. Rare diseases can be divided into genetically inherited and nongenetically inherited diseases, which can present different degrees of severity (a). The steps for rare disease diagnosis are essential, as with the diagnosis in hand, the healthcare professional can assess patient prognosis and treatment options, which might be specific for the disease being treated or unspecific, focusing on mitigating disease symptoms (b).
direct experience with a given condition [1]. These conditions are frequently further complicated by genetic and phenotypic heterogeneity. Compared with common and complex conditions that strike hundreds of millions of people such as diabetes, cancer, among others, rare diseases can lack similar levels of interest among the general public, medical and research communities, and pharmaceutical companies. Moreover, the fact that drug development in general is complicated, time-consuming and expensive, with extremely low success rates further complicates the situation [2]. In this context, orphan drugs are defined as compounds used for treating rare diseases [3]. The current review focuses on progress related to diagnosis, management and treatment of rare diseases that have a genetic origin, with emphasis on diagnostic tools, existing and in-development treatments, and the use of online and web-based resources for diagnosis, research and patient support.
Progress in molecular diagnosis of rare diseases Since 2010, the number of genes and mutations found per year has grown rapidly, thanks to improvements in DNA sequencing technologies and big data analysis [4,5]. Orphanet currently lists 3573 genes associated with rare diseases (May 2017). Many commercial and customizable gene-sequencing panels are available for relatively low-cost analysis of genes related to specific disorders or groups of diseases, and directories of diagnostic laboratories and the genetic tests that they offer can be found on sites such as Orphanet. For a more comprehensive analysis, exome sequencing has become technically feasible and more cost-effective, offering new opportunities for Mendelian disease diagnosis and research [4,6]. Exome sequencing limits sequencing mainly to the protein-coding regions of the human genome. These 180 000 2
exons constitute 2% of the whole genome but contain an estimated 85% of heritable Mendelian disease-causing mutations [4]. However, it must be remembered that variants affecting regulatory and noncoding DNA regions might be the cause of some cases of rare diseases [7]. Currently, the cost of sequencing an exome in the clinical setting is
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Treatment options: current and future therapies The issue of therapies for rare diseases goes hand-in-hand with the discussion of diagnosis, because in the end any patient being tested for a genetic disease (or any healthcare professional recommending a test) wants to know what treatments the results might indicate. The general public are now more aware of the availability of genetic tests, and so the expectation of effective therapies will increase. However, diagnosis, possibly leading to improved disease management, often does not lead to disease-modifying treatments [14,15]. For metabolic disorders, successful disease management frequently results in significant improvement in quality-of-life, because such diseases are often responsive to therapy that targets pathophysiological features, such as enzyme replacement and/or dietary therapy [14]. For instance, hypophosphatasia is an inborn error of metabolism with available enzyme replacement therapy. Since 2012, asfotase alfa, a chimeric recombinant protein with an alkaline phosphatase ectodomain, has provided clinical evidence for successful management of the disease [16]. Currently, asfotase alfa is approved for use in Japan, Canada, the EU and the USA. In the absence of afostase alfa, patient management reverts to supportive action [16]. In 2016, Tarailo-Graovac et al. [14] provided evidence that, at least for neurometabolic disorders, whole-exome sequencing combined with deep clinical phenotyping resulted in a 44% rate of change in treatment beyond genetic counseling for patients with
intellectual developmental disorders and unexplained metabolic phenotype. In other words, the combination of clinical and genetic information has led to customization of patient management, which included dietary changes for at least five probands, among other strategies. It has been estimated that such modifications resulted in increased quality-of-life. In addition to enzyme replacement and dietary therapy, gene and cellular therapy options are also increasingly available. For diseases such as severe combined immunodeficiency (SCID), cellular therapy based in bone marrow transplant is available over several years and is sufficient to cure patients [17]. Nevertheless, the underlying genetic defect is not reverted. Therefore, strategies available frequently fail to deal with the primary cause of rare diseases, which is the genetic alteration. Several countries have introduced an orphan legislation, with incentives to produce and increase access to appropriate treatments for some patients with rare diseases [18,19]. However, high costs and a lack of transparency remain an issue. A summary of rare genetic diseases, their estimated incidence according to the literature, genes associated, current treatments (and estimated costs), as well as companies providing treatments is provided in Table 1.
