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Is There Treatment for “Genetic” Disease?
Molecular Genetics and Metabolism 68, 93–102 (1999) Article ID mgme.1999.2907, available online at http://www.idealibrary.com on
MINIREVIEW Is There Treatment for “Genetic” Disease? 1 Charles R. Scriver and Eileen P. Treacy 2 The De Belle Laboratory for Biochemical Genetics, McGill University Health Centre, McGill University-Montreal Children’s Hospital Research Institute, Montreal, Canada Received July 15, 1999
It has always been the hope that better knowledge of the cause and pathogenesis of a particular disease would improve its treatment; better still could prevent it. To a great extent, this hope has materialized for a range of nutritional and infectious diseases, some of which had achieved epidemic proportions during human history. Now it is the turn of so-called genetic diseases to enter this arena of hope. Homo sapiens is the only species on earth which intentionally modifies experience, thereby modifying natural selection. Homo sapiens is Homo modificans. We can manipulate experience to maintain health. We seek cures of diseases; in their absence, we attempt control; and if we cannot control, we provide care. There are no cures yet for genetic disease; we are doing better with control, and we can provide care. Treatment of genetic disease involves modified selection and directed adaptation; it is focused on individuals and in many ways it is a cultural activity. The ultimate goal is to restore the normal metrical trait value in the target area of treatment. Walter B. Cannon called that area ho-
meostasis—where there is biological “homing in” on the central tendency (1,2). The problem is that treatment of a genetic disease, whether “simple” or “complex” in its origins, all too often fails to restore normal homeostasis in the appropriate bodily or cellular space. Two classic examples illustrate: one is a common disorder in the class of complex traits, the other a rare disease in the class of single gene disorders presumed to be simpler in their mechanism of pathogenesis than in the complex traits.
1
THE COMPLEX TRAIT EXAMPLE Type 1 diabetes mellitus formerly killed children. It was assumed that the discovery of insulin would solve the problem of Type 1 diabetes. It did not quite do that, even though we decorated some of the discoverers of insulin with a Nobel Prize. Survival rates improved decidedly, but the long-term complications of the disease, such as retinopathy, renal failure, neuropathy, and the effects of maternal diabetes on the fetus, have continued to be serious complications of the disease treated with insulin. The Diabetes Control and Complications Trial Research Group (DCCT) (3) compared outcomes of conventional and intensive treatment protocols. Intensive treatment requires much more aggressive control of blood glucose with an external, continuous-infusion insulin pump or multiple daily intramuscular injections. The DCCT study showed that intensive treatment achieves better control of capillary blood glucose, less glycosylation of hemoglobin, and significantly fewer complications involving eyes,
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This article had its origins in a presentation at the Symposium on Recent Advances in the Treatment of Genetic Diseases held at the annual meeting of the American Society of Human Genetics, Denver, Colorado, Oct. 27–31, 1998. It is also an abbreviated version of the chapter by Treacy, Valle, and Scriver on Treatment of Genetic Disease in the forthcoming 8th edition of The Metabolic and Molecular Bases of Inherited Disease (McGraw–Hill, New York). 2 To whom correspondence should be addressed at Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Room A-717, Montreal, Quebec, Canada H3H 1P3. Fax: 514-9344329. E-mail: [email protected]. 93
1096-7192/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.
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TABLE 1 Rates of Complications in Type 1 Diabetic Mellitus Following “Conventional” and “Intensive” Treatment (from ref. 3) Rate/100 patient years
Retinopathy Albuminuria Neuropathy
Conventional treatment
Intensive treatment
Percentage of risk reduction
4.7 3.4 9.8
1.2 2.2 3.1
76 34 69
kidneys, and peripheral nerves (Table 1). Two messages are clear: (a) better treatment of diabetes requires very intensive restoration of glucose homeostasis; (b) the treatment process is difficult. THE MENDELIAN EXAMPLE Inborn errors of metabolism, once thought to be untreatable diseases, can and do respond to modern forms of treatment in some instances. The modifying strategies (Fig. 1) either alter the extrinsic environment or restore intrinsic homeostasis by other means, in some cases by replacing the mutant gene product with the normal type. Phenylketonuria (PKU), for example, is a success story and early onset dietary treatment clearly prevents severe mental retardation (4). However, a generation of experience with treatment reveals that cognitive development in general is half a standard deviation below normal; and premature termination of treatment, in adolescence for example, can have unfavorable consequences. Accordingly, new International Guidelines for more aggressive and potentially lifelong treatment of PKU are now recommended (5,6). However, these and other guidelines are not always compatible with the wishes of many patients, who seek a better therapeutic lifestyle. A better dietary product is one approach. Besides their poor organoleptic properties, low phenylalanine treatment diets can lack essential nutrients, such as the fatty acid decosahexanoic acid, which is necessary for normal brain development (7). One of several alternatives for the treatment of PKU is to restore phenylalanine homeostasis with enzyme substitution therapy using phenylalanine ammonia lyase. This enzyme converts phenylalanine into harmless trans-cinnamic acid and it can be given orally in a protected formulation. Oral phenylalanine ammonia lyase treat-
ment, in the mouse model of PKU, effectively lowers blood phenylalanine levels (8,9). Type 1 diabetes mellitus and PKU thus each illustrate a simple message: the principles of treatment of a genetic disease for either “complex” or “monogenic” disease may be clear enough; the practice to restore homeostasis in tolerable fashion is often something else. Homeostasis in H. sapiens is a product of tinkering and fine tuning by complex evolutionary processes. Accordingly, one cannot expect a treatment invented today to be anything but primitive and awkward if it is to replace a design achieved by millions of years of evolution. But a detailed knowledge of the pathogenesis behind the genetic disease always helps. Here are three examples. The successful treatment of familial hypercholesterolemia with statin drugs and bile acid binding resins came about from research that explained both the pathogenesis of hypercholesterolemia in LDL receptor deficiency and why dietary treatment alone fails (10). The work and its sources were decorated by a Nobel Prize. The treatment of hereditary tyrosinemia by any previous means was essentially a failure until the pathogenesis of this disease was better known. Artificial inhibition of the tyrosine pathway, with NTBC to block excess formation of succinylacetone, has changed the natural history of this disease (11,12). The treatment of osteogenesis imperfecta, particularly for the allelic variants affecting collagen structure, was generally unsatisfactory until the use of bisphosphonate pamidronate. This drug decreases bone turnover and thus improves bone density and the patient’s comfort (13). COMMENT Allelic heterogeneity and other biological factors imply that each patient has his or her own form of “the” disease. Accordingly, different mutant genotypes could require different forms of therapy. In this context, combinatorial drug design holds promise (14), where the therapeutic molecule is made to fit the mutant molecule and restore function. If evolution learned to make combinatorial molecules called antibodies, H. sapiens will eventually learn to make combinatorial drugs to fit the patient’s particular disease; that is one of the emerging challenges for treatment (control) of genetic diseases.
