EJINME-02608; No of Pages 6 European Journal of Internal Medicine xxx (2013) xxx–xxx
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Review article
Gene therapy as a new treatment option for inherited monogenic diseases Pol F. Boudes 152 East Delaware Avenue, Pennington, NJ 08534, USA
a r t i c l e
i n f o
Article history: Received 28 August 2013 Received in revised form 15 September 2013 Accepted 18 September 2013 Available online xxxx Keywords: Gene therapy Inherited monogenic disorders SCID Hemophilia B Lipoprotein lipase Deficiency
a b s t r a c t Background: Gene therapy, replacing a defective gene by a functional copy, has been in development for more than 40 years. Initial efforts involved engineering viral vectors to deliver genes to the appropriate cells. Early successes in severe combined immunodeficiency (SCID) were later derailed by safety issues including host reaction to the vector and gene insertion near promoters that favored secondary leukemia. Methods: Systematic review of the literature using PubMed.gov with key word gene therapy from 1972 to March 2013. Google search with key word gene therapy. Results: Despite early setbacks, progresses for monogenic diseases continued unabated. Patients with SCIDs have been cured and the first gene therapy has been approved for lipoprotein lipase deficiency. Many clinical research studies are ongoing as part of systematic clinical development program with a view to have more gene therapies approved. Conclusion: Our review highlights progresses and questions that remain to be answered to make gene therapy an integral part of our therapeutic arsenal. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Physicians are now able to correct the genetic defect of patients affected with rare inheritable diseases. This review focuses on some remarkable clinical results obtained with gene therapy for monogenic disorders and highlights new directions that could have major impacts on medical practice. 1.1. Early developments The transfer of genes for a therapeutic benefit has been tried for more than 40 years [1]. The principle is simple: a defective gene is replaced by a functional copy that corrects the problem. Gene therapy focuses on three components: the therapeutic gene, the vector that delivers it, and the mode of administration. In the mid-1980s, the concept came closer to reality when the first “cure” was reported in little mice. These mice, a model for human pituitary dwarfism, have reduced levels of growth hormone. Scientists succeeded in inserting a rat growth hormone gene into the pro-nucleus of mice egg and the deficiency was corrected [2]. However, the gene was not controlled and gigantism resulted, an early indication that transferred genes needed to be regulated. Despite this first success, gene therapy turned out to be more challenging than anticipated [3]. Because a gene's transfer can also be done by modifying a cell that is re-introduced in the patient's body, monogenic diseases of blood cells, E-mail address: [email protected].
such as sickle cell disease or β-thalassemia, were initially considered [3]. In these diseases, the molecular defects were understood and the target cell, the hematopoietic stem cell (HSC) was easily accessible. It could be genetically corrected ex-vivo and transplanted back. Hence, gene therapy had a major advantage over the conventional transplantation of HSCs from compatible donors: it was available for all patients and avoided graft rejection [4]. Unfortunately, the regulation of the different globins chains was more complex than anticipated and it was not possible to transfer the β-globin gene in a sufficient number of HSCs to obtain an appropriate erythrocyte precursor expression [5]. Thus, in the mid-1980s, scientists turned to a rare disorder that was thought simpler to address, severe combined immunodeficiency disease (SCID) due to deficiency of the enzyme adenosine deaminase (ADA-SCID) [3,6]. SCIDs include multiple genetic defects, all leading to impaired differentiation of T lymphocytes with, for some, additional blocks in the differentiation of B lymphocytes and/or natural killer (NK) lymphocytes [7]. SCID, in its X-linked form (SCID-X1), is the most common and also known as the bubble boy disease. Infant boys have chronic diarrhea, severe opportunistic infections and fail to thrive. In the absence of immune reconstitution by allogeneic bone marrow transplantation (BMT), kids generally die within the first two years of life. ADA-SCID, the second most common form, was the first for which the genetic and molecular defects were identified [8]. The first ADA-SCID clinical trials were published in the mid-90s. The gene transfer was attempted ex vivo into umbilical cord blood cells or autologous T lymphocytes using a murine retroviral vector [6,9,10]. Retroviral vectors require cell proliferation for efficient transduction and thus, can be used for disorders of blood cells. Unfortunately, in these studies, not enough cells could be transduced for a sufficient time.
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Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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Other attempts where pursued in non-hematologic genetic diseases such as cystic fibrosis [11], Duchenne muscular dystrophy [12] or familial hypercholesterolemia [13]. Adenoviruses were used as vectors. Adenoviruses are easy to produce but can induce local inflammation as well as immune reaction that limit the expression of transgene expression. Again, the results were disappointing [14]. Despite these difficulties, efforts continued unabated and in the late 1990s better gene transfer protocols and vectors were developed. Successful treatments in animal models were reported [15]. With the new millennium, the first successful gene therapy was reported in boys with SCID-X1 [16]. SCID-X1 is characterized by an early block in T cell and NK cell differentiation caused by mutations of the gene encoding the γc cytokine receptor subunit of interleukin-2, -4, -7, -9, and -15 receptors, which deliver growth and differentiation signals to lymphoid progenitors. In this landmark study, boys who lacked HLA-identical donors had their HSC transduced ex-vivo with a retrovirus containing the γc gene and transferred back to them. The genetically modified cells, replete with a functional γc gene, were expected to populate patients' marrow. Indeed, after 10 months of follow-up these boys appeared cured [16] and with more than one year of follow-up for some, eight of the nine patients were doing well and living in a normal environment [17]. 2. Safety concerns While successes were reported in children with SCID-X1, a major safety issue was derailing another gene therapy trial. In September 1999, four days after receiving gene therapy with an adenovirus vector infused into his liver, an 18-year-old boy died [18]. He was suffering from ornithine transcarbamylase deficiency (OTCD), an inherited liver disease which causes ammonia build up in the blood. The boy died of multiple-organ failure attributed to an immune reaction to the adenovirus. The case, widely publicized [19], alarmed the public and many medical institutions as, at that time, 30% of all gene therapy studies were using adenovirus vectors [20]. The FDA put the OTCD trial on hold and halted two other trials that infused adenoviruses into patients' liver [21]. With more information about the death of this patient, serious breaches of good clinical practices (GCPs) were highlighted. They included a failure to report to the FDA and to the Recombinant DNA Advisory Committee (RAC) a change in the way the virus was to be delivered. The RAC was established in 1974 by the National Institute of Health (NIH) to address public concerns regarding the safety of genetic material. The RAC reviews human gene transfer research for institutions receiving NIH funding [22]. Even more troubling, patient volunteers who participated in the OTCD program before the boy's death–but who were given lower doses of virus–suffered significant liver toxicity that was not reported, as mandated, to the FDA. With this critical information, the FDA could have prevented this tragedy [23].