Gene therapy Gene therapies are strategies for permanent treatment of genetic diseases. Gene therapies seek to correct the DNA alterations responsible for any given genetic disease, either by replacing the defective gene or by inserting normal copies of such genes in the genome. Despite the simple rationale, successful gene therapy requires correct and efficient delivery of new genetic information into a relevant percentage of target cells, which must survive and proliferate in the host to sustain the beneficial effects without eliciting negative responses [20]. Initially developed focusing on cancer treatment, gene therapy has expanded its application from cancer toward monogenic, rare diseases, aiming to benefit from reduced development risk when dealing with diseases with very clear and defined genetic etiology. Also, the possibility of receiving orphan status is an important attraction factor. Therefore, the first clinical trials for gene therapy were in the rare disease field (for a comprehensive review, see Ref. [21]). Initiated by the success of recent clinical trials, the field is now developing T cell and oncolytic viral therapies focused in other areas [22]. Initially, ex vivo transfection was the main strategy for gene therapy and, owing to ease of cell isolation, initial efforts focused on blood disorders [23–25]. Later in vivo trials showed limited success, and suffered the setback of the 1999 death of a patient in a trial based on adenovirus-mediated correction of ornithine transcarbamylase deficiency [26]. Also, the lack of efficiency in other trials fed a gradual decline in interest. More recently, viruses including lentiviruses and g-retroviruses have been improved regarding genotoxicity and integration [21], emerging as vehicles for hematopoietic stem cell transduction and treatment of disorders such as adenosine deaminase deficiency, SCID [27,28], b-thalassemia [29], X-linked adrenoleukodystrophy [30] and Wiskott–Aldrich syndrome [31]. Positive results have also been reported using adeno-associated virus (AAV) [22] in the treatment of familial lipoprotein lipase deficiency, a rare disorder that results in childhood-onset severe
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of CNVs being benign [10]. More recently, DNA sequencing on the genomic scale, using paired-end and split-read approaches, has become a viable option for cytogenetic analysis [11]. The problem arises in the interpretation of CNVs and the determination as to which are pathological and which are benign. Although data such as population frequency can help in the determination of probable pathogenicity, many CNVs end up being classified as ‘of unknown clinical significance’ [10]. The rare nature of many pathological CNVs makes their interpretation difficult owing to lack of other patients for comparison [12,13]. For this reason, deposition of data in clinical structural variant databases is an important process. The European Cytogenetics Association Register of Unbalanced Chromosome Aberrations (ECARUCA) is fed mainly by a network of European cytogenetics researchers focused on identifying chromosomal anomalies in rare diseases. The database contains data from >5000 patients, listing almost 7000 chromosomal anomalies with 2713 distinct CNVs. More than 50% of the listed anomalies are deletions, and the most frequent structural anomalies apart from deletions are duplications, followed by rings, triplications and uniparental disomy. The Decipher database (https://decipher.sanger.ac.uk) is a repository for genomic variants (mainly CNVs) that has collected >30 000 CNVs from >21 000 patients with rare diseases. Equally important in the evaluation of molecular cytogenetic profiles in patients with rare diseases are databases of normal genomic variation, the most important being the Database of Genomic Variants (DGV; http://dgv.tcag.ca/). DGV contains data regarding structural variation in normal samples, and as such is an important negative screening tool, because a CNV listed in DGV is less likely to be responsible for a rare disease.