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FIG. 1. Ten different approaches to the treatment of inborn errors of metabolism. (1) Supportive; (2) substrate (metabolite) restriction; (3) enhanced elimination of metabolite; (4) shunting to alternative pathways; (5) cofactor (vitamin) replacement therapy (physiological or pharmacologic dosages); (6) enhancement of enzyme activity; (7) replacement of product metabolite; (8) feedback inhibition (such as the use of HMG CoA reductase inhibitors); (9) cellular/tissue implantation/transplantation; (10) gene therapy.
THE INBORN ERROR OF METABOLISM AS A MODEL FOR TREATMENT OF GENETIC DISEASE Sir Archibald Garrod described four inborn errors of metabolism in his Croonian Lectures of 1908 (15). The next 90 years witnessed a 100-fold increase in recognized and documented “inborn errors of metabolism”. Modalities of treatment have also expanded in the latter half of this century, from the first report of successful dietary control of hyperphenylalaninemia in PKU (16) to recent reports of enzyme replacement therapy (17), allotransplantation (18), and stem cell therapy (19,20). Many reports on the promises of somatic cell gene therapy have also appeared (21–23). While the perceived role for somatic cell gene therapy and mechanisms for its implementation have evolved (22,24,25), and phase-I gene therapy trials are in progress, the evidence for a sustained clinical response to gene therapy is still meager in any Mendelian disorder. Accordingly, our
comments are focused on conventional approaches to the treatment of genetic disease, notably the inborn errors of metabolism. Meanwhile the expanding sensitivity of technologies such as tandem mass spectrometry for screening and diagnosis for many inborn errors of metabolism will give further challenge to the need for effective treatments (26 –29). Treatment of hereditary metabolic disease attempts to restore physiological homeostasis by various modalities (Fig. 1); they have operated at four general levels: (i) At the organismal (clinical) level, where, for example, there are opportunities for surgical correction of a variant phenotype; (ii) at the metabolite level, where it may be possible to prevent substrate accumulation and toxicity or to repair product depletion and the effects of the corresponding deficiency; (iii) at the protein level, where it may be feasible to activate or stabilize a mutant protein with pharmacological doses of coenzyme or a drug or
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TABLE 2 Effect of Mendelian Disease on Phenotype Parameter: Descriptors for Scoring System a Score: 0–3 Component and manifestations Effect on biological selection Longevity Reproductive capability Effect on development Somatic growth Intellectual Effect on social adaptation Learning handicap Work handicap Cosmetic impairment a
0
1
2
3
None None
Premature postreproductive death Impaired
Death during reproductive interval —
None None
Impaired Mild (IQ 70–80)
— Moderate (IQ 50–70)
Height/weight ,3rd centile Severe (IQ , 50)
None None None
Remedial schooling Mild restriction Mild
Special program Sheltered workshop Moderate
Uneducable No capability Major
Death before reproductive age Inability to reproduce or death before reproductive age
Scoring system used to measure effect of the genetic diseases before and after treatment (from ref. 32).
