PERSPECTIVE Tambuyzer Box 1. Examples of rare disease treatments and their analogy to personalized healthcare Enzyme replacement therapies for lysosomal storage disorders Enzyme replacement therapies(ERTs) are used as treatment for very rare genetic disorders such as lysosomal storage disorders. We elieve that they represent some good examples of personalized healthcare applications in practice, which are used in the medic. practice outside the field of oncology. Some of the disorders which are treated, are life-threatening or seriously debilitating. They are very rare diseases as indicated in FIGURE l, and relate to a genetic defect in the lysosomes, vesicles that are part of the human cell containing enzymes, which are each responsible for the elimination of a specific substrate used by the cell. If that does not happen, partially or totally the cell will store these substrates and after a while this will make the cell malfunction. Each enzyme defect can cause a different lysosomal storage disorder, and each type can be very heterogeneous in its clinical manifestation Before ERTs are used, the disease needs to be confirmed by a dna test to ensure that the treatment will benefit the patient and will justify the cost of treatment. Clinical trials are setup with small patient groups and a registry is developed to follow-up the treatment longitudinally by registering patient data Infrastructure, education, treatment guidelines and protocols had to be developed from scratch. Each disease can ave subtypes in which the treatment may work better or worse. Examples of such already approved ERTs are: Cerezyme for Gaucher disease, Fabrazyme and Replagal for Fabry disease, Myozyme for Pompe disease, Elaprasee for Mucopolysaccharidosis-lI (MPS-lI[Hunter diseaseD), Aldurazyme for MPS-I(Hurler-Scheie disease) and Naglazyme for MPS VI ene therapy applications Gene therapy is the correction of a genetic defect by providing a correct copy of the defected gene combined with a way to build this corrected copy into the cells expressing the gene. Gene therapy will need a confirmed diagnosis and strict clinical trials to show positive patient outcomes, and may also have to be controlled very tightly in terms of safety aspects, but it has the potential to dramatically change the life of the treated patients Gene therapy will be another excellent example of personalized healthcare's commonalities with the rare disease field. No gene therapy-based medicines are approved yet, but it is believed that this will happen in the future, and very likely for rare diseases first. Successful cinical results have been shown recently in treating some Parkinsons disease patients [130]. An example of a gene therapy application for a rare disease that is moving forward in clinical trials is the correction of Leber Congenital amaurosis Type 2, a form of hereditary blinding disorder belonging to the group of retinitis pigmentosa [131]. Theodor Karl Gustav von Leber described a form of nherited blindness in 1869, known as Leber's congenital amaurosis(LCA). In 1997, a related genetic defect in LCA2 was traced to gene RPE65, an enzyme required for photopigment generation. In 1998, the same blinding mutation was found in Briard dogs, and transgeni knockout mice were developed with the RPE65 gene deleted resulting in visual impairment so an animal model is available. That made bsequent clinical trials possible and three independent clinical trials are now underway, of which two are in the US and one is in the UK. Treatment of nonsense mutations Ataluren[132] is an investigational (experimental)drug that is designed to enable the formation of a functioning protein in a patient with a genetic disorder due to a nonsense mutation. The complexity of the product and its delivery to patients is that it will only be possible to use for the treatment of genetic disorders that are caused by nonsense mutations, and not in patients who have other types of mutations. Nonsense mutations are single-point alterations in the genetic code that prematurely stop the translation process, thereby preventing production of a full-length, functional protein. This product is an excellent example of the promise that healthcare holds to address significant unmet medical needs across different diseases, with the potential to make a major positive difference in the lives of patients and their families. It is being studied in several rare diseases, indluding duchenne muscular dystrophy (DMD), a degenerative genetic muscular disorder, cystic fibrosis and hemophilia. Its use in medical practice will require gene sequencing to identify the patients that may benefit from the treatment. a case study by students at the Karolinska Institute, Stockholm, Sweden, as part of a study organized by Science/Business(Brussels, Belgium) notes