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TABLE 1
Q7 Partial list of rare genetic diseases, incidence in populations, genes associated, treatment costs, drugs and pharmaceutical and Q8
biotechnology industries commercializing the drugs
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Disease (OMIM)
Incidence
Genes associated
Treatment costs in US$ (per patient per year)
Drugs
Companies
Cystic fibrosis (CF) (#219700)
1:2500
CFTR
US$200 000
Kalydeco1
Vertex Pharmaceuticals (VRTX)
Fabry disease (#301500)
1:50 000
a-Galactosidase A (a-GAL)
US$200 000–300 000
Replagal Fabrazyme1
Shire Pharmaceuticals (SHPG) Sanofi-Genzyme (SNY-GENZ)
Gaucher disease (Types I and II) (#230800)
1:50 000 (general population) 1:1000 (Ashkenazi Jewish)
GBA (b-glucocerebrosidase)
US$300 000
Elelypso Cerezyme1
Pfizer (PFE) Sanofi-Genzyme (SNY-GENZ)
Hemolytic uremic syndrome (aHUS) (#609536)
1: 100 000 to 1: 1 000 000
C5
US$400 000–500 000
Soliris1
Alexion Pharmaceuticals (ALXN)
Hereditary angioedema (#106100)
1:30–50 000
C1NH, SERPING1
US$300 000
Cinryze1
ViroPharma (acquired by Shire Pharmaceuticals SHPG)
MPS I or Hurler syndrome (#607014)
1:100 000
GNS, HGSNAT, NAGLU and SGSH
US$365 000
Elaprase1
Shire Pharmaceuticals (SHPG)
MPS IV or Moreteauz– Lame disease (#253010)
1:100 000
GALNS and GLB1
US$500 000
Naglazyme1
Shire Pharmaceuticals (SHPG) Biomarin (BMRN)
Nieman–Pick, type C (#257220)
1:150 000
NPC1, NPC2
US$100 000
Zavesca1 (Miglustat)
Actelion Pharmaceuticals (ALIOF)
Pompe disease (#232300)
1:40 000
GAA
US$298 000
MyozymeTM
Sanofi-Genzyme (SNY-GENZ)
Progeria (#176670)
1:3 000 000
LMNA
US$250 000
Lonafarnib
Merck Corporation (MRK)
Hypophosphatasia (HPP) (#146300)
1:100 000
ALP (TNSALP)
US$285 000
Strensiq1
Alexion Pharmaceuticals (ALXN)
hypertriglyceridemia [22,32]. Other clinical trials at different stages of development are: Leber’s congenital amaurosis type 2 (NCT00999609), cystic fibrosis (NCT00004533), choroideremia (NCT01461213), muscular dystrophy (NCT00428935) and a1antitrypsin deficiency ( NCT00377416) (https://clinicaltrials. gov/). The most recent developments in gene therapy have seen the appearance of gene-editing tools, such as zinc finger nucleases (ZFNs), transcription-activator-like effector nucleases (TALENs) and, more recently, clustered regularly interspaced short palindromic repeat-associated systems (CRISPR-Cas), placing gene therapy on the brink of a revolution [33]. The main advantage of such tools is the possibility of specifically targeting and correcting disease-causing mutations. Following several proof-of-concept assays, ZFNs have been tested clinically since the late 2000s (NCT02800369, NCT00842634, NCT02388594, NCT01252641, NCT01044654, NCT02500849, NCT02225665, NCT02695160, NCT02702115). The first clinical trials are also underway using CRISPR to delete PD-1 in cancer patients (NCT02793856, NCT02867345, NCT02863913, NCT02867332). Although not yet recruiting, these trials will be important in the future for rare diseases. Recently, RNAi has been tested clinically to silence defective genes by knockdown of target mRNAs. As of September 2016, 35 trials were registered at clinicaltrials.gov. Despite scarce available data, therapeutic effects have been registered in some of these trials [33]. Nevertheless, RNAi application is restricted to diseases 4
in which gene knockdown, although not complete, is of interest. The idea of modifying the DNA sequence of patients with a genetic disease recently became more attainable with the discovery and adaptation of the CRISPR-Cas9 system [34–36]. This mechanism was discovered in bacteria as an adaptive immune defense, but has since been used for editing DNA in several species, including humans [35]. The most recent iterations of the technology permit precise cutting and replacement of DNA sequences, creating the potential for repair of mutations [36,37]. In June 2016, the first clinical trial using CRISPR received provisional approval in the USA [38]. The trial, developed by the University of Pennsylvania, is focused on cancer immunotherapy, and will use CRISPR-modified T cells from cancer patients for tumor targeting [38]. Another trial is underway in China, with the objective of knocking out the PD-1 gene in T cells of patients with non-small-cell lung cancer [39]. No trials have yet started for a specific rare genetic disease, but we believe that this technology could be a game changer in the rare diseases field.