where lost function of the normal protein is restored by replacing the protein itself; (iv) at the cellular level by transplantation, or implantation, so as to repopulate the body with integrated and regulated cellular and gene product activity, an area where there has been particular and significant, if imperfect, progress (30). These well-known approaches are discussed in detail elsewhere (31). Some informative examples described above and below reveal the “process variables” of treatment; however, “outcome variables” (the efficacy of the treatment) must be analyzed before success or failure can be declared. OUTCOMES OF TREATMENT The efficacy of treatment for human genetic diseases has been measured systematically on three successive occasions during the past 2 decades. The measurements were derived from metanalyses of published reports describing the phenotypes of diseases before they were treated and during or after the treatment process. In the first of these reports (32) the method of obtaining semiquantitative measurements was described (see Table 2). Mendelian genetic diseases were represented by a total group of 351 different entities selected at random from Mendelian Inheritance in Man, 5th edition (33). As a group, Mendelian disorders responded poorly to the treatments available at the time; only one in seven
showed any encouraging response. However, there was a subset of 65 inborn errors of metabolism and these were reexamined in more detail because knowledge about their cause, pathogenesis, and manifestations was relatively better than that for the larger set of disorders. Analysis of the inborn errors of metabolism revealed that 12% could be successfully treated, that is, their manifestations were fully controlled. These disorders (n 5 8) were all conditions in which normal homeostatic parameters could be reestablished by the treatment modality. On the other hand, only a partial response was achieved in 40% of the inborn errors of metabolism, and 48% showed no response to the treatment (32). The same subset of 65 inborn errors of metabolism was revisited a decade later, using literature cited in the 10th edition of Mendelian Inheritance in Man (34). The same disorders (12% of the sample) were again deemed fully treatable; no new diseases had been added to this group. However, the “untreatable” set had diminished to 31% of the 65 diseases, while those with a partial response had increased to 57%. These improvements in the treatment effect over the decade were attributed to better understanding of the need for compliance and support systems, better drugs and treatment products, and in the use of transplantation technology where it was feasible. A third analysis was undertaken in 1998 by one
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FIG. 2. Effect of the therapy on disease entities named in MMBID-7 and CD-ROM additions. Of 517 entities, 145 disorders could not be analyzed because of insufficient information. For the remaining 372 diseases, 46 (12%) demonstrated complete response to treatment, 200 (54%) showed partial benefit, and 126 (39%) showed no response to treatment. An altered DNA sequence had been characterized in ;70% of the 372 diseases (hatched areas), for which the number in each subgroup is given in parenthesis) (from ref. 31).
of us (E.T.) using the 7th edition of The Metabolic and Molecular Bases of Inherited Disease (1995) and its CD Rom update (1997) for the metanalysis. It covered 571 different Mendelian disorders (Fig. 2), 372 of which could be scored to measure efficacy of treatment by the methods described in Table 1. A cloned gene with variant alleles had been described in over 70% of the diseases selected for this measurement of treatment efficacy. Fortysix diseases (still only 12% of the sample) now responded successfully to treatment; 200 diseases (54%) had a partial response and the remainder (34%) had no significant response (Fig. 2). The distribution of these responses has been more or less consistent over the past 2 decades and continues to reflect the ability (or inability) of the treatment process to repair the pathogenic dishomeostasis. On the other hand, the small but growing number of independent diseases responding better to treatment reflects a number of factors among which are (i) the growth of specialized teams and centers dedicated to diagnosis and treatment of (hereditary metabolic) disease, (ii) the development and availability of more effective disease-targeted treatment modalities. An important factor in the tardy achievement of greater
success in the treatment of genetic diseases (including inborn errors of metabolism) is the orphan character of the patients, their diseases, and their medications. The special societal problem of orphan diseases and their treatment has become a recognized issue in recent years (35). MODALITIES OF TREATMENT The modalities of treatment for genetic disease must change either the experience or the genotype that is harmful. The goal is to revert a harmful phenotype to the normal state. Until now, “euphenic” treatments have not employed gene therapy. Meantime, it has become apparent that each patient with a designated and particular form of genetic disease (diagnosis) is likely to have “his/her own disease” and therefore to require specific treatment that must be adjusted accordingly to the individual. This is the case for at least two obvious reasons: (i) patients with a locus-specific genetic disorder may have different alleles which confer subtle but different consequences on phenotype; (ii) different patients (even siblings) with a similar locusspecific mutant genotype will have different genomic backgrounds which could modify phenotype and the
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FIG. 3. The different modalities of treatment utilized in the 372 disorders mentioned in Fig. 2. A specific disorder may have been amenable to one or more therapies; hence, percentages reflect relative contribution among all experiences.
treatment response (see ref. 36). Accordingly, we anticipate the emergence of patient-specific therapy for genetic disease in the future. Meantime, treatment strategies can be classified according to the current and basic set of modalities (Fig. 3), as assessed in our latest analysis (31); supportive measures such as dietary intervention, product replacement, and pharmacological therapies remain the mainstay of treatment. However, significant headway has been made in the areas of protein replacement, tissue transplantation, and pharmacological interventions. For example, following the successful use of macrophage-targeted glucocerebroside for the treatment of Gaucher disease (37), enzyme therapy has now been introduced for the treatment of Hurler syndrome (38,39) and successfully utilized in animal models including MPS VII (40), Pompe disease (41), and phenylketonuria (8). The use of tissue transplantation has also improved to include cell therapy (42), and marrowderived mesenchymal cells and maternal umbilical cord blood (43) have been used to treat a range of conditions (44,20).
NEW AND OLD MOLECULES: NEW THERAPIES? Because of the individuality conferred by genotypic and genomic variation, we recognize that each patient with a genetic disease, even a particular one, is an “orphan” in need of a specific therapy. In essence, genetic knowledge will lead to individualized medicine (45); or, to put it another way, the therapy must fit the variant protein and its function and the pathogenic process that has to be reversed. Even in the first generation of therapies for genetic diseases—notably for hereditary metabolic disease—it was becoming apparent that each patient required adaptation of the treatment protocol to his or her particular requirements. This had to be accomplished by rather blunt instruments of therapy, but in the future one anticipates the emergence of much better instruments in the form of drugs and phenotype-specific variants of therapy. The following examples illustrate this point of view. Cystic fibrosis (MIM 219700). Many mutant alleles occur at the CFTR locus. They can be fitted into
TREATMENT FOR “GENETIC” DISEASE?
