By this point in the book, we feel sure you as readers have appreciated the heavy emphasis on diagnostics. In fact, the mainstay of clinical genetics is still in identifying the etiology and pathogenesis of specific disorders. However, as the practice of clinical genetics has progressed, so have advances in therapies. There are now several available modalities of genetic treatments. Up until recently, however, most treatments provided by medical geneticists primarily involved counseling and case management. The treatment of inborn errors of metabolism (IEM) dates back to the mid-1960s. These treatments have involved dietary adjustments, specialized formulas, and vitamin/cofactor supplementation. More recently tissue transplantation and enzyme replacement therapies have become available. New treatment modalities have been developed for non-metabolic disorders. Bioengineered pharmaceuticals are now commonplace. Other treatment options like personalized medicine strategies, tissue cloning, gene correction, and true gene therapy all sit poised for transition out of clinical trials and into standard medical care. In the first section of this chapter we will discuss the mechanisms of the different modes of genetic therapies. In the second section we will discuss the clinical application of these therapies.
Part 1: Background and Systems Integration
What are Genetic Therapies?
In the broadest sense, genetic therapies can include any treatment or medical intervention for genetic disorders. Alternatively, it can include a treatment that uses a genetically based technology regardless of the disease etiology. Thus, one could propose that an aortic replacement surgery for a patient with Marfan syndrome could be classified as a “genetic therapy.” Likewise, a monoclonal antibody treatment for cancer or multiple sclerosis might be considered a “genetic therapy.” A narrower definition of “gene therapy” would be only those treatments in which there is actual manipulation of the patient’s DNA to produce a therapeutic response. For the purposes of this chapter, we will shoot for somewhere in between.
Conventional “Therapies”
The discipline of clinical genetics began to emerge in the 1960s. The role of the clinical geneticist was primarily diagnostic back then. Genetic testing at that point was largely limited to low resolution (400 band) G-banded chromosome studies and a handful of metabolic tests. Likewise, no molecular therapies existed then. The clinical geneticist functioned primarily as a diagnostician. Beyond diagnostics, the geneticist had a limited number of modalities in which to “treat” the patient. Over time, the type of roles that a geneticist performs has greatly expanded. Currently the majority of clinical geneticists work in a primarily academic environment. Still there are increasing numbers of clinical geneticists in private practice or working as members of single-specialty teams like a large pediatric practice in which they do some pediatrics, but manage the genetic patients for the group.
Case management
This has always been a key role of the geneticist. Patients with genetic disorders often have conditions that are rarely encountered by other health care professionals. As such, the question of: “what do we do for them?” is an often asked query. The clinical geneticist in collaboration with the patient’s primary care physician and other ancillary health care providers plays a key role in assuring that their patients receive the requisite screening, surveillance, and ancillary medical services that are unique and specific to their diagnosis. Examples of such management would include assuring that all patients with Down syndrome have an echocardiogram at the time of diagnosis, or that patients with Beckwith-Wiedemann syndrome have periodic tumor surveillance (serum alpha-fetoprotein levels and renal ultrasounds).
Genetic counseling
This is an independent discipline. A genetic counselor is a health care professional trained in the science of genetics and the social sciences of psychology and counseling. They are accomplished in working with families throughout their experience with the clinical genetics team. Genetic counselors are particularly adept in explaining the complex concepts of genetics to nonmedical persons. They also excel in crisis intervention, resource identification, and coordination of services. Training in genetic counseling is a 2 or 3 year specialized master’s degree. Genetic counselors are certified by the National Board of Genetic Counseling. At the present time, genetic counselors can be separately licensed in only a handful of states in the United States. Genetic counselors may work with pregnant couples and cancer patients. Others provide supportive care in managing pediatric and adult medicine patients and in genetics laboratories.