These ‘dark days’ for the field raised multiple scientific and regulatory issues [19]. Also troubling was a new set of safety problems, this time developing in boys with SCID-X1, the very same boys that were previously considered possibly cured from their disease [17]. During the follow up of the previously mentioned study [16], initially two [24,25] and then four of 10 children in this French trial [26] and 1 of 10 children from a similar trial in the UK [27] developed a secondary leukemia. So much hope was raised that this was immensely disappointing. Luckily, the academic teams did not give up and worked harder to understand what happened. The leukemic T-cell clones from boys showed integration of the replacement gene near the LMO2 T cell oncogene [24]. The growth advantage of the gene-corrected T cells combined with the activation of LMO2 explained the leukemia. Retroviral vectors, while integrating randomly into the host genome, show a preference for transcriptionally active genes and contain sequences that are prone to activating nearby genes [26]. It was thought that the likelihood of such an event could be reduced [28,29]. However, a similar insertion of a retroviral vector near the EVI1-MDS1 proto-oncogenes led to the clonal expansion of myeloid cells in two patients with chronic granulomatous disease (CGD) [30]. The level of marked neutrophil rose because of oligoclonal outgrowth of transduced cells with vector inserted in the proto-oncogene. After 2 years, both patients developed myelodysplastic syndromes, with one requiring BMT and the other dying of sepsis [31]. 3. Recent advances Despite these issues, clinical trials continued unabated. Between 1990 and 2007, more than 1500 studies utilizing viral and non-viral vectors were approved [32]. Since 2007 approximately 100 are approved each year [33]. We report here on the most significant developments (Table 1). 3.1. SCIDs and murine γ retroviral vectors For boys enrolled in the SCID-X1 study, after eleven years of followup, data were encouraging. While leukemia developed within 2 to 5 years in 5 children with one dying as a consequence, 18 of 20 treated boys were alive. The immunodeficiency was corrected in 17 and, for most, the correction of the T cell immunodeficiency was nearly complete, notably in four of the five boys who underwent chemotherapy for secondary leukemia [34]. Unlike SCID-X1 and GCD, the efficacy and safety in ADA-SCID are remarkable. ADA-SCID is a fatal autosomal recessive form of SCID characterized by impaired immunity, recurrent infections and failure to thrive. Because of the ADA deficiency toxic levels of purine metabolites accumulate and cause hepatic, skeletal, and neurologic problems. While a hematopoietic stem-cell transplant from an HLA-identical sibling is the treatment of choice, it is only available to few [35]. Enzyme
Table 1 Recent important clinical progresses with gene therapy for monogenic disorders. Name
Gene/protein
Vector
Delivery
Indication
Results
Glybera®
Lipoprotein lipase
AAV1
Intra-muscular
LPD, approved EU
NA
Adenosine deaminase
Murine retrovirus
HSC infusion
ADA-SCID
NA
γc
Murine retrovirus
HSC infusion
SCID-X1
Lenti-D™
ABCD1
Lentivirus
HSC infusion
X-ALD
NA
RPE65
AAV2
Subretinal injection
Leber's amaurosis
Lentiglobin®
β-Globin
Lentivirus
HSC infusion
β-Thalassemia
Decreased pancreatitis. No major safety issue. Immunodeficiency corrected. No major safety issue. Immunodeficiency corrected. Safety: secondary leukemia. Disease stabilized. No major safety issue. Vision improved. No major safety issue. Anemia corrected. No major safety issue.
AAV: adeno-associated virus; LPD: lipoprotein-lipase deficiency; NA: not applicable; HSC: hematopoietic stem cells; ADA-SCID: Severe combined immunodeficiency due to adenosine deaminase deficiency; SCID-X1: X-linked severe combined immunodeficiency; X-ALD: X-linked adrenoleukodystrophy.
Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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replacement with bovine ADA can correct metabolic alterations but often fails to correct the immunodeficiency. Its use is limited by the development of neutralizing antibodies against the bovine enzyme and high cost [36]. Intravenous immunoglobulin replacement is also necessary. The retroviral transduction of HSCs with the ADA gene demonstrated excellent efficacy [37]. The protocol included bone marrow conditioning with busulfan and ADA enzyme replacement therapy was halted. This was done to increase engraftment of gene-modified cells and provide a growth advantage over diseased cells in which purine metabolites accumulate. This resulted in the polyclonal correction of hematopoietic lineages. The ADA transgene was expressed in lymphocytes and red blood cells, thereby leading to systemic detoxification and restoration of the immune function. After a median follow-up of eight years, all of the 10 children infused with gene therapy were alive [38]. In five, intravenous globulin replacement was discontinued and an antigen antibody response was elicited after exposure to vaccines or viral antigens. These children could live a normal life [38]. With this study, gene therapy was, finally, delivering on its promises [39]. 3.2. X-linked adrenoleukodystrophy, β-thalassemia and lentiviral vectors HIV-based lentiviruses are vectors in which HIV genes have been deleted. These retroviruses create double-stranded DNA copies of their RNA and transduce non-dividing cells [40]. A higher level of gene transfer to HSCs and hematopoietic progenitor is achieved. These features provided a rationale to target β-thalassemia, sickle cell disease [41,42] or X-linked adrenoleukodystrophy (X-ALD) [43]. The first successful use of a lentiviral vector was reported for X-ALD. X-ALD is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. Boys develop a severe lipid storage disorder with brain demyelination. Two years after the gene transfer in autologous HSCs a polyclonal reconstitution was detected, with granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. Furthermore, after a year post infusion, the demyelination stopped in two patients. This outcome appears, at least, comparable to allogeneic hematopoietic cell transplantation [44]. In a β-thalassemia study, the β-globin gene was transferred by a lentiviral vector to HSCs to an 18-year-old a patient. After 33 months, he was able to forgo transfusions and leave a quasi normal life [45]. In spite of low-efficiency of gene transfer, 10% of the patient's blood cells contained viral integrants in the HMGA2 gene, apparently resulting in increased gene expression and a growth advantage. Thus far, this has not caused an adverse consequence and could indicate that the risks of insertional mutagenesis can be outweighed by other benefits [46]. 3.3. Hemophilia, Parkinson's disease, inherited blindness and adeno-associated viruses (AAV) AAV vectors derive from a non-pathogenic, human parvovirus with a single-stranded DNA. They are attractive because they can insert genetic material at a specific site on chromosome 19, transfer genes to numerous cells, express different tissue tropisms depending on their viral capsid (serotypes), and have lower inflammatory responses [47]. Animal experiments were encouraging [48,49]. For example, the transfer of hepatic coagulation factor IX gene resulted in long term correction of hemophilia B in dogs with immune tolerance to factor IX [50]. In humans, however, pre-existing antibodies against the capsid of the AAV2 serotype, or a CD8+ T cell response to the capsid prevented a successful outcome [51]. Parkinson's disease (PD) provides a central nervous system model. In a trial, the gene for glutamic acid decarboxylase (GAD) was transferred with AAV2 vectors directly into the sub-thalamic nucleus of PD patients and some clinical efficacy was observed [52]. However, results in this disease are difficult to interpret and more data are needed [53].