different classes according to their effect on the synthesis, modification, insertion, and function of the CFTR protein functioning as a chloride channel in the apical membrane of specific epithelial cells. Accordingly, different drugs have particular actions to reverse the effect of a mutant CFTR allele (46). This line of thinking emerged in a paper by Howard et al. (47), who recognized that aminoglycosides could read through stop codons; Dietz and Hamosh (48) objected that although this (desirable) outcome may occur in vitro with expressed cDNA, it is unlikely to occur in vivo with a genomic sequence. Nonetheless, that this classic disease may respond to allele-specific therapy was the intent of the original work (47). Apoptosis. Hereditary tyrosinemia, type I (MIM 276700), involves a complex pathogenic process in which apoptosis plays a role and caspase inhibitors of apoptosis may be useful in preventing this aspect of the phenotype (49). The possibility that inhibitors of apoptosis could play a therapeutic role in other metabolic and in neurological diseases (e.g., Huntington disease) where apoptosis occurs is a possibility for the future. Familial hypertrophic cardiomyopathy (MIM 192600). An animal model (50) of this disorder reveals that inhibition of calcineurin, a calcium-dependent phosphatase, can be achieved with cyclosporin and the drug FK506. Both drugs will prevent the disease (cardiomyopathy) in the animal model. Tay–Sachs disease (MIM 272800 and variants). Knockout hexosaminidase-A-deficient mouse models (52,51) have no overt brain disease and only modest accumulation of GM2 ganglioside in neurons. This surprising phenotype (in the mouse model) is due to enhanced activity of brain sialidase in mice which is capable of converting GM2 to GA2, thus bypassing the missing enzyme; in vitro insertion of sialidase activity in human Tay–Sachs disease neurons ameliorates the disease phenotype (53). The possibility of enhancing sialidase activity in vivo in the various forms of human Tay–Sachs disease thus emerges. Diseases of defective glycosylation (MIM 601785, 601786). Carbohydrate-deficient glycoprotein syndromes are multisystem disorders characterized by defective glycosylation of glucoconjugates. The original clinical observation (MIM 212065) has led to intensive interest in the possibility of treating diseases where glycosylation has gone wrong (54). Mannose supplementation improves the phenotype
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in phosphomannose isomerase deficiency (MIM 602579) (55), and fucose supplementation has a similar effect in leukocyte adhesion disorder-Type II (MIM 266265) (56). Diseases of cholesterol homeostasis. Cholesterol is an essential metabolite. Pathways catalyzed by proteins with entertaining names such as Sonic hedgehog exist for embryonic use of cholesterol in early development of the organism (57); other pathways are used for the disposal and synthesis of cholesterol in the mature organism (10). Disorders of the former lead to forms of metabolic dysmorphogenesis such as holoprosencephaly (57). The Smith– Lemli–Opitz syndrome (MIM 270400) is a particular form of dysmorphogenesis accountable to deficiency of 3b-hydroxysterol-D7-reductase (EC 1.3.1.21) activity (57,58); it responds to cholesterol supplementation (59). Some forms of chondrodysplasia punctata may have impaired cholesterol biosynthesis and thus have options for therapy (60). In cholesterol dishomeostasis of the mature organism associated with LDL receptor deficiency (MIM 143890), homeostasis can be reset by therapy with statin drugs (61) which inhibit the enzyme HMG CoA reductase in the cholesterol biosynthesis pathway. This fact has led to a prediction: the prognosis for this form of coronary artery disease will decidedly change for the better (62). The statin drugs have also been useful in other diseases. For example, in one patient with a particular form of Niemann–Pick Type C disease (MIM 257220), brain cholesterol storage was attenuated (63); and in X-linked adrenoleukodystrophy (and variants) (MIM 300100), statins will lower concentrations of very long chain fatty acids (64). In the latter disease, the further possibility of combined therapy may exist if an in vitro observation with cultured cells, showing that 4-phenylbutyrate both increases beta oxidation of VLCFA and promotes peroxisome proliferation, is validated in vivo (65). These examples show the relevance of a larger theme. The Human Genome Project (or better still, the whole set of genome projects) is expanding the repertoire of mapped and cloned genes in which allelic variation can account for Mendelian and complex trait diseases (45). The Project will result in new arrays of diagnostic reagents and through pharmacogenomics will lead to the prediction of drug responsiveness, in particular variant phenotypes. It will also lead to strategies that may even prevent occurrence of the disease. The achievement, in var-
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ious ways, of both control and cure of “genetic disease” looks more promising than was the case until the present time and when both happen they will be seen as an economical “high technology” (66). Meantime, the Human Genome Project also enhances our understanding of pathogenesis of the various diseases, at the biological level, and this knowledge will also lead to better treatment. Effective working interfaces among clinicians, patients, and scientists (67,68) and with the pharmaceutical industry (69) will benefit all. At the beginning of a new century and millenium all such initiatives will be in keeping with the vision presented by Garrod at the beginning of the 20th century when he described the medical significance of the inborn errors of metabolism (15); surmized why humans can have idiosyncratic responses to not unusual experiences (70); and hypothesized that (inherited) “diatheses” are biological risk factors affecting susceptibilities and resistance to our common diseases (71). His medical vision was simply premature— by a half century and more.
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We thank Robert Barnes for helpful discussion about the treatment of diabetes mellitus. The authors are supported by funds from Le Fonds de Recherche en Sante´ du Que´bec (FRSQ) (E.T.) and the MRC (C.R.S.).