Stem cell therapy Stem cells used for therapy can be either allogeneic or autologous, if the genetic correction of the mutations is performed before therapy. Currently, the former is the more common option. This strategy has provided impressive results, especially for SCID – the first disease to be successfully treated by hematopoietic stem cell therapy >45 years ago [40,17]. Osteogenesis imperfecta (OI), caused by defective type I collagen, and characterized by painful
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fractures, skeletal deformities and retarded bone growth from fetal life, has also shown strong response to treatment [41–43]. In addition to pharmacological treatments, treating OI with mesenchymal stem cells (MSCs) has delivered exciting results. In 2002, six infants who received systemic MSC infusions responded positively to therapy with accelerated growth velocity of bone during the first 6 months post infusion [43]. Because the treatment was shown to be promising and safe, in utero MSC infusions were also tested, with the first report published in 2005 [44]. This child received MSC infusions prenatally (at week 24) as well as at 4 and 8 years of age, and showed important improvements in several aspects. Another patient identified with the same mutation, who did not receive cellular therapy, succumbed at 5 months of age, despite pharmacological treatment [41,42]. Since this first prenatal study with MSC therapy for OI, other children have been treated with positive results. Stem cells are being tested in several other rare diseases, such as rare retinopathies using embryonic stem cells (ESCs) [45] and induced pluripotent stem cells (iPSCs), as well as in Myasthenia gravis [46], inborn errors of the metabolism [47], cystic fibrosis, mitochondrial disorders (NCT02427178), rare degenerative diseases such as Tay–Sachs disease, among others. Cell therapy is at different stages of development for each of these disorders and only a small fraction of rare diseases is currently under clinical trials, according to clinicaltrials.gov (rare retinopathies: NCT01344993, NCT01469832 and NCT01345006; inborn errors of metabolism: NCT00176904; cystic fibrosis: NCT01916577; Myasthenia gravis: NCT00424489; mitochondrial disorders: NCT02427178; other immune primary immunodeficiency disorders: NCT00579137, NCT01652092). iPSCs also have an important role in rare disease research owing to their potential for modeling of diseases in vitro. Through the collection of blood [48], skin [49] or even urine [50] from patients, it is possible to produce iPSCs and to differentiate these cells with high efficiency into most cell types of interest [50–53]. This means that it is possible to generate virtually endless material for research and to study the effects of any mutation detected in patients over the phenotype of several cells. Before this technology, tissue-specific cell lines from rare disease patients were not easily obtainable, owing to the frequent difficulty of performing biopsies. These cell lines have already proven useful in several contexts. For instance, iPS cell lines derived from Hutchinson–Gilford progeria syndrome (HGPS) patients were established in 2011 [54]. HGPS-iPSCs were shown to faithfully mimic the disease; and, when differentiated into smooth muscle cells, showed premature senescence phenotypes associated with vascular ageing — a hallmark of progeria. iPSCs have been generated from Xeroderma pigmentosum (XP), the first known rare autosomal recessive genetic disorder associated with defective repair of damaged DNA [55]. Although the genetic mutations associated with the disease are already known and an XP mouse model has already been obtained, XP mice fail to reproduce the neurological abnormalities observed in humans, with the result that the underlying mechanisms of such neurological observations have not yet been clarified. By producing XP-iPSCs it was possible to generate neurons and neural stem cells, the latter showing hypersensitivity to DNA-damage-induced apoptosis. XP-iPSCs provided the
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first molecular clues underlying the neurodegeneration observed in XP patients [55]. It is expected that information provided by in vitro models of disease will be increasingly important not only for acquiring knowledge regarding disease etiology but also for disease management, through personalized toxicity, diagnosis and response screening assays [56,57]. These publications are excellent references regarding the ever-growing list of genetic disorders already modeled by iPS cell lines and the use of ‘trials on a dish’. Combined with tissue engineering and other strategies to achieve complex organs and bodies in vitro, these technologies will change research approaches, not only for rare diseases but also for other genetic disorders.