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In 2008, clinical improvements were reported with gene therapy in patients with Leber's congenital amaurosis due to a mutation in RPE65 [54–56]. RPE65 encodes an enzyme that catalyzes the conversion of all-trans-retinyl esters to 11-cis-retinal which is required for phototransduction. The defect associated with the RPE65 mutation leads to degeneration of rods and cones and vision impairment. The gene was administered sub-retinally with an AAV2 vector expressing RPE65 under the control of a human RPE65 promoter. While the clinical improvement was limited [54,55], others reported gain in light sensitivity and a better ability to walk through a maze [56]. The clinical effect was maintained at one-year [57]. The effect was also maintained in one of the other study [58]. A subsequent trial in 12 patients aged 8–44 years showed that the visual improvement was age-dependent [59]. Earlier intervention, when there is less photoreceptor damage, resulted in gains in ambulatory vision. This is an important observation for diseases affecting tissues with limited regenerative capacities [60]. Most recently, a study demonstrated that the peripheral infusion of an AAV8 vector expressing a codon-optimized human factor IX transgene in six patients with severe hemophilia B resulted in long term expression of factor IX of up to 11% of normal levels with an acceptable safety profile [61]. Moreover, these levels of expression were sufficient to improve the bleeding phenotype [61]. This experience was highlighted as another landmark study for gene therapy as it could replace the current factor IX protein therapy of hemophilia B and be successfully applied to other monogenic disorders [62]. 4. Regulatory challenges Developments in gene therapies for oncology are worth mentioning. In 2003, China approved Gendicine™, an adenovirus vector engineered to express p53. The treatment showed tumor regression among 99 patients with head and neck squamous cell carcinoma [63]. Gendicine™ however is not available outside China and, with published data, the risk benefit profile is difficult to evaluate [64], particularly against chemotherapy and radiotherapy [65]. In the US, Advexin™, also an adenoviral vector carrying the p53 gene developed for head and neck cancer, failed to gain regulatory approval. The FDA rejected the application in 2008. Concomitantly, the application for cancer associated with Li–Fraumeni syndrome was withdrawn in Europe. Soon after, the maker of Advexin™, Introgen, filed for bankruptcy [66]. In 2009, the Committee on Human Medicinal Products (CHMP) rejected Cerepro™ for the treatment of malignant glioma, an adenovirus containing the Herpes simplex virus-thymidine kinase gene and the first gene therapy to be considered for approval in Europe. The trial was underpowered and failed to show efficacy [67]. Ark Therapeutics, the maker of Cerepro™, also ceased its activities [68]. In 2010, insufficient efficacy halted the development of TNFerade™, an adenovector that delivers the tumor necrosis factor alpha gene in patients with advanced pancreatic cancer [69]. 5. Gene therapy breaks through In July 2012 the European Medicine Agency (EMA) recommended Glybera® (alipogene tiparvovec) for approval for the treatment of lipoprotein lipase deficiency (LPLD) [70]. Patients with this disorder of triglyceride metabolism experience severe acute pancreatitis attacks that can be fatal. The CHMP, which makes final recommendations for marketing authorization in the EU, concurred and the European Commission (EC) approved Glybera® in November 2012 (Table 1). Glybera® is the first gene therapy approved in the Western world. With this breakthrough event, gene therapy becomes a reality. Glybera® is an AAV1 engineered to express lipoprotein lipase and delivered into muscles. This first approval followed a convoluted regulatory saga and took place in an environment where hostility towards genetic engineering
Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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is a concern [71]. The original application was submitted in January 2010, but the EMA recommended against it. A re-examination was requested by the sponsor, Amsterdam Molecular Therapeutics. With the same data, the EMA reversed its decision. In October 2011 though, the CHMP disagreed with the EMA, a rare event, and rejected the application. There was allegedly not enough evidence for a persisting effect in lowering triglycerides to be clinically relevant and too few patients (N = 27) from whom long-term data were available. Following this decision, the sponsor ceased its activities and its assets were transferred to a new company, UniQure. In January 2012, the EC, usually only a rubber stamp for CHMP recommendations, asked the committee to reexamine the approval for a restricted indication for patients who have experienced either severe or multiple pancreatitis attacks. Further analysis suggested that patients receiving Glybera® experienced fewer pancreatitis attacks. This provided a clinical rationale for the application. The third CHMP review, however, resulted in another negative opinion, even though a narrow majority favored approval. The restricted indication included only 12 patients and data showing a reduction in postprandial plasma chylomicrons, a potential biomarker of activity, were only available for five patients. Recognizing “the difficulty of obtaining data in this rare disease,” the CHMP asked UniQure to request a fourth reexamination, after which a sufficient majority in favor of authorization was obtained. The CHMP concluded that the benefits of Glybera in this subset of patients were greater than the risks [72]. The EC ratified the decision in November 2012 [73]. 6. Next steps Some important questions have to be addressed to confirm the first gene therapy successes (Table 2). 7. Clinical questions The remarkable efficacy of gene therapy in ADA-SCID and SCID-X1 needs to be reproduced in other diseases. Previous regulatory hurdles indicate that the higher the clinical evidence, the more successful gene therapy will be. Benefits on biochemical markers, such as postprandial plasma chylomicrons or triglyceride levels, were not sufficient and Glybera®'s indication was restricted to a sub-group for which a clinical benefit, the reduction in pancreatitis attack, appeared documented. The mechanism by which secondary leukemia developed for SCIDX1 or GCD has been explained and should be controlled with better vectors and gene engineering. As few patients are available, safety will remain an ongoing concern. So far, some gene therapies have been remarkably well tolerated but the bad surprises of the first decades should be kept in mind. Moving forward we need to treat more patients and
Table 2 Questions facing gene therapy. Topic
Questions
Clinical safety and efficacy
Can we better control inserted gene (site of insertion, regulatory elements)? Can we control immunogenicity towards the gene or the vector and move from single to repeated administration? Can we develop vectors with tissue-specific tropism to avoid traumatic local injections? Will international collaboration for clinical trials pick-up? Can we deliver earlier treatment in the natural history of the disease, before irreversible damages occur (e.g. CNS diseases)? Regulatory Are the processes in place sufficient or do we need to develop new pathway for approval? Commercialization How can we better finance clinical research? Is gene therapy commercially viable? Do we need to invent another pricing and reimbursement model? CNS: central nervous system.