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MINIREVIEW Is There Treatment for “Genetic” Disease? 1 Charles R. Scriver and Eileen P. Treacy 2 The De Belle Laboratory for Biochemical Genetics, McGill University Health Centre, McGill University-Montreal Children’s Hospital Research Institute, Montreal, Canada Received July 15, 1999
It has always been the hope that better knowledge of the cause and pathogenesis of a particular disease would improve its treatment; better still could prevent it. To a great extent, this hope has materialized for a range of nutritional and infectious diseases, some of which had achieved epidemic proportions during human history. Now it is the turn of so-called genetic diseases to enter this arena of hope. Homo sapiens is the only species on earth which intentionally modifies experience, thereby modifying natural selection. Homo sapiens is Homo modificans. We can manipulate experience to maintain health. We seek cures of diseases; in their absence, we attempt control; and if we cannot control, we provide care. There are no cures yet for genetic disease; we are doing better with control, and we can provide care. Treatment of genetic disease involves modified selection and directed adaptation; it is focused on individuals and in many ways it is a cultural activity. The ultimate goal is to restore the normal metrical trait value in the target area of treatment. Walter B. Cannon called that area ho-
meostasis—where there is biological “homing in” on the central tendency (1,2). The problem is that treatment of a genetic disease, whether “simple” or “complex” in its origins, all too often fails to restore normal homeostasis in the appropriate bodily or cellular space. Two classic examples illustrate: one is a common disorder in the class of complex traits, the other a rare disease in the class of single gene disorders presumed to be simpler in their mechanism of pathogenesis than in the complex traits.
1
THE COMPLEX TRAIT EXAMPLE Type 1 diabetes mellitus formerly killed children. It was assumed that the discovery of insulin would solve the problem of Type 1 diabetes. It did not quite do that, even though we decorated some of the discoverers of insulin with a Nobel Prize. Survival rates improved decidedly, but the long-term complications of the disease, such as retinopathy, renal failure, neuropathy, and the effects of maternal diabetes on the fetus, have continued to be serious complications of the disease treated with insulin. The Diabetes Control and Complications Trial Research Group (DCCT) (3) compared outcomes of conventional and intensive treatment protocols. Intensive treatment requires much more aggressive control of blood glucose with an external, continuous-infusion insulin pump or multiple daily intramuscular injections. The DCCT study showed that intensive treatment achieves better control of capillary blood glucose, less glycosylation of hemoglobin, and significantly fewer complications involving eyes,
1
This article had its origins in a presentation at the Symposium on Recent Advances in the Treatment of Genetic Diseases held at the annual meeting of the American Society of Human Genetics, Denver, Colorado, Oct. 27–31, 1998. It is also an abbreviated version of the chapter by Treacy, Valle, and Scriver on Treatment of Genetic Disease in the forthcoming 8th edition of The Metabolic and Molecular Bases of Inherited Disease (McGraw–Hill, New York). 2 To whom correspondence should be addressed at Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Room A-717, Montreal, Quebec, Canada H3H 1P3. Fax: 514-9344329. E-mail: [email protected]. 93
1096-7192/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.
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TABLE 1 Rates of Complications in Type 1 Diabetic Mellitus Following “Conventional” and “Intensive” Treatment (from ref. 3) Rate/100 patient years
Retinopathy Albuminuria Neuropathy
Conventional treatment
Intensive treatment
Percentage of risk reduction
4.7 3.4 9.8
1.2 2.2 3.1
76 34 69
kidneys, and peripheral nerves (Table 1). Two messages are clear: (a) better treatment of diabetes requires very intensive restoration of glucose homeostasis; (b) the treatment process is difficult. THE MENDELIAN EXAMPLE Inborn errors of metabolism, once thought to be untreatable diseases, can and do respond to modern forms of treatment in some instances. The modifying strategies (Fig. 1) either alter the extrinsic environment or restore intrinsic homeostasis by other means, in some cases by replacing the mutant gene product with the normal type. Phenylketonuria (PKU), for example, is a success story and early onset dietary treatment clearly prevents severe mental retardation (4). However, a generation of experience with treatment reveals that cognitive development in general is half a standard deviation below normal; and premature termination of treatment, in adolescence for example, can have unfavorable consequences. Accordingly, new International Guidelines for more aggressive and potentially lifelong treatment of PKU are now recommended (5,6). However, these and other guidelines are not always compatible with the wishes of many patients, who seek a better therapeutic lifestyle. A better dietary product is one approach. Besides their poor organoleptic properties, low phenylalanine treatment diets can lack essential nutrients, such as the fatty acid decosahexanoic acid, which is necessary for normal brain development (7). One of several alternatives for the treatment of PKU is to restore phenylalanine homeostasis with enzyme substitution therapy using phenylalanine ammonia lyase. This enzyme converts phenylalanine into harmless trans-cinnamic acid and it can be given orally in a protected formulation. Oral phenylalanine ammonia lyase treat-
ment, in the mouse model of PKU, effectively lowers blood phenylalanine levels (8,9). Type 1 diabetes mellitus and PKU thus each illustrate a simple message: the principles of treatment of a genetic disease for either “complex” or “monogenic” disease may be clear enough; the practice to restore homeostasis in tolerable fashion is often something else. Homeostasis in H. sapiens is a product of tinkering and fine tuning by complex evolutionary processes. Accordingly, one cannot expect a treatment invented today to be anything but primitive and awkward if it is to replace a design achieved by millions of years of evolution. But a detailed knowledge of the pathogenesis behind the genetic disease always helps. Here are three examples. The successful treatment of familial hypercholesterolemia with statin drugs and bile acid binding resins came about from research that explained both the pathogenesis of hypercholesterolemia in LDL receptor deficiency and why dietary treatment alone fails (10). The work and its sources were decorated by a Nobel Prize. The treatment of hereditary tyrosinemia by any previous means was essentially a failure until the pathogenesis of this disease was better known. Artificial inhibition of the tyrosine pathway, with NTBC to block excess formation of succinylacetone, has changed the natural history of this disease (11,12). The treatment of osteogenesis imperfecta, particularly for the allelic variants affecting collagen structure, was generally unsatisfactory until the use of bisphosphonate pamidronate. This drug decreases bone turnover and thus improves bone density and the patient’s comfort (13). COMMENT Allelic heterogeneity and other biological factors imply that each patient has his or her own form of “the” disease. Accordingly, different mutant genotypes could require different forms of therapy. In this context, combinatorial drug design holds promise (14), where the therapeutic molecule is made to fit the mutant molecule and restore function. If evolution learned to make combinatorial molecules called antibodies, H. sapiens will eventually learn to make combinatorial drugs to fit the patient’s particular disease; that is one of the emerging challenges for treatment (control) of genetic diseases.