the following Duchenne muscular dystrophy is a complex, inherited disorder-a perfect target for the potential of personalized medicine. The ailment affects one in 3500 males worldwide, making it the most common form of about 20 kinds of muscular dystrophy. Average life expectancy is less than 30 years. There is no cure- just inadequate treatment, with many side effects, by corticosteroids to slow or manage the disease progression. DMD sufferers cannot produce dystrophin, a protein that is an essential component of muscle. This is caused by a variety of genetic faults, which interrupt the production of the protein. Now, a number of potential treatments for DMD are in clinical development, targeting different ways of overriding the genetic faults to permit normal protein synthesis. Different treatments will be needed for different segments of the patient population, and patients will need to be genotyped to see which mutation they carry Enter personalized medicine .. not just the treatment will be personalized; the delivery mechanism could end up having to be tailormade, as well, depending on where the patient lives"[roll Gene sequencing brings us a step closer to personal genome sequencing, discussed in a recent article published in The Lancet. Genome sequencing comes with many practical challenges before it will enter the clinical practice [19, 201, but holds enormous potential. In terms of costs, the goal of completely sequencing a human genome for USS 1000 is believed to be in sight While a company may provide the financ- The objectives of such disease registries are: ing and IT backbone, patient and physician confidentiality for the registry is strictly main- To enhance the understanding of the variabl tained and the registry itself is often governed ity, progression and natural history of the dis- by an independent scientific or medical board ease with the ultimate goal of better guiding of advisors and assessing therapeutic interventions Personalized Medicine(2010)7(5) w
Perrsppective Tambuyzer Tambuyzer While a company may provide the financing and IT backbone, patient and physician confidentiality for the registry is strictly maintained and the registry itself is often governed by an independent scientific or medical board of advisors. The objectives of such disease registries are: To enhance the understanding of the variability, progression and natural history of the disease with the ultimate goal of better guiding and assessing therapeutic interventions; Box 1. Examples of rare disease treatments and their analogy to personalized healthcare. Enzyme replacement therapies for lysosomal storage disorders Enzyme replacement therapies (ERTs) are used as treatment for very rare genetic disorders such as lysosomal storage disorders. We believe that they represent some good examples of personalized healthcare applications in practice, which are used in the medical practice outside the field of oncology. Some of the disorders which are treated, are life-threatening or seriously debilitating. They are very rare diseases as indicated in Figure 1, and relate to a genetic defect in the lysosomes, vesicles that are part of the human cell containing enzymes, which are each responsible for the elimination of a specific substrate used by the cell. If that does not happen, partially or totally, the cell will store these substrates and after a while this will make the cell malfunction. Each enzyme defect can cause a different lysosomal storage disorder, and each type can be very heterogeneous in its clinical manifestation. Before ERTs are used, the disease needs to be confirmed by a DNA test to ensure that the treatment will benefit the patient and will justify the cost of treatment. Clinical trials are setup with small patient groups and a registry is developed to follow-up the treatment longitudinally by registering patient data. Infrastructure, education, treatment guidelines and protocols had to be developed from scratch. Each disease can have subtypes in which the treatment may work better or worse. Examples of such already approved ERTs are: Cerezyme® for Gaucher disease, Fabrazyme® and Replagal® for Fabry disease, Myozyme® for Pompe disease, Elaprase® for Mucopolysaccharidosis-II (MPS-II [Hunter disease]), Aldurazyme® for MPS-I (Hurler-Scheie disease) and Naglazyme® for MPS VI. Gene therapy applications Gene therapy is the correction of a genetic defect by providing a correct copy of the defected gene combined with a way to build this corrected copy into the cells expressing the gene. Gene therapy will need a confirmed diagnosis and strict clinical trials to show positive patient outcomes, and may also have to be controlled very tightly in terms of safety aspects, but it has the potential to dramatically change the life of the