collect long term safety. A global collaboration between clinicians will be essential to achieve this [74]. SCIDs constitute a best case scenario: a single cell lineage is affected and HSCs are easily accessible to be corrected and re-infused. The success in a β-thalassemia patient is encouraging but needs replication. Beyond bone marrow, gene therapy should address disease of other organs and, with each new disease, specific questions will have to be answered. The eye is an immunologically privileged organ. With a local administration, the host immune reaction against the vector or the gene product is minimized. The immune reaction will be important to address with a systemic administration of a gene or with the direct administration in a ‘non-privileged’ organ. Glybera® is administered with a concomitant immunosuppression and is restricted to patients who produce at least 5% of the deficient protein. This appears logical and prudent but the benefits remain to be demonstrated. Similarly, the repeated use of gene therapy in the same patient, which might be necessary in case of insufficient or transient effect, needs to be attempted. The central nervous system (CNS) is an important target as many diseases affecting this organ are incurable. The best method of gene delivery into the CNS is still to be found. The systemic delivery of vectors that demonstrate CNS tropism could offer a convenient solution. New data will be gathered from ongoing studies in ALD and lysosomal storage diseases (LSDs). For diseases affecting specialized organ with limited capacity to regenerate, an early intervention is necessary. This was demonstrated in Leber's amaurosis where the effect of gene therapy was clearly age dependant. Early intervention will require a change of paradigm as currently, new and innovative therapies tend to be restricted to the most severe cases. Collecting more data on the natural history of rare monogenetic diseases will also help to better understand when an early intervention should be done. All these questions will have to be integrated in our genetic counseling, and for some diseases, integrated into neonatal screening strategies. Efforts for trans-atlantic collaboration are ongoing [74]. Multiple clinical trials are performed for diseases such as the Wiskott–Aldrich syndrome, hemophilia B, Pompe disease, metachromatic leukodystrophy, cystic fibrosis, and Sanfilippo syndrome. These will determine if initial successes can be repeated. Patients are also enrolled in longterm follow-up studies that will provide long term safety data [75]. 8. Regulatory questions Now that the first gene therapy has been approved in Europe, what will be the situation with the US? Will the FDA also approve Glybera® or will the additional requests for data be made? The European approval of the first gene therapy was convoluted [73] but let's hope that the regulatory path will be ‘normalized’ and the decision will solely be based on the merit of the data. Regulatory processes, already in place, can address the specificities of gene therapy [76]. In Europe there is a marketing authorization under ‘exceptional circumstances’ [77] and in the US a conditional approval mechanism and the recent ‘breakthrough designation’ [78]. Beyond Glybera®, another registration will confirm the validity of this method. Hopefully, we will not have to wait 18 years, as was the case for the second approval of an ‘antisense therapy’ [79]. Gene therapy for SCIDs seem to be best positioned, notably ADA-SCID with its remarkable efficacy and, up to now, excellent safety profile. The alliance between a private foundation and a large pharmaceutical company brings together the appropriate expertise to achieve this goal [80]. 9. Commercialization Until now, gene therapy has been mostly funded by government and/or charitable organizations. The fragmentation of research efforts
Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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and the difficulty to access funding are hurdles for this technology to enter the clinic [74]. Private financing is also necessary. For years, private investors have been deterred by safety scares and the lack of foreseeable returns. Recent successes, including Glybera®'s approval, triggered a renewed interest. New companies, such as UniQure in Europe or Bluebird Bio in the US, have been created and large pharmaceutical companies entered the field [80,81]. Irrespective of the balance between public and private funding, cooperation between both sectors will be essential. Can gene therapy be successfully commercialized? The first answer will come from Glybera®. No pricing and reimbursement information is yet available. ADA-SCID exemplifies why gene therapy could be economically viable. Patients are cured and the cost of bone marrow transplantation, life-long enzyme therapy and intravenous immunoglobulin injection, treatment of co-morbidities (e.g. infections) and hospitalizations are avoided. Despite the rarity of the disease, these benefits should make gene therapy viable for its developer. New pricing models are necessary. For ADA-SCID, a one shot cure represents a new paradigm. Up to now, the field of rare disease is relying on an economic model based on enzyme replacement therapy for LSDs with lifelong weekly or bi-weekly infusions for up to €400,000 a year [82]. For gene therapy, the model could be to charge a fixed amount when the therapy is delivered, and to renew this amount for each unit of time the patient remains free of the disease, for instance every year. This could be done until the patient is definitively cured. Five years disease-free is considered a cure in cancers and a similar approach could be envisaged for gene therapy. This model allows better predictability of revenues for investors and expenses for payers. Learning points • With gene therapy, a defective gene is replaced by a functional copy with the objective to correct a clinical disease. • Gene therapy is made up of three components: the therapeutic gene, the vector that delivers it, and the mode of administration. • Over the past 40 years, major progresses have been made to improve viral vectors, from adenoviruses, to lentiviruses and adeno-associated viruses and to deliver genes in association with key regulatory elements. • The early clinical developments were challenged by safety problems that are now well understood and can be prevented. • Important clinical results have been obtained in multiple monogenic diseases, such as severe combined immunodeficiencies and hemophilia B. • In 2012, the first gene therapy has been approved in Europe for the treatment of for the treatment of lipoprotein lipase deficiency bringing hope of major future achievements. Conflict of interest None. References [1] Friedmann T, Roblin R. Gene therapy for human genetic disease? Science 1972;175: 949–55. [2] Hammer RE, Palmiter RD, Brinster RL. Partial correction of murine hereditary growth disorder by germ-line incorporation of a new gene. Nature 1984;311:65–7. [3] Anderson WF. Prospects for human gene therapy. Science 1984;226:401–9. [4] Parkman R. The application of bone marrow transplantation (BMT) to the treatment of genetic diseases. Science 1986;232:1373–8. [5] Mulligan RC. The basic science of gene therapy. Science 1993;260:926–32. [6] Kohn DB, Weinberg KI, Nolta JA, Heiss LN, Lenarsky C, Crooks GM, et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat Med 1995;1:1017–23. [7] Buckley RH. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med 2000;343:1313–24.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Review article
Gene therapy as a new treatment option for inherited monogenic diseases Pol F. Boudes 152 East Delaware Avenue, Pennington, NJ 08534, USA
a r t i c l e
i n f o