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FIG. 1. Ten different approaches to the treatment of inborn errors of metabolism. (1) Supportive; (2) substrate (metabolite) restriction; (3) enhanced elimination of metabolite; (4) shunting to alternative pathways; (5) cofactor (vitamin) replacement therapy (physiological or pharmacologic dosages); (6) enhancement of enzyme activity; (7) replacement of product metabolite; (8) feedback inhibition (such as the use of HMG CoA reductase inhibitors); (9) cellular/tissue implantation/transplantation; (10) gene therapy.
THE INBORN ERROR OF METABOLISM AS A MODEL FOR TREATMENT OF GENETIC DISEASE Sir Archibald Garrod described four inborn errors of metabolism in his Croonian Lectures of 1908 (15). The next 90 years witnessed a 100-fold increase in recognized and documented “inborn errors of metabolism”. Modalities of treatment have also expanded in the latter half of this century, from the first report of successful dietary control of hyperphenylalaninemia in PKU (16) to recent reports of enzyme replacement therapy (17), allotransplantation (18), and stem cell therapy (19,20). Many reports on the promises of somatic cell gene therapy have also appeared (21–23). While the perceived role for somatic cell gene therapy and mechanisms for its implementation have evolved (22,24,25), and phase-I gene therapy trials are in progress, the evidence for a sustained clinical response to gene therapy is still meager in any Mendelian disorder. Accordingly, our
comments are focused on conventional approaches to the treatment of genetic disease, notably the inborn errors of metabolism. Meanwhile the expanding sensitivity of technologies such as tandem mass spectrometry for screening and diagnosis for many inborn errors of metabolism will give further challenge to the need for effective treatments (26 –29). Treatment of hereditary metabolic disease attempts to restore physiological homeostasis by various modalities (Fig. 1); they have operated at four general levels: (i) At the organismal (clinical) level, where, for example, there are opportunities for surgical correction of a variant phenotype; (ii) at the metabolite level, where it may be possible to prevent substrate accumulation and toxicity or to repair product depletion and the effects of the corresponding deficiency; (iii) at the protein level, where it may be feasible to activate or stabilize a mutant protein with pharmacological doses of coenzyme or a drug or
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TABLE 2 Effect of Mendelian Disease on Phenotype Parameter: Descriptors for Scoring System a Score: 0–3 Component and manifestations Effect on biological selection Longevity Reproductive capability Effect on development Somatic growth Intellectual Effect on social adaptation Learning handicap Work handicap Cosmetic impairment a
0
1
2
3
None None
Premature postreproductive death Impaired
Death during reproductive interval —
None None
Impaired Mild (IQ 70–80)
— Moderate (IQ 50–70)
Height/weight ,3rd centile Severe (IQ , 50)
None None None
Remedial schooling Mild restriction Mild
Special program Sheltered workshop Moderate
Uneducable No capability Major
Death before reproductive age Inability to reproduce or death before reproductive age
Scoring system used to measure effect of the genetic diseases before and after treatment (from ref. 32).