treated patients. Gene therapy will be another excellent example of personalized healthcare’s commonalities with the rare disease field. No gene therapy-based medicines are approved yet, but it is believed that this will happen in the future, and very likely for rare diseases first. Successful clinical results have been shown recently in treating some Parkinson’s disease patients [130]. An example of a gene therapy application for a rare disease that is moving forward in clinical trials is the correction of Leber Congenital Amaurosis Type 2, a form of hereditary blinding disorder belonging to the group of retinitis pigmentosa [131]. Theodor Karl Gustav von Leber described a form of inherited blindness in 1869, known as Leber’s congenital amaurosis (LCA). In 1997, a related genetic defect in LCA2 was traced to gene RPE65, an enzyme required for photopigment generation. In 1998, the same blinding mutation was found in Briard dogs, and transgenic knockout mice were developed with the RPE65 gene deleted resulting in visual impairment so an animal model is available. That made subsequent clinical trials possible and three independent clinical trials are now underway, of which two are in the US and one is in the UK. Treatment of nonsense mutations Ataluren® [132] is an investigational (experimental) drug that is designed to enable the formation of a functioning protein in a patient with a genetic disorder due to a nonsense mutation. The complexity of the product and its delivery to patients is that it will only be possible to use for the treatment of genetic disorders that are caused by nonsense mutations, and not in patients who have other types of mutations. Nonsense mutations are single-point alterations in the genetic code that prematurely stop the translation process, thereby preventing production of a full-length, functional protein. This product is an excellent example of the promise that personalized healthcare holds to address significant unmet medical needs across different diseases, with the potential to make a major positive difference in the lives of patients and their families. It is being studied in several rare diseases, including Duchenne muscular dystrophy (DMD), a degenerative genetic muscular disorder, cystic fibrosis and hemophilia. Its use in medical practice will require gene sequencing to identify the patients that may benefit from the treatment. A case study by students at the Karolinska Institute, Stockholm, Sweden, as part of a study organized by Science/Business (Brussels, Belgium) notes the following: “Duchenne muscular dystrophy is a complex, inherited disorder – a perfect target for the potential of personalized medicine. The ailment affects one in 3500 males worldwide, making it the most common form of about 20 kinds of muscular dystrophy. Average life expectancy is less than 30 years. There is no cure – just inadequate treatment, with many side effects, by corticosteroids to slow or manage the disease progression. DMD sufferers cannot produce dystrophin, a protein that is an essential component of muscle. This is caused by a variety of genetic faults, which interrupt the production of the protein. Now, a number of potential treatments for DMD are in clinical development, targeting different ways of overriding the genetic faults to permit normal protein synthesis. Different treatments will be needed for different segments of the patient population, and patients will need to be genotyped to see which mutation they carry. Enter personalized medicine … not just the treatment will be personalized; the delivery mechanism could end up having to be tailormade, as well, depending on where the patient lives” [101]. Gene sequencing brings us a step closer to personal genome sequencing, discussed in a recent article published in The Lancet. Genome sequencing comes with many practical challenges before it will enter the clinical practice [19,20], but holds enormous potential. In terms of costs, the goal of completely sequencing a human genome for US$1000 is believed to be in sight [4]. 574 Personalized Medicine (2010) 7(5) future science group Lessons learned from the field of rare diseases Perspective