Article history: Received 28 August 2013 Received in revised form 15 September 2013 Accepted 18 September 2013 Available online xxxx Keywords: Gene therapy Inherited monogenic disorders SCID Hemophilia B Lipoprotein lipase Deficiency
a b s t r a c t Background: Gene therapy, replacing a defective gene by a functional copy, has been in development for more than 40 years. Initial efforts involved engineering viral vectors to deliver genes to the appropriate cells. Early successes in severe combined immunodeficiency (SCID) were later derailed by safety issues including host reaction to the vector and gene insertion near promoters that favored secondary leukemia. Methods: Systematic review of the literature using PubMed.gov with key word gene therapy from 1972 to March 2013. Google search with key word gene therapy. Results: Despite early setbacks, progresses for monogenic diseases continued unabated. Patients with SCIDs have been cured and the first gene therapy has been approved for lipoprotein lipase deficiency. Many clinical research studies are ongoing as part of systematic clinical development program with a view to have more gene therapies approved. Conclusion: Our review highlights progresses and questions that remain to be answered to make gene therapy an integral part of our therapeutic arsenal. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Physicians are now able to correct the genetic defect of patients affected with rare inheritable diseases. This review focuses on some remarkable clinical results obtained with gene therapy for monogenic disorders and highlights new directions that could have major impacts on medical practice. 1.1. Early developments The transfer of genes for a therapeutic benefit has been tried for more than 40 years [1]. The principle is simple: a defective gene is replaced by a functional copy that corrects the problem. Gene therapy focuses on three components: the therapeutic gene, the vector that delivers it, and the mode of administration. In the mid-1980s, the concept came closer to reality when the first “cure” was reported in little mice. These mice, a model for human pituitary dwarfism, have reduced levels of growth hormone. Scientists succeeded in inserting a rat growth hormone gene into the pro-nucleus of mice egg and the deficiency was corrected [2]. However, the gene was not controlled and gigantism resulted, an early indication that transferred genes needed to be regulated. Despite this first success, gene therapy turned out to be more challenging than anticipated [3]. Because a gene's transfer can also be done by modifying a cell that is re-introduced in the patient's body, monogenic diseases of blood cells, E-mail address: [email protected].
such as sickle cell disease or β-thalassemia, were initially considered [3]. In these diseases, the molecular defects were understood and the target cell, the hematopoietic stem cell (HSC) was easily accessible. It could be genetically corrected ex-vivo and transplanted back. Hence, gene therapy had a major advantage over the conventional transplantation of HSCs from compatible donors: it was available for all patients and avoided graft rejection [4]. Unfortunately, the regulation of the different globins chains was more complex than anticipated and it was not possible to transfer the β-globin gene in a sufficient number of HSCs to obtain an appropriate erythrocyte precursor expression [5]. Thus, in the mid-1980s, scientists turned to a rare disorder that was thought simpler to address, severe combined immunodeficiency disease (SCID) due to deficiency of the enzyme adenosine deaminase (ADA-SCID) [3,6]. SCIDs include multiple genetic defects, all leading to impaired differentiation of T lymphocytes with, for some, additional blocks in the differentiation of B lymphocytes and/or natural killer (NK) lymphocytes [7]. SCID, in its X-linked form (SCID-X1), is the most common and also known as the bubble boy disease. Infant boys have chronic diarrhea, severe opportunistic infections and fail to thrive. In the absence of immune reconstitution by allogeneic bone marrow transplantation (BMT), kids generally die within the first two years of life. ADA-SCID, the second most common form, was the first for which the genetic and molecular defects were identified [8]. The first ADA-SCID clinical trials were published in the mid-90s. The gene transfer was attempted ex vivo into umbilical cord blood cells or autologous T lymphocytes using a murine retroviral vector [6,9,10]. Retroviral vectors require cell proliferation for efficient transduction and thus, can be used for disorders of blood cells. Unfortunately, in these studies, not enough cells could be transduced for a sufficient time.
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Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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Other attempts where pursued in non-hematologic genetic diseases such as cystic fibrosis [11], Duchenne muscular dystrophy [12] or familial hypercholesterolemia [13]. Adenoviruses were used as vectors. Adenoviruses are easy to produce but can induce local inflammation as well as immune reaction that limit the expression of transgene expression. Again, the results were disappointing [14]. Despite these difficulties, efforts continued unabated and in the late 1990s better gene transfer protocols and vectors were developed. Successful treatments in animal models were reported [15]. With the new millennium, the first successful gene therapy was reported in boys with SCID-X1 [16]. SCID-X1 is characterized by an early block in T cell and NK cell differentiation caused by mutations of the gene encoding the γc cytokine receptor subunit of interleukin-2, -4, -7, -9, and -15 receptors, which deliver growth and differentiation signals to lymphoid progenitors. In this landmark study, boys who lacked HLA-identical donors had their HSC transduced ex-vivo with a retrovirus containing the γc gene and transferred back to them. The genetically modified cells, replete with a functional γc gene, were expected to populate patients' marrow. Indeed, after 10 months of follow-up these boys appeared cured [16] and with more than one year of follow-up for some, eight of the nine patients were doing well and living in a normal environment [17]. 2. Safety concerns While successes were reported in children with SCID-X1, a major safety issue was derailing another gene therapy trial. In September 1999, four days after receiving gene therapy with an adenovirus vector infused into his liver, an 18-year-old boy died [18]. He was suffering from ornithine transcarbamylase deficiency (OTCD), an inherited liver disease which causes ammonia build up in the blood. The boy died of multiple-organ failure attributed to an immune reaction to the adenovirus. The case, widely publicized [19], alarmed the public and many medical institutions as, at that time, 30% of all gene therapy studies were using adenovirus vectors [20]. The FDA put the OTCD trial on hold and halted two other trials that infused adenoviruses into patients' liver [21]. With more information about the death of this patient, serious breaches of good clinical practices (GCPs) were highlighted. They included a failure to report to the FDA and to the Recombinant DNA Advisory Committee (RAC) a change in the way the virus was to be delivered. The RAC was established in 1974 by the National Institute of Health (NIH) to address public concerns regarding the safety of genetic material. The RAC reviews human gene transfer research for institutions receiving NIH funding [22]. Even more troubling, patient volunteers who participated in the OTCD program before the boy's death–but who were given lower doses of virus–suffered significant liver toxicity that was not reported, as mandated, to the FDA. With this critical information, the FDA could have prevented this tragedy [23].