where lost function of the normal protein is restored by replacing the protein itself; (iv) at the cellular level by transplantation, or implantation, so as to repopulate the body with integrated and regulated cellular and gene product activity, an area where there has been particular and significant, if imperfect, progress (30). These well-known approaches are discussed in detail elsewhere (31). Some informative examples described above and below reveal the “process variables” of treatment; however, “outcome variables” (the efficacy of the treatment) must be analyzed before success or failure can be declared. OUTCOMES OF TREATMENT The efficacy of treatment for human genetic diseases has been measured systematically on three successive occasions during the past 2 decades. The measurements were derived from metanalyses of published reports describing the phenotypes of diseases before they were treated and during or after the treatment process. In the first of these reports (32) the method of obtaining semiquantitative measurements was described (see Table 2). Mendelian genetic diseases were represented by a total group of 351 different entities selected at random from Mendelian Inheritance in Man, 5th edition (33). As a group, Mendelian disorders responded poorly to the treatments available at the time; only one in seven
showed any encouraging response. However, there was a subset of 65 inborn errors of metabolism and these were reexamined in more detail because knowledge about their cause, pathogenesis, and manifestations was relatively better than that for the larger set of disorders. Analysis of the inborn errors of metabolism revealed that 12% could be successfully treated, that is, their manifestations were fully controlled. These disorders (n 5 8) were all conditions in which normal homeostatic parameters could be reestablished by the treatment modality. On the other hand, only a partial response was achieved in 40% of the inborn errors of metabolism, and 48% showed no response to the treatment (32). The same subset of 65 inborn errors of metabolism was revisited a decade later, using literature cited in the 10th edition of Mendelian Inheritance in Man (34). The same disorders (12% of the sample) were again deemed fully treatable; no new diseases had been added to this group. However, the “untreatable” set had diminished to 31% of the 65 diseases, while those with a partial response had increased to 57%. These improvements in the treatment effect over the decade were attributed to better understanding of the need for compliance and support systems, better drugs and treatment products, and in the use of transplantation technology where it was feasible. A third analysis was undertaken in 1998 by one
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97
FIG. 2. Effect of the therapy on disease entities named in MMBID-7 and CD-ROM additions. Of 517 entities, 145 disorders could not be analyzed because of insufficient information. For the remaining 372 diseases, 46 (12%) demonstrated complete response to treatment, 200 (54%) showed partial benefit, and 126 (39%) showed no response to treatment. An altered DNA sequence had been characterized in ;70% of the 372 diseases (hatched areas), for which the number in each subgroup is given in parenthesis) (from ref. 31).
of us (E.T.) using the 7th edition of The Metabolic and Molecular Bases of Inherited Disease (1995) and its CD Rom update (1997) for the metanalysis. It covered 571 different Mendelian disorders (Fig. 2), 372 of which could be scored to measure efficacy of treatment by the methods described in Table 1. A cloned gene with variant alleles had been described in over 70% of the diseases selected for this measurement of treatment efficacy. Fortysix diseases (still only 12% of the sample) now responded successfully to treatment; 200 diseases (54%) had a partial response and the remainder (34%) had no significant response (Fig. 2). The distribution of these responses has been more or less consistent over the past 2 decades and continues to reflect the ability (or inability) of the treatment process to repair the pathogenic dishomeostasis. On the other hand, the small but growing number of independent diseases responding better to treatment reflects a number of factors among which are (i) the growth of specialized teams and centers dedicated to diagnosis and treatment of (hereditary metabolic) disease, (ii) the development and availability of more effective disease-targeted treatment modalities. An important factor in the tardy achievement of greater
success in the treatment of genetic diseases (including inborn errors of metabolism) is the orphan character of the patients, their diseases, and their medications. The special societal problem of orphan diseases and their treatment has become a recognized issue in recent years (35). MODALITIES OF TREATMENT The modalities of treatment for genetic disease must change either the experience or the genotype that is harmful. The goal is to revert a harmful phenotype to the normal state. Until now, “euphenic” treatments have not employed gene therapy. Meantime, it has become apparent that each patient with a designated and particular form of genetic disease (diagnosis) is likely to have “his/her own disease” and therefore to require specific treatment that must be adjusted accordingly to the individual. This is the case for at least two obvious reasons: (i) patients with a locus-specific genetic disorder may have different alleles which confer subtle but different consequences on phenotype; (ii) different patients (even siblings) with a similar locusspecific mutant genotype will have different genomic backgrounds which could modify phenotype and the
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FIG. 3. The different modalities of treatment utilized in the 372 disorders mentioned in Fig. 2. A specific disorder may have been amenable to one or more therapies; hence, percentages reflect relative contribution among all experiences.
treatment response (see ref. 36). Accordingly, we anticipate the emergence of patient-specific therapy for genetic disease in the future. Meantime, treatment strategies can be classified according to the current and basic set of modalities (Fig. 3), as assessed in our latest analysis (31); supportive measures such as dietary intervention, product replacement, and pharmacological therapies remain the mainstay of treatment. However, significant headway has been made in the areas of protein replacement, tissue transplantation, and pharmacological interventions. For example, following the successful use of macrophage-targeted glucocerebroside for the treatment of Gaucher disease (37), enzyme therapy has now been introduced for the treatment of Hurler syndrome (38,39) and successfully utilized in animal models including MPS VII (40), Pompe disease (41), and phenylketonuria (8). The use of tissue transplantation has also improved to include cell therapy (42), and marrowderived mesenchymal cells and maternal umbilical cord blood (43) have been used to treat a range of conditions (44,20).
NEW AND OLD MOLECULES: NEW THERAPIES? Because of the individuality conferred by genotypic and genomic variation, we recognize that each patient with a genetic disease, even a particular one, is an “orphan” in need of a specific therapy. In essence, genetic knowledge will lead to individualized medicine (45); or, to put it another way, the therapy must fit the variant protein and its function and the pathogenic process that has to be reversed. Even in the first generation of therapies for genetic diseases—notably for hereditary metabolic disease—it was becoming apparent that each patient required adaptation of the treatment protocol to his or her particular requirements. This had to be accomplished by rather blunt instruments of therapy, but in the future one anticipates the emergence of much better instruments in the form of drugs and phenotype-specific variants of therapy. The following examples illustrate this point of view. Cystic fibrosis (MIM 219700). Many mutant alleles occur at the CFTR locus. They can be fitted into
TREATMENT FOR “GENETIC” DISEASE?