Lessons learned from the field of rare diseases PERSPECTIVE To assist the medical community with the community of treating specialists and stimulates development of recommendations for physician and patient education and exchange monitoring patients of knowledge To assist patients in learning about their dis., To be useful for health technology assessment, the data queried for, need to be incorporated ease and to report on patient outcomes to help the regis for registries setup for the follow- design, which may often not (ye ptimize patient care; To evaluate the long-term effectiveness of up of clinical trials or postapproval regulatory the treatments, to report outcomes to demands, and therefore, we may need adaptive The challenges faced in developing registries To provide clinical data for further product and the methods for capturing patient data and outcomes may be important for personal The supranational or global nature of such ized healthcare applications in real-life settings egistry will increase understanding (natural Nevertheless, registries also have limitations history, ethnicity and genetics)of and aware- the data gathered are less controlled than in a ness about the rare disease and the therapy(tim- clinical trial setting and related to all patients of ng, dosing and outcomes), facilitate physician which data are stored, and not to a specifically patient monitoring and setup of therapeutic defined cohort of patients. These data may there- goals, support the development of diagnosis, fore also contain bias. Moreover, registries only disease-monitoring and disease-management contain data as defined at the time of the design uidelines, and analyze(long-term)treatment of the registry, and therefore, may be limited in outcomes. It helps develop an international the responses that can be obtained from them Sandhoff No CNS involvement orde GM1 gangliosides Gaucher Infantile Batten Mixed Scheie(MPS-I S) Hurler-Scheie(MPS-l H/S) Juvenile Batten Niemann-Pick A Maroteaux-Lamy(MPS-vI) Hurler(MPS-l H) leukodystrophy Late infantile Batten Morquio MPS-v) Krabbe Hunter(MPS-l Figure 1. An overview of the relative frequency of lysosomal storage diseases. There are diseases caused by deficient enzymes in the liposomes. If they have involvement in the CNS, replacement enzymes are not able to pass through the blood-brain barrier because of their size. This means that such diseases are not targets for enzyme replacement therapies, and that another therapeutic approach is neede MPS: Mucopolysaccharidosis. w. futuremedicine cor
Perrsppective Tambuyzer Tambuyzer To assist the medical community with the development of recommendations for monitoring patients; To assist patients in learning about their disease and to report on patient outcomes to help optimize patient care; To evaluate the long-term effectiveness of the treatments, to report outcomes to the authorities; To provide clinical data for further product development for the disease. The supranational or global nature of such registry will increase understanding (natural history, ethnicity and genetics) of and awareness about the rare disease and the therapy (timing, dosing and outcomes), facilitate physician patient monitoring and setup of therapeutic goals, support the development of diagnosis, disease-monitoring and disease-management guidelines, and analyze (long-term) treatment outcomes. It helps develop an international community of treating specialists and stimulates physician and patient education and exchange of knowledge. To be useful for health technology assessment, the data queried for, need to be incorporated in the registry design, which may often not (yet) be the case for registries setup for the followup of clinical trials or postapproval regulatory demands, and therefore, we may need adaptive registries in the future. The challenges faced in developing registries and the methods for capturing patient data and outcomes may be important for personalized healthcare applications in real-life settings. Nevertheless, registries also have limitations: the data gathered are less controlled than in a clinical trial setting and related to all patients of which data are stored, and not to a specifically defined cohort of patients. These data may therefore also contain bias. Moreover, registries only contain data as defined at the time of the design of the registry, and therefore, may be limited in the responses that can be obtained from them. Gaucher No CNS involvement CNS involved Mixed Juvenile Batten Fabry Metachromatic leukodystrophy Sanfilippo A (MPS-IIIA) Late infantile Batten Krabbe Hunter (MPS-II) Morquio (MPS-IV) Pompe Niemann-Pick C Tay-Sachs Hurler (MPS-I H) Sanfilippo B (MPS-IIIB) Maroteaux-Lamy (MPS-VI) Niemann-Pick A Cystinosis Hurler-Scheie (MPS-I H/S) Scheie (MPS-I S) Infantile Batten GM1 gangliosidosis MPS-II/III Sandhoff Other (9 disorders) Figure 1. An overview of the relative frequency of lysosomal storage diseases. There are diseases caused by deficient enzymes in the liposomes. If they have involvement in the CNS, replacement enzymes are not able to pass through the blood–brain barrier because of their size. This means that such diseases are not targets for enzyme replacement therapies, and that another therapeutic approach is needed. MPS: Mucopolysaccharidosis. Data taken from [21]. future science group www.futuremedicine.com 575 Lessons learned from the field of rare diseases Perspective