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) wPerrsppective Tambuyzer Tambuyzer While a company may provide the financ￾ing and IT backbone, patient and physician confidentiality for the registry is strictly main￾tained and the registry itself is often governed by an independent scientific or medical board of advisors. The objectives of such disease registries are: ƒ To enhance the understanding of the variabil￾ity, progression and natural history of the dis￾ease 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 ƒ 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. ƒ 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. ƒ 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 ƒ 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. ƒ 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 ƒ 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]. ƒ 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