different classes according to their effect on the synthesis, modification, insertion, and function of the CFTR protein functioning as a chloride channel in the apical membrane of specific epithelial cells. Accordingly, different drugs have particular actions to reverse the effect of a mutant CFTR allele (46). This line of thinking emerged in a paper by Howard et al. (47), who recognized that aminoglycosides could read through stop codons; Dietz and Hamosh (48) objected that although this (desirable) outcome may occur in vitro with expressed cDNA, it is unlikely to occur in vivo with a genomic sequence. Nonetheless, that this classic disease may respond to allele-specific therapy was the intent of the original work (47). Apoptosis. Hereditary tyrosinemia, type I (MIM 276700), involves a complex pathogenic process in which apoptosis plays a role and caspase inhibitors of apoptosis may be useful in preventing this aspect of the phenotype (49). The possibility that inhibitors of apoptosis could play a therapeutic role in other metabolic and in neurological diseases (e.g., Huntington disease) where apoptosis occurs is a possibility for the future. Familial hypertrophic cardiomyopathy (MIM 192600). An animal model (50) of this disorder reveals that inhibition of calcineurin, a calcium-dependent phosphatase, can be achieved with cyclosporin and the drug FK506. Both drugs will prevent the disease (cardiomyopathy) in the animal model. Tay–Sachs disease (MIM 272800 and variants). Knockout hexosaminidase-A-deficient mouse models (52,51) have no overt brain disease and only modest accumulation of GM2 ganglioside in neurons. This surprising phenotype (in the mouse model) is due to enhanced activity of brain sialidase in mice which is capable of converting GM2 to GA2, thus bypassing the missing enzyme; in vitro insertion of sialidase activity in human Tay–Sachs disease neurons ameliorates the disease phenotype (53). The possibility of enhancing sialidase activity in vivo in the various forms of human Tay–Sachs disease thus emerges. Diseases of defective glycosylation (MIM 601785, 601786). Carbohydrate-deficient glycoprotein syndromes are multisystem disorders characterized by defective glycosylation of glucoconjugates. The original clinical observation (MIM 212065) has led to intensive interest in the possibility of treating diseases where glycosylation has gone wrong (54). Mannose supplementation improves the phenotype
99
in phosphomannose isomerase deficiency (MIM 602579) (55), and fucose supplementation has a similar effect in leukocyte adhesion disorder-Type II (MIM 266265) (56). Diseases of cholesterol homeostasis. Cholesterol is an essential metabolite. Pathways catalyzed by proteins with entertaining names such as Sonic hedgehog exist for embryonic use of cholesterol in early development of the organism (57); other pathways are used for the disposal and synthesis of cholesterol in the mature organism (10). Disorders of the former lead to forms of metabolic dysmorphogenesis such as holoprosencephaly (57). The Smith– Lemli–Opitz syndrome (MIM 270400) is a particular form of dysmorphogenesis accountable to deficiency of 3b-hydroxysterol-D7-reductase (EC 1.3.1.21) activity (57,58); it responds to cholesterol supplementation (59). Some forms of chondrodysplasia punctata may have impaired cholesterol biosynthesis and thus have options for therapy (60). In cholesterol dishomeostasis of the mature organism associated with LDL receptor deficiency (MIM 143890), homeostasis can be reset by therapy with statin drugs (61) which inhibit the enzyme HMG CoA reductase in the cholesterol biosynthesis pathway. This fact has led to a prediction: the prognosis for this form of coronary artery disease will decidedly change for the better (62). The statin drugs have also been useful in other diseases. For example, in one patient with a particular form of Niemann–Pick Type C disease (MIM 257220), brain cholesterol storage was attenuated (63); and in X-linked adrenoleukodystrophy (and variants) (MIM 300100), statins will lower concentrations of very long chain fatty acids (64). In the latter disease, the further possibility of combined therapy may exist if an in vitro observation with cultured cells, showing that 4-phenylbutyrate both increases beta oxidation of VLCFA and promotes peroxisome proliferation, is validated in vivo (65). These examples show the relevance of a larger theme. The Human Genome Project (or better still, the whole set of genome projects) is expanding the repertoire of mapped and cloned genes in which allelic variation can account for Mendelian and complex trait diseases (45). The Project will result in new arrays of diagnostic reagents and through pharmacogenomics will lead to the prediction of drug responsiveness, in particular variant phenotypes. It will also lead to strategies that may even prevent occurrence of the disease. The achievement, in var-
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ious ways, of both control and cure of “genetic disease” looks more promising than was the case until the present time and when both happen they will be seen as an economical “high technology” (66). Meantime, the Human Genome Project also enhances our understanding of pathogenesis of the various diseases, at the biological level, and this knowledge will also lead to better treatment. Effective working interfaces among clinicians, patients, and scientists (67,68) and with the pharmaceutical industry (69) will benefit all. At the beginning of a new century and millenium all such initiatives will be in keeping with the vision presented by Garrod at the beginning of the 20th century when he described the medical significance of the inborn errors of metabolism (15); surmized why humans can have idiosyncratic responses to not unusual experiences (70); and hypothesized that (inherited) “diatheses” are biological risk factors affecting susceptibilities and resistance to our common diseases (71). His medical vision was simply premature— by a half century and more.
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We thank Robert Barnes for helpful discussion about the treatment of diabetes mellitus. The authors are supported by funds from Le Fonds de Recherche en Sante´ du Que´bec (FRSQ) (E.T.) and the MRC (C.R.S.).
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