These ‘dark days’ for the field raised multiple scientific and regulatory issues [19]. Also troubling was a new set of safety problems, this time developing in boys with SCID-X1, the very same boys that were previously considered possibly cured from their disease [17]. During the follow up of the previously mentioned study [16], initially two [24,25] and then four of 10 children in this French trial [26] and 1 of 10 children from a similar trial in the UK [27] developed a secondary leukemia. So much hope was raised that this was immensely disappointing. Luckily, the academic teams did not give up and worked harder to understand what happened. The leukemic T-cell clones from boys showed integration of the replacement gene near the LMO2 T cell oncogene [24]. The growth advantage of the gene-corrected T cells combined with the activation of LMO2 explained the leukemia. Retroviral vectors, while integrating randomly into the host genome, show a preference for transcriptionally active genes and contain sequences that are prone to activating nearby genes [26]. It was thought that the likelihood of such an event could be reduced [28,29]. However, a similar insertion of a retroviral vector near the EVI1-MDS1 proto-oncogenes led to the clonal expansion of myeloid cells in two patients with chronic granulomatous disease (CGD) [30]. The level of marked neutrophil rose because of oligoclonal outgrowth of transduced cells with vector inserted in the proto-oncogene. After 2 years, both patients developed myelodysplastic syndromes, with one requiring BMT and the other dying of sepsis [31]. 3. Recent advances Despite these issues, clinical trials continued unabated. Between 1990 and 2007, more than 1500 studies utilizing viral and non-viral vectors were approved [32]. Since 2007 approximately 100 are approved each year [33]. We report here on the most significant developments (Table 1). 3.1. SCIDs and murine γ retroviral vectors For boys enrolled in the SCID-X1 study, after eleven years of followup, data were encouraging. While leukemia developed within 2 to 5 years in 5 children with one dying as a consequence, 18 of 20 treated boys were alive. The immunodeficiency was corrected in 17 and, for most, the correction of the T cell immunodeficiency was nearly complete, notably in four of the five boys who underwent chemotherapy for secondary leukemia [34]. Unlike SCID-X1 and GCD, the efficacy and safety in ADA-SCID are remarkable. ADA-SCID is a fatal autosomal recessive form of SCID characterized by impaired immunity, recurrent infections and failure to thrive. Because of the ADA deficiency toxic levels of purine metabolites accumulate and cause hepatic, skeletal, and neurologic problems. While a hematopoietic stem-cell transplant from an HLA-identical sibling is the treatment of choice, it is only available to few [35]. Enzyme
Table 1 Recent important clinical progresses with gene therapy for monogenic disorders. Name
Gene/protein
Vector
Delivery
Indication
Results
Glybera®
Lipoprotein lipase
AAV1
Intra-muscular
LPD, approved EU
NA
Adenosine deaminase
Murine retrovirus
HSC infusion
ADA-SCID
NA
γc
Murine retrovirus
HSC infusion
SCID-X1
Lenti-D™
ABCD1
Lentivirus
HSC infusion
X-ALD
NA
RPE65
AAV2
Subretinal injection
Leber's amaurosis
Lentiglobin®
β-Globin
Lentivirus
HSC infusion
β-Thalassemia
Decreased pancreatitis. No major safety issue. Immunodeficiency corrected. No major safety issue. Immunodeficiency corrected. Safety: secondary leukemia. Disease stabilized. No major safety issue. Vision improved. No major safety issue. Anemia corrected. No major safety issue.
AAV: adeno-associated virus; LPD: lipoprotein-lipase deficiency; NA: not applicable; HSC: hematopoietic stem cells; ADA-SCID: Severe combined immunodeficiency due to adenosine deaminase deficiency; SCID-X1: X-linked severe combined immunodeficiency; X-ALD: X-linked adrenoleukodystrophy.
Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
P.F. Boudes / European Journal of Internal Medicine xxx (2013) xxx–xxx
replacement with bovine ADA can correct metabolic alterations but often fails to correct the immunodeficiency. Its use is limited by the development of neutralizing antibodies against the bovine enzyme and high cost [36]. Intravenous immunoglobulin replacement is also necessary. The retroviral transduction of HSCs with the ADA gene demonstrated excellent efficacy [37]. The protocol included bone marrow conditioning with busulfan and ADA enzyme replacement therapy was halted. This was done to increase engraftment of gene-modified cells and provide a growth advantage over diseased cells in which purine metabolites accumulate. This resulted in the polyclonal correction of hematopoietic lineages. The ADA transgene was expressed in lymphocytes and red blood cells, thereby leading to systemic detoxification and restoration of the immune function. After a median follow-up of eight years, all of the 10 children infused with gene therapy were alive [38]. In five, intravenous globulin replacement was discontinued and an antigen antibody response was elicited after exposure to vaccines or viral antigens. These children could live a normal life [38]. With this study, gene therapy was, finally, delivering on its promises [39]. 3.2. X-linked adrenoleukodystrophy, β-thalassemia and lentiviral vectors HIV-based lentiviruses are vectors in which HIV genes have been deleted. These retroviruses create double-stranded DNA copies of their RNA and transduce non-dividing cells [40]. A higher level of gene transfer to HSCs and hematopoietic progenitor is achieved. These features provided a rationale to target β-thalassemia, sickle cell disease [41,42] or X-linked adrenoleukodystrophy (X-ALD) [43]. The first successful use of a lentiviral vector was reported for X-ALD. X-ALD is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. Boys develop a severe lipid storage disorder with brain demyelination. Two years after the gene transfer in autologous HSCs a polyclonal reconstitution was detected, with granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. Furthermore, after a year post infusion, the demyelination stopped in two patients. This outcome appears, at least, comparable to allogeneic hematopoietic cell transplantation [44]. In a β-thalassemia study, the β-globin gene was transferred by a lentiviral vector to HSCs to an 18-year-old a patient. After 33 months, he was able to forgo transfusions and leave a quasi normal life [45]. In spite of low-efficiency of gene transfer, 10% of the patient's blood cells contained viral integrants in the HMGA2 gene, apparently resulting in increased gene expression and a growth advantage. Thus far, this has not caused an adverse consequence and could indicate that the risks of insertional mutagenesis can be outweighed by other benefits [46]. 3.3. Hemophilia, Parkinson's disease, inherited blindness and adeno-associated viruses (AAV) AAV vectors derive from a non-pathogenic, human parvovirus with a single-stranded DNA. They are attractive because they can insert genetic material at a specific site on chromosome 19, transfer genes to numerous cells, express different tissue tropisms depending on their viral capsid (serotypes), and have lower inflammatory responses [47]. Animal experiments were encouraging [48,49]. For example, the transfer of hepatic coagulation factor IX gene resulted in long term correction of hemophilia B in dogs with immune tolerance to factor IX [50]. In humans, however, pre-existing antibodies against the capsid of the AAV2 serotype, or a CD8+ T cell response to the capsid prevented a successful outcome [51]. Parkinson's disease (PD) provides a central nervous system model. In a trial, the gene for glutamic acid decarboxylase (GAD) was transferred with AAV2 vectors directly into the sub-thalamic nucleus of PD patients and some clinical efficacy was observed [52]. However, results in this disease are difficult to interpret and more data are needed [53].