Resources for researchers, healthcare professionals and patients It is important that tools and platforms exist to support patients, their relatives, as well as healthcare professionals and researchers in the search for information to help in the diagnosis and selection of specific treatments available or even ongoing clinical trials for specific diseases. For the physician, investigating a suspected rare disease the Online Mendelian Inheritance in Man (OMIM) and Orphanet databases are an important starting point. OMIM (http://www.omim.org/) is an online catalog describing genetic syndromes and genes. It provides the research history, phenotypic information, as well as data regarding mode of inheritance genetic heterogeneity (Table 2). Orphanet [58] is a more recently developed resource that focuses on providing descriptions of rare diseases (including genes and clinical characteristics), as well as providing a diagnostic assistance tool and information regarding pharmacological compounds available for rare diseases (orphan drugs). These and other databases are interlinked to facilitate access to complementary data (Table 2). Other tools are aimed at guiding molecular analysis. For example, FindZebra (http:// www.findzebra.com/) is a search engine that specializes in rare diseases, and has proven as helpful and relevant as basic Google searches [59]. Whereas Google’s ranking algorithm attempts to rank search results based on the popularity of the articles, FindZebra’s algorithm is solely concerned with the number of times the specified query appears in the article [59]. As a result, FindZebra can be an important web-based tool for healthcare professionals trying to learn more about rare diseases (Table 2, Fig. 2), as well as for patients seeking information. Masino et al. [60] developed an algorithm that uses semantic similarity to clinical descriptor terms to prioritize genes for analysis based on associations between genes and groups of terms according to existing databases and the published literature. The GeneReviews1 website (https://www.ncbi.nlm.nih.gov/books/NBK1116/ ) is another useful tool for information regarding genetic diseases, including gene-testing resources and clinical management. Other important resources are Human Phenotype Ontology and MeSH, which classify and annotate clinical terms relating to human syndromes to standardize vocabulary for database searching, and for reporting findings. The number of genetic diseases for which the causative gene(s) is not yet known is steadily decreasing, and these diseases are increasingly rare. Because it is difficult to convincingly propose a causative gene based on one case or family alone, and because a
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TABLE 2
Q9 List of web-based and computer-aided tools available to help in diagnosing and managing rare genetic diseases Resource
Link to resource
Purpose of the resource
CORD
https://www.raredisorders.ca
CORD provides a strong common voice to advocate for health policy and a healthcare system that works for those with rare disorders in Canada
DataGenno
https://www.datagenno.com
DataGenno is a clinical rare disorder database that also contains areas for information exchange and sharing of biomedical news
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Eurordis
https://www.eurordis.org
Provide information about specific rare genetic disorders
FindZebra
http://www.findzebra.com/
FindZebra is a search engine that uses freely available information to suggest diagnoses for rare diseases
GeneReviews1
https://www.ncbi.nlm.nih.gov/ books/NBK1116/
Tool to learn about a given genetic disease and to learn about genetic testing and clinical management
genepeeks
https://www.genepeeks.com
Catalog of genetic profiles from egg and sperm bank donations, enabling couples to choose or to decline a gamete based on whether recessive mutations for rare genetic diseases are in the same genes as in the fertile partner
https://www.google.com
Google is a search engine in the internet that uses an algorithm to search results based on a ranking system
NORD
https://rarediseases.org/
Created with the goal of supporting patients and families with orphan and rare diseases, with a view to advocating for research into and development of treatments for rare diseases
OMIM
https://www.omim.org/
Public online catalog describing genetic syndromes and genes. Provides research history, phenotypic information, as well as data regarding mode of inheritance of genetic heterogeneity
Orphanet
http://www.orpha.net/consor/ cgi-bin/index.php
Provides descriptions of rare diseases as well as providing a diagnostic assistance tool and information regarding pharmacological compounds available for these diseases
PatientsLikeMe
https://www.patientslikeme.com/
Offers a forum for patients with different disorders to share their experiences and find help for themselves
Phenome Central
https://phenomecentral.org/
The objective of this resource is to connect researchers working on similar cases that might have the same genetic etiology combining genotypic and phenotypic information
PubMed
https://www.ncbi.nlm.nih.gov/pubmed
Database of biomedical literature meant to provide citations for biomedicine and molecular biology resources
research group will be unlikely to encounter more than one single case, resources such as Phenome Central (https://www. phenomecentral.org/; part of the Matchmaker Exchange) [61,62] could be used. The objective of this resource is to connect researchers working on cases that might have the same genetic etiology. By securely entering phenotypic and/or genotypic information, a researcher can find options for collaboration with the objective of producing more-robust data. Patients and families are becoming increasingly involved in the management of their conditions, and the internet contains many resources aimed at providing information to patients, and involving them in their medical care (Table 2) [63,64]. In a review of participant-centered initiatives, Kaye et al. [65] described the concept of digital platforms including social media as a tool for empowering patients, as well as mutual benefits such as increased trust on the part of the patients, and increased recruitment for research and epidemiological studies. Online platforms such as DataGenno help to strengthen connections and initiate interactions between people with similar interests [66,67]. Another interesting concept is the genepeeks company which promises to catalog genetic profiles of egg and sperm bank donations, enabling couples to accept or decline a gamete based on whether recessive mutations are in the same genes as in the fertile partner [68]. 6
The National Organization for Rare Disorders (NORD; https:// rarediseases.org/) was created in the 1980s with the goal of supporting patients and families with orphan diseases – to advocate for research into and development of treatments for rare diseases. Similar groups exist in Europe: Eurordis (https://www.eurordis. org/), and in Canada: Canadian Organization for Rare Disorders (CORD; https://www.raredisorders.ca). As well as providing excellent general information regarding rare diseases, these platforms are a starting point for those seeking support and information from patient organizations devoted to specific disorders (Table 2). There are important issues, however, with the use of social networking in this context. Whereas easy access to information is important, the implications for the privacy of patients is a valid concern [64] (https://www2.deloitte.com/content/dam/Deloitte/ mx/Documents/life-sciences-health-care/mx (esmx)Social% 20Networking%20in%20Life%20Sciences_2010.pdf). Therefore, Q4 those who collect information such as big data must make clear the policies regarding the privacy and the consent of the individuals sharing information [69]. When privacy concerns are minimized, more people are willing to take action through websites like PatientsLikeMe (Table 2) – a social network where individuals share stories about their experiences to communities of patients with the same disease [70]. Data sharing and open communication are key to maximizing the diagnostic potential of available resources.