Interdisciplinary specialty teams
Many patients with genetic disorders will have multiple and complex needs. The range of specialists needed to optimize outcomes can be staggering. It would be nearly impossible for a family to make independent visits to all of these specialists. Besides the practical issues of making multiple medical visits, coordination among specialists can be extremely cumbersome. A successful solution to this problem is the formation of interdisciplinary teams. Interdisciplinary specialty teams assemble a selected group of specialists needed to provide optimal care for a specific disorder. One advantage of such teams is of course the fact that the patient can obtain “one stop shopping”, i.e., all of the necessary specialists under one roof. One especially important advantage is the coordination of care. Not only are all of the specialists in one place, but they can talk directly to one another rather than trying to communicate by letters, emails, or phone conversations. The list of possible specialty teams in theory is as long as the list of known disorders. Table 14-1 lists some of the most common interdisciplinary clinics in which clinical geneticists and genetic counselors participate.
Table 14-1. Examples of Interdisciplinary Clinics Involving Medical Genetics/Genetic Counseling
Autism
Cancer genetics
Connective tissue disorders
Disorders of sexual differentiation (DSDs)
Down syndrome
Endogenetics/growth disorders
Fetal alcohol syndrome
Metabolic disorders
Neurogenetics
Neuromuscular
Neurosensory genetics
Hereditary hearing loss
Ocular/retinal genetics
Orofacial clefts/craniofacial
Perinatal management
The final conventional therapy to mention is that of the treatment of inborn errors of metabolism. If you would like a review of these disorders, Chapter 8 covers the physiology of them in some detail. Although the treatment of most genetic conditions remains limited, therapy for IEMs began in earnest in the 1960s and has continued to progress. Multiple novel approaches for the treatment of metabolic disorders have been developed. Table 14-2provides a summary of some of the major types of approaches. Critical partners in these therapies are dieticians with special expertise in metabolic disorders (metabolic dieticians).
Table 14-2. Possible Treatment Modalities for Inborn Errors of Metabolism
Dietary modification
Avoidance of offending substance
Galactosemia
Restriction of intake of specific dietary elements
Phenylketonuria
Distribution of calories
Glycogen storage disorders
Enzyme replacement therapies
Gaucher, Fabry, Pompe
Cofactor replacement
Biotinidase
Detoxifying agents
Hyper-ammonemias
Bone marrow transplantation
Some storage disorders
Gene therapy
ADA deficiency (SCIDS)
Combination therapy
Biopharmaceuticals
The term biopharmaceuticals in general refers to medicines developed using various biotechnologies. If the technique utilized involves manipulation of nucleic acids (DNA or RNA), these may commonly be referred to as “genetically engineered drugs.” Such medicines may be proteins, nucleic acids, or even microbes. They can be used for therapeutic or in vivo diagnostic purposes. Often the generation of these drugs requires some sort of biologic system to manufacture the compound from the assembled genetic template. These would include such different methods as biological secretions (such as milk), cultured cells (such as Chinese hamster ovaries), or selected gene activation in human cells. A few examples of such drugs are given in Table 14-3. This list provides only a representative sample of an ever increasing number of such drugs.
Table 14-3. Examples of Genetically Engineered Drugs
Alpha-interferon
Azidothymidine (AZT)
Enzyme replacement therapies for inborn errors of metabolism
Acid alpha-glucosidase (Pompe disease)
Alpha-galactosidase A (Fabry disease)
Alpha-L iduronidase (Hurler syndrome)
Arylsulfatase B (Maroteaux-Lamy syndrome)
Glucocerebrosidase (Gaucher disease)
Iduronate-2-sulfatase (Hunter syndrome)
Tissue-nonspecific isozyme of alkaline phosphatase (hypophosphatasia)
Erythropoietin
Factor VIII (hemophilia A)
Hepatitis B vaccine
Human growth hormone (hGH)
Human insulin
Tissue plasminogen activator (TPA)
Gene Therapy
The concept of genetic correction was discussed in Chapter 7 in the Clinical Correlation section. In that section we discussed a new class of drug that has the potential for therapy for genetic disorders that are nonsense mutation mediated. The mechanism of action is that it allows ribosomes to read past premature stop codons. For details, you may want to refer back to that section. This investigational new drug is currently in clinical trials. If studies do eventually demonstrate that this is an effective therapy it would be truly amazing. The medication is taken orally as a tasteless powder that can be dissolved in liquids such as water or milk. Clearly this is the first of what is likely to become many related drugs that share in common a mechanism of correcting genetic errors. However, just because a mutation is corrected, it does not necessarily mean that the problem is fixed. This is covered more in the second section of this chapter.
Table 14-4. Requirements for Gene Therapy
Gene expression sufficiently understood
Gene transfer into target cells possible
Pathogenesis of disorder sufficiently understood
Recombinant gene technology
Relevant gene cloned
Relevant gene identified
Sufficient and appropriate expression of the gene at the appropriate time
Sufficient and appropriate expression of the gene for the appropriate length of time
Target cell(s) known
Genetic correction as described before could represent one form of “gene therapy.” In a more narrow definition, true gene therapy could mean the treatment of a disorder by the introduction of a genetic element. While the concept of introducing genes into host systems seems rather straightforward, the mechanics are far from simple. The basic requirements for effective gene therapy are listed in Table 14-4. In general, three basic types of information need to be available. The nature of the mutation involved, the type of function that the gene in question performs (i.e., pathogenesis), and an effective method of gene transfer must be understood. An understanding of the mutation would include knowledge of site of the mutation, the nature of the amino acid change(s), and the expression pattern (dominant versus recessive, and so forth). Most importantly, the pathogenesis of the condition should be well understood. For instance a mutation in a gene that affects a developmental embryonic process would not be a good candidate for gene therapy. For example correcting a mutation in a gene that controls limb bud growth would not be helpful in a child already born with a malformed or missing arm. Correcting the gene after the fact would be of no help. In contrast, correcting the abnormality in a gene that controls an ongoing process would have the potential to effect a true cure. Thus, correcting a mutation in a gene that codes for an enzymatic protein would have the potential of producing a normal enzyme which from that time forward could perform the normal biological function for the patient.
Cloning
There are very few words that invoke a more guttural response from society than the term “cloning.” This is unfortunate—and largely a function of misinformation and misunderstanding. The lay public generally perceives cloning as the duplication of a genetically identical human. This of course is replete with all sorts of ethical and social implications. However, cloning in a literal sense refers to the process of making a genetically identical copy of something, not necessarily an entire organism.
Cloning has proved to be a very effective strategy in a variety of different settings. For example, cloning is used routinely in agriculture today. Plants grown from cuttings are literally clones of the parent plant. Also, livestock produced by splitting embryos at the 4-cell stage that can be grown into a separate embryo will improve the overall yield for a herd. Such applications can even be used to re-establish colonies of endangered or extinct species.
Cloning can occur at many different levels. Cloning of a specific DNA segment can be used to obtain material for further study. The resulting cloned (copied) collections of DNA molecules are maintained in clone libraries. A second type of cloning exploits the natural process of cell division to make many copies of an entire cell. The genetic makeup of these cloned cells, called a cell line, is identical to the original cell. Cloning may also occur at the tissue or organ level. Such efforts have tremendous potential for medical treatments as described in the following section. And of course, yet another type of cloning produces complete, genetically identical organisms such as Dolly the famous Scottish sheep.
Personalized Medicine
In the Clinical Correlation section of Chapter 1 we introduced the concept of personalized medicine. We defined personalized medicine as the application of genomic and molecular data to an individual’s health care. The general principles of personalized medicine are to tailor the delivery of health care, facilitate the discovery and clinical testing of new products, and to help determine a person’s predisposition to a particular disease or condition. Personalized medicine develops not only the tools to help providers deliver the care that works best “on average,” but at the same time develop a new class of tools for identifying and employing the best care for each individual patient. In a very real sense, personalized medicine is the ultimate “genetic therapy.”
Part 2: Medical Genetics
Clinical genetics is a relatively new discipline in medicine. Specialists exclusively practicing as geneticists began to appear in the 1960s. Slowly, the number of practicing clinical geneticists has risen to a little over 1000 by 2007. But this still only represents 0.18% of all practicing physicians in the United States. For much of the past five decades, the majority of the work done by genetic physicians has focused on diagnostics. Geneticists are skilled in the evaluation of individuals and families in an attempt to identify the etiology of a particular condition or set of symptoms. The identification of an etiology is a critical piece of the health care of an individual. For many people, simply knowing “why” is important for their own piece of mind and for dealing with the particulars of the condition. Knowing the cause can also help the family in many other ways such as identifying co-morbid conditions, defining prognosis, and for recurrence risk counseling.
In the realm of clinical genetics, therapeutics has always tended to lag behind diagnostics. Still, the role of the physician has traditionally focused not just on diagnostics, but on treatments. There are many reasons for this discrepancy. In Chapter 11 we discussed the amazing and rapid advances in genetic testing and screening. These advances continue to increase diagnostic yields and the amount of information that can be given to families. For the foreseeable future, clinical geneticists will continue to play a major role in the discovery of the causes of disease spurred by the ever-increasing number of powerful molecular tools that are constantly being introduced. In this section we will highlight the second aspect–therapeutics. The past 10 years has seen a dramatic rise in the number of therapeutic options that the geneticist has to work with. While the therapies employed by the geneticist may not be as tangible as the removal of an inflamed appendix, these are treatments all the same.
It is important to note that geneticists are not the only physicians who utilize genetic therapies. Oncologists, for example, have used genetic therapies for decades. Genotype information is routinely used to direct specific therapies, and DNA/RNA based tools are being increasingly used. With the continued advancements of genetic technologies, all health care providers will be using “genetic therapies” in the not so distant future (and in fact, the future may be now).
Conventional “Therapies”
Case management
The past decade has seen a great emphasis placed on establishing the Family Centered Medical Home. Primary care physicians are trained to function as the center of a medical system of care where the medical home where all of the patient’s information and care resides. In this regards, the medical genetics team can function as a Medical Home Neighbor, a professional partner of the medical home who works in collaboration to assure comprehensive and patient centered services. Many of the patients that the geneticist cares for have complex problems and require access to a plethora of specialists and services. Coordination of care is the key issue. Geneticists are not here to assume care, but to bring to the medical home expertise and information about genetic disorders that will complement the work being done in the primary care setting.
Genetic counseling
The mainstay of genetic therapies from the beginning has been to provide genetic counseling. Genetic counseling is the complex process of providing critical information about genetic conditions to a family in a process that is understandable, relevant, and sensitive. Medical geneticists work in collaboration with genetic counselors to provide this information. As with most medical practices, there are differences in the division of labor from practice to practice. Regardless of who does what part, the key element is that families get the information they need in a format that is both understandable and useful. A major challenge of genetic counseling is in the explanation of difficult concepts. Genetics is not typically a day-to-day conversation for most people. Of course, patients vary greatly in their level of understanding. In addition, the acute stress of the situation may cloud interpretation and retention. Also, as has been discussed throughout the last 13 chapters, current technology can be quite complicated.
Consider this scenario: You have a patient who is a 7-year-old boy who you have just diagnosed with fragile X syndrome (Figure 4-27). In order to inform the family of the type of inheritance that is seen in fragile X, you would want to tell the family: “your child has fragile X syndrome, which is an X-linked semi-dominant trait that shows genetic anticipation due to an expanding trinucleotide repeat in the FMR-1 gene.” Presumably you, the reader, took a little while to grasp these concepts as you worked you way through Chapter 12. Think then about how you might explain the above information to the child’s mother who has no medical background, did not finish high school, and, because she is a carrier of a fragile X expansion, has an IQ of 75 herself!
Often, genetic diagnoses are made and discussed under extremely stressful conditions. For example, there are few situations that are more intense than the discovery of an unanticipated congenital anomaly in the delivery room. The birth of a child with congenital anomalies represents a loss of the perceived “normal” child. Parents in these situations will experience the typical stages of grieving. Likewise simply having a child with special needs adds another level of pressure to the already difficult task of raising a child. Persons with Special Health Care Needs (SHCN) present added stresses to parenting in many ways including financial, loss of insurance, time off work (multiple specialists), fear or jealousy of siblings, need for respite, and the unfortunate discomfort associated with public curiosity and meddling. In addition, the diagnosis of a genetic disorder in a family often exacerbates pre-existing conflicts and tension. The current divorce rate in the United States is a little over 50%. For families with special needs children the estimates are 85%! It is here that the genetic counselor or other psychosocial ancillary care person can be useful. Working with families in these situations and helping them maneuver the complex process of dealing with often overwhelming circumstances is why the discipline exists.
Interdisciplinary services
Think for a moment about the example of a child born with a cleft lip and palate (Figure 10-8). An initial assumption would be that child with a cleft would need a surgeon to repair the cleft, and that would pretty much take care of the situation. In reality, there are multiple possible medical complications and extenuating conditions of oro-facial clefting. Current health care standards now recommend that all children with clefts, be evaluated and have their care coordinated through a cleft team. The ideal team that provides care for children with clefts is comprised at least 14 different specialists! A list of specialists that might participate in a cleft lip and palate team is provided in Table 14-5. Granted, not every child will need to see every specialist on every visit. Still, in order to achieve optimal outcomes, children with clefts and other craniofacial malformations need access to such a team. Just imagine what it would mean for the family if they had to make visits to all of these specialists independently. Interdisciplinary services, such as a cleft team, epitomize family-centered services. Not only are all of the specialists under one roof at one time–“one stop shopping”–but communication is optimized. The team can make coordinated treatment plans and recommendations that will optimize the outcomes for each patient. As noted in the first section of this chapter, many different types of interdisciplinary teams exist. Table 14-1 lists some of the more common types of teams in which participation by the clinical geneticist is particularly helpful.
Table 14-5. List of Specialties on a Cleft Lip and Palate Team
Primary team members
Audiology
Dentistry (pediatric and adult)
Clinical genetics
Genetic counseling
Otolaryngology
Orthodontics
Plastic surgery
Speech pathology
Accessible specialists
Behavioral psychology
Neuropsychology
Ophthalmology
Oral maxillofacial surgery
Prosthodontics
Treatment of inborn errors of metabolism
The earliest true treatments for genetic disorders were those for metabolic disorders. The development of a modified formula low in phenylalanine that was effective in treatment of phenylketonuria (PKU) was reported by Professor Horst Bickel around 1955 (see Table 8-11). This therapy prevented the mental retardation and high likelihood of death in infants with untreated PKU. Since that time the treatment of PKU has become quite sophisticated (refer to the Clinical Correlation Section of Chapter 8). The treatment of PKU stands as the premier example of successful treatment of inborn errors of metabolism. Multiple, often combined, therapies are now available for many metabolic disorders. Primary treatment options include dietary modifications, cofactor replacement, administration of detoxifying agents, enzyme replacement therapies, and tissue transplantation (see Clinical Correlation section).
Biopharmaceuticals
The first mass produced pharmaceutical manufactured using genetic engineering was human insulin produced from altered Escherichia coli bacteria in 1982. Over the last 30 years many such drugs have been developed (Table 14-3). The development of these drugs has greatly enhanced medical treatment for many disorders. Currently the vast majority of persons treated with insulin now use a form made by genetic engineering rather than extraction from bovine or porcine sources–as was the case into the 1970s.
One particularly fascinating story in this regards is that of growth hormone therapy. Human growth hormone deficiency (GHD) was discovered in the 1920s. Shortly thereafter, attempts to treat GHD began. Early strategies used growth hormone (GH) extracted from cattle–as was the case with insulin. In the 1950s the first treatments with GH extracted from human (cadaver) pituitary began. In 1960, the federal government established the National Pituitary Agency to centralize and administer the distribution of pituitary-source GH. The need for such an agency was that this source of GH was quite limited and needed to be rationed and prioritized for dissemination—only the most severe GHD children could be treated. The use of human pituitary GH extracts was halted in 1985 when several children receiving this therapy were found to have a lethal neurodegenerative disorder known as Creutzfeldt-Jakob disease. (Creutzfeldt-Jakob disease is part of a family of disorders known as transmissible spongiform encephalopathies. One such condition that you may be familiar with is the so called “mad cow disease.”) Fortunately, at around the same time that CJD was reported in these patients, genetically engineered human growth hormone (hGH) was in the final stages of development. Currently there are several companies that now make hGH by genetic engineering techniques. This technology has resulted in an adequate, uninterrupted supply of GH for all persons needing the drug. Also, the risk of biological contamination—as in the pituitary source GH—has been eliminated.
The story of the development of genetically engineered hGH is a fascinating one. There are many intriguing facets of this story if you find yourself inclined to search for more information. Likewise, there are other examples of other conditions in which treatment has been revolutionized by the development of similar therapies. It is, however, important to point out that things are not always as simple as they first appear. While genetically engineered drugs are wonderfully exciting and helpful, their development has not been without complications. Several important issues have emerged that are clinically relevant in their use.
Cost is a significant issue in the use of genetically engineered drugs. The research and development (R&D) costs of bringing these drugs can be staggering. In the case of human insulin, these costs can be shared across a large population–with almost 10% of the US population developing diabetes mellitus sometime in their life. Thus most people with diabetes can take engineered human insulin at a very affordable cost. However, this is not the case with other, less common disorders. Take for instance the example above of hGH. Currently an annualized cost of treatment is around $20,000-40 000 per year depending on the age and size of the patient. For conditions that are even less common the costs can be staggering. Current annualized cost estimates for the treatment of some of the lysosomal storage disorders are: Gaucher disease (∼ $150,000 per year), Fabry disease (∼ $250,000 per year), or Hunter syndrome (∼ $500,000 per year). As one might imagine, payment for drugs this expensive is a very difficult problem to deal with. Some of the more critical issues along these lines include:
1. Who will pay for the drug?
2. Life-time maximum payments (ceilings) even if there is payment coverage.
3. When does the treatment become standard therapy instead of investigational?
4. Is there such a thing as a cost:benefit ratio that can be objectively applied?
Other problems that have been encountered with such therapies have included problems with the product development and manufacturing. There are also fiscal considerations from the manufacturer’s side. What if the drug is not fiscally sound, i.e., what if it is not worth making? If the decision is made to stop production, what about the patients who were dependent on the pharmaceutical? On the other end of the spectrum, there are potential problems with expanded use/abuse. Going back to our example of hGH, there have been significant issues raised regarding its potential uses. Originally hGH was used solely for treating patients with complete growth hormone deficiency (GHD). Over time, with abundant supplies, its use has been expanded to partial GHD. In addition, the use of hGH has been expanded to a variety of other conditions (Table 14-6). Note the last indication listed in Table 14-6. The FDA has now approved the use of hGH therapy for normal variant short stature! A very long, intense ethical discussion can ensue over the pros and cons of treating “normally short” children. It is beyond the scope of this chapter to do so. However, you are encouraged to simply ponder what potential issues such a usage of hGH raises. Yet another possibility is the abuse of hGH as a performance enhancing drug. Many recent stories about high profile athletes and “doping” charges highlight the potential for abuse of such therapies.
Table 14-6. Licensed Indications for the Use of Human Growth Hormone Therapy
Growth hormone deficiency (complete and partial)
Turner syndrome/SHOX gene mutations
Chronic renal failure
Prader-Willi syndrome
Intrauterine growth retardation (without catch-up growth by age 2 years)
Normal variant (idiopathic) SS
The final conclusion of all of this is simple. Genetically engineered pharmaceuticals are truly amazing in their potential to treat human disease. They often present the first method ever developed for treating certain complex and rare disorders. Still, caution has to be maintained. While the science may be straightforward, the practical application (getting the drug to the patient) may be fraught with many unanticipated complications.
Gene Therapy
The first thing that comes to mind for most people when genetic treatments are discussed is the term “gene therapy.” Gene therapy may be defined in several different ways. Narrowly defined gene therapy could mean using DNA as a pharmacologic agent. Alternatively, one could define it as those therapies in which genes (more specifically runs of nucleic acids) are transported into a patient’s body to effect a therapeutic outcome. The greatest hurdle in implementing gene therapy is the difficulty in transferring the normal gene sequence into a living organism without disrupting normal biological functions. Simply put, how do you get the correct gene into the correct place without producing unwanted problems? Many different techniques for gene transfer have been tried. Some of the more commonly employed strategies include viral vectors, plasmids, chemical methods, and anti-sense oligonucleotide strands.
One of the early success stories in human gene therapy was the treatment of severe combined immunodeficiency (SCIDS) in the 1990s. SCIDS as the name implies is an immunodeficiency disorder with symptoms in early childhood. The disorder is an autosomal recessive disorder caused by mutations in the gene adenosine deaminase (ADA). Inactivity of this enzyme renders white