3
In 2008, clinical improvements were reported with gene therapy in patients with Leber's congenital amaurosis due to a mutation in RPE65 [54–56]. RPE65 encodes an enzyme that catalyzes the conversion of all-trans-retinyl esters to 11-cis-retinal which is required for phototransduction. The defect associated with the RPE65 mutation leads to degeneration of rods and cones and vision impairment. The gene was administered sub-retinally with an AAV2 vector expressing RPE65 under the control of a human RPE65 promoter. While the clinical improvement was limited [54,55], others reported gain in light sensitivity and a better ability to walk through a maze [56]. The clinical effect was maintained at one-year [57]. The effect was also maintained in one of the other study [58]. A subsequent trial in 12 patients aged 8–44 years showed that the visual improvement was age-dependent [59]. Earlier intervention, when there is less photoreceptor damage, resulted in gains in ambulatory vision. This is an important observation for diseases affecting tissues with limited regenerative capacities [60]. Most recently, a study demonstrated that the peripheral infusion of an AAV8 vector expressing a codon-optimized human factor IX transgene in six patients with severe hemophilia B resulted in long term expression of factor IX of up to 11% of normal levels with an acceptable safety profile [61]. Moreover, these levels of expression were sufficient to improve the bleeding phenotype [61]. This experience was highlighted as another landmark study for gene therapy as it could replace the current factor IX protein therapy of hemophilia B and be successfully applied to other monogenic disorders [62]. 4. Regulatory challenges Developments in gene therapies for oncology are worth mentioning. In 2003, China approved Gendicine™, an adenovirus vector engineered to express p53. The treatment showed tumor regression among 99 patients with head and neck squamous cell carcinoma [63]. Gendicine™ however is not available outside China and, with published data, the risk benefit profile is difficult to evaluate [64], particularly against chemotherapy and radiotherapy [65]. In the US, Advexin™, also an adenoviral vector carrying the p53 gene developed for head and neck cancer, failed to gain regulatory approval. The FDA rejected the application in 2008. Concomitantly, the application for cancer associated with Li–Fraumeni syndrome was withdrawn in Europe. Soon after, the maker of Advexin™, Introgen, filed for bankruptcy [66]. In 2009, the Committee on Human Medicinal Products (CHMP) rejected Cerepro™ for the treatment of malignant glioma, an adenovirus containing the Herpes simplex virus-thymidine kinase gene and the first gene therapy to be considered for approval in Europe. The trial was underpowered and failed to show efficacy [67]. Ark Therapeutics, the maker of Cerepro™, also ceased its activities [68]. In 2010, insufficient efficacy halted the development of TNFerade™, an adenovector that delivers the tumor necrosis factor alpha gene in patients with advanced pancreatic cancer [69]. 5. Gene therapy breaks through In July 2012 the European Medicine Agency (EMA) recommended Glybera® (alipogene tiparvovec) for approval for the treatment of lipoprotein lipase deficiency (LPLD) [70]. Patients with this disorder of triglyceride metabolism experience severe acute pancreatitis attacks that can be fatal. The CHMP, which makes final recommendations for marketing authorization in the EU, concurred and the European Commission (EC) approved Glybera® in November 2012 (Table 1). Glybera® is the first gene therapy approved in the Western world. With this breakthrough event, gene therapy becomes a reality. Glybera® is an AAV1 engineered to express lipoprotein lipase and delivered into muscles. This first approval followed a convoluted regulatory saga and took place in an environment where hostility towards genetic engineering
Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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is a concern [71]. The original application was submitted in January 2010, but the EMA recommended against it. A re-examination was requested by the sponsor, Amsterdam Molecular Therapeutics. With the same data, the EMA reversed its decision. In October 2011 though, the CHMP disagreed with the EMA, a rare event, and rejected the application. There was allegedly not enough evidence for a persisting effect in lowering triglycerides to be clinically relevant and too few patients (N = 27) from whom long-term data were available. Following this decision, the sponsor ceased its activities and its assets were transferred to a new company, UniQure. In January 2012, the EC, usually only a rubber stamp for CHMP recommendations, asked the committee to reexamine the approval for a restricted indication for patients who have experienced either severe or multiple pancreatitis attacks. Further analysis suggested that patients receiving Glybera® experienced fewer pancreatitis attacks. This provided a clinical rationale for the application. The third CHMP review, however, resulted in another negative opinion, even though a narrow majority favored approval. The restricted indication included only 12 patients and data showing a reduction in postprandial plasma chylomicrons, a potential biomarker of activity, were only available for five patients. Recognizing “the difficulty of obtaining data in this rare disease,” the CHMP asked UniQure to request a fourth reexamination, after which a sufficient majority in favor of authorization was obtained. The CHMP concluded that the benefits of Glybera in this subset of patients were greater than the risks [72]. The EC ratified the decision in November 2012 [73]. 6. Next steps Some important questions have to be addressed to confirm the first gene therapy successes (Table 2). 7. Clinical questions The remarkable efficacy of gene therapy in ADA-SCID and SCID-X1 needs to be reproduced in other diseases. Previous regulatory hurdles indicate that the higher the clinical evidence, the more successful gene therapy will be. Benefits on biochemical markers, such as postprandial plasma chylomicrons or triglyceride levels, were not sufficient and Glybera®'s indication was restricted to a sub-group for which a clinical benefit, the reduction in pancreatitis attack, appeared documented. The mechanism by which secondary leukemia developed for SCIDX1 or GCD has been explained and should be controlled with better vectors and gene engineering. As few patients are available, safety will remain an ongoing concern. So far, some gene therapies have been remarkably well tolerated but the bad surprises of the first decades should be kept in mind. Moving forward we need to treat more patients and
Table 2 Questions facing gene therapy. Topic
Questions
Clinical safety and efficacy
Can we better control inserted gene (site of insertion, regulatory elements)? Can we control immunogenicity towards the gene or the vector and move from single to repeated administration? Can we develop vectors with tissue-specific tropism to avoid traumatic local injections? Will international collaboration for clinical trials pick-up? Can we deliver earlier treatment in the natural history of the disease, before irreversible damages occur (e.g. CNS diseases)? Regulatory Are the processes in place sufficient or do we need to develop new pathway for approval? Commercialization How can we better finance clinical research? Is gene therapy commercially viable? Do we need to invent another pricing and reimbursement model? CNS: central nervous system.
collect long term safety. A global collaboration between clinicians will be essential to achieve this [74]. SCIDs constitute a best case scenario: a single cell lineage is affected and HSCs are easily accessible to be corrected and re-infused. The success in a β-thalassemia patient is encouraging but needs replication. Beyond bone marrow, gene therapy should address disease of other organs and, with each new disease, specific questions will have to be answered. The eye is an immunologically privileged organ. With a local administration, the host immune reaction against the vector or the gene product is minimized. The immune reaction will be important to address with a systemic administration of a gene or with the direct administration in a ‘non-privileged’ organ. Glybera® is administered with a concomitant immunosuppression and is restricted to patients who produce at least 5% of the deficient protein. This appears logical and prudent but the benefits remain to be demonstrated. Similarly, the repeated use of gene therapy in the same patient, which might be necessary in case of insufficient or transient effect, needs to be attempted. The central nervous system (CNS) is an important target as many diseases affecting this organ are incurable. The best method of gene delivery into the CNS is still to be found. The systemic delivery of vectors that demonstrate CNS tropism could offer a convenient solution. New data will be gathered from ongoing studies in ALD and lysosomal storage diseases (LSDs). For diseases affecting specialized organ with limited capacity to regenerate, an early intervention is necessary. This was demonstrated in Leber's amaurosis where the effect of gene therapy was clearly age dependant. Early intervention will require a change of paradigm as currently, new and innovative therapies tend to be restricted to the most severe cases. Collecting more data on the natural history of rare monogenetic diseases will also help to better understand when an early intervention should be done. All these questions will have to be integrated in our genetic counseling, and for some diseases, integrated into neonatal screening strategies. Efforts for trans-atlantic collaboration are ongoing [74]. Multiple clinical trials are performed for diseases such as the Wiskott–Aldrich syndrome, hemophilia B, Pompe disease, metachromatic leukodystrophy, cystic fibrosis, and Sanfilippo syndrome. These will determine if initial successes can be repeated. Patients are also enrolled in longterm follow-up studies that will provide long term safety data [75]. 8. Regulatory questions Now that the first gene therapy has been approved in Europe, what will be the situation with the US? Will the FDA also approve Glybera® or will the additional requests for data be made? The European approval of the first gene therapy was convoluted [73] but let's hope that the regulatory path will be ‘normalized’ and the decision will solely be based on the merit of the data. Regulatory processes, already in place, can address the specificities of gene therapy [76]. In Europe there is a marketing authorization under ‘exceptional circumstances’ [77] and in the US a conditional approval mechanism and the recent ‘breakthrough designation’ [78]. Beyond Glybera®, another registration will confirm the validity of this method. Hopefully, we will not have to wait 18 years, as was the case for the second approval of an ‘antisense therapy’ [79]. Gene therapy for SCIDs seem to be best positioned, notably ADA-SCID with its remarkable efficacy and, up to now, excellent safety profile. The alliance between a private foundation and a large pharmaceutical company brings together the appropriate expertise to achieve this goal [80]. 9. Commercialization Until now, gene therapy has been mostly funded by government and/or charitable organizations. The fragmentation of research efforts
Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
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and the difficulty to access funding are hurdles for this technology to enter the clinic [74]. Private financing is also necessary. For years, private investors have been deterred by safety scares and the lack of foreseeable returns. Recent successes, including Glybera®'s approval, triggered a renewed interest. New companies, such as UniQure in Europe or Bluebird Bio in the US, have been created and large pharmaceutical companies entered the field [80,81]. Irrespective of the balance between public and private funding, cooperation between both sectors will be essential. Can gene therapy be successfully commercialized? The first answer will come from Glybera®. No pricing and reimbursement information is yet available. ADA-SCID exemplifies why gene therapy could be economically viable. Patients are cured and the cost of bone marrow transplantation, life-long enzyme therapy and intravenous immunoglobulin injection, treatment of co-morbidities (e.g. infections) and hospitalizations are avoided. Despite the rarity of the disease, these benefits should make gene therapy viable for its developer. New pricing models are necessary. For ADA-SCID, a one shot cure represents a new paradigm. Up to now, the field of rare disease is relying on an economic model based on enzyme replacement therapy for LSDs with lifelong weekly or bi-weekly infusions for up to €400,000 a year [82]. For gene therapy, the model could be to charge a fixed amount when the therapy is delivered, and to renew this amount for each unit of time the patient remains free of the disease, for instance every year. This could be done until the patient is definitively cured. Five years disease-free is considered a cure in cancers and a similar approach could be envisaged for gene therapy. This model allows better predictability of revenues for investors and expenses for payers. Learning points • With gene therapy, a defective gene is replaced by a functional copy with the objective to correct a clinical disease. • Gene therapy is made up of three components: the therapeutic gene, the vector that delivers it, and the mode of administration. • Over the past 40 years, major progresses have been made to improve viral vectors, from adenoviruses, to lentiviruses and adeno-associated viruses and to deliver genes in association with key regulatory elements. • The early clinical developments were challenged by safety problems that are now well understood and can be prevented. • Important clinical results have been obtained in multiple monogenic diseases, such as severe combined immunodeficiencies and hemophilia B. • In 2012, the first gene therapy has been approved in Europe for the treatment of for the treatment of lipoprotein lipase deficiency bringing hope of major future achievements. Conflict of interest None. References [1] Friedmann T, Roblin R. Gene therapy for human genetic disease? Science 1972;175: 949–55. [2] Hammer RE, Palmiter RD, Brinster RL. Partial correction of murine hereditary growth disorder by germ-line incorporation of a new gene. Nature 1984;311:65–7. [3] Anderson WF. Prospects for human gene therapy. Science 1984;226:401–9. [4] Parkman R. The application of bone marrow transplantation (BMT) to the treatment of genetic diseases. Science 1986;232:1373–8. [5] Mulligan RC. The basic science of gene therapy. Science 1993;260:926–32. [6] Kohn DB, Weinberg KI, Nolta JA, Heiss LN, Lenarsky C, Crooks GM, et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat Med 1995;1:1017–23. [7] Buckley RH. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med 2000;343:1313–24.
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Please cite this article as: Boudes PF, Gene therapy as a new treatment option for inherited monogenic diseases, Eur J Intern Med (2013), http://dx.doi.org/10.1016/j.ejim.2013.09.009