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Problems
Challenges
for the average patient to get diagnosed in the USA
Clinical and phenotypic evaluation
It takes
PubMed
8 physicians for the average patient to get proper diagnosis The average patient receives
2 or 3 misdiagnoses before being properly diagnosed Only
45% of patients
Rare disease misdaignosis takes a great toll on patients′ physical emotional and economical health
Less than suspected for a disease receive a satisfactory molecular diagnosis
A database of biomedical literature for professional and amateur interest
PatientsLikeMe A forum for average patients with different diseases to share information about themselves
FindZebra A search engine for physicians that offers possible rare disease diagnoses
have all their costs covered by insurance providers
50% of patients
A search engine that uses an algorithm to search results based on a ranking system
Genetic and genomic analyses
DataGenno A rare disease database that offers interactive access to updated information Drug Discovery Today
FIGURE 2
Problems, challenges and solutions for rare disease management. Rare diseases demand a great amount of time, effort and resources to reach a diagnosis. This depiction shows the main problems in diagnosing rare diseases, the challenges posed and describes some of the web-based and online solutions that can significantly contribute to facilitating patient diagnosis, ascertaining the right treatment and providing patient support.
The P6 concept in helping disease diagnosis and treatment P6 is defined by six words: predictive, preventive, personalized, participatory, psycho-cognitive and public – aspects that empower patients with information [71,72]. Predictive medicine involves the use of DNA-sequencing technologies to identify the genetic causes of possible diseases before they manifest themselves with dangerous symptoms. Preventive medicine encourages the prevention of diseases before any true harm can occur. Personalized medicine is based upon an understanding that different individuals respond differently to similar treatments, rather than treating patients as a collective group. Participatory medicine involves a medical environment where patients and physicians interact in many ways to share information [5]. Psycho-cognitive aspects must be considered to empower the patient and their relatives with information and data, increase his or her quality-of-life and transform them from passive recipients into active decision makers. Finally, public dissemination of information through web-based resources is creating a new paradigm where patients can gain information and support, and in turn provide the same to others. Big data will be a definite driver toward the P6 medicine approach, and it will simultaneously bring benefits to other areas of the life sciences field, especially for patients with rare genetic disorders [5]. Thus, using these tools, the patient will be empow-
ered to facilitate their own diagnosis and make decisions on the treatment together with the healthcare professionals.
Concluding remarks and future perspectives In recent years, medicine has taken advantage of the information age. Mobile technologies, sensors, genome sequencing and advances in predictive analytics software make it possible to capture vast amounts of information about our individual makeup and the environment [67,73]. The sum of this information could transform medicine, turning a field aimed at treating the average patient into one that is customized to each person [1,4,5,14]. Data collection is changing the role of patients, offering them a chance to play a central part in their own care [73]. This kind of information will be useful and interesting for anyone, but it can become essential for millions living with chronic conditions like diabetes, heart disease and depression. It will also be important in diagnosing and treating rare genetic diseases (the so-called orphan diseases); however, it is important for patients to be able to put information in the correct context or perspective with the input of a knowledgeable healthcare professional [1,64]. The main responsibility remains with the healthcare professionals, who must keep themselves informed and up-to-date; however, patients and their relatives are taking actions to facilitate diagnosis and the correct treatment for rare genetic diseases.
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It takes
7.6 years
Web-based solutions
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Conflicts of interest
Acknowledgments
The authors declare that there are no conflicts of interest related to this review article.
The authors are supported by FAPDF, CNPq and CAPES. F.F.C. was supported by The Maeve MacNicholas Memorial Foundation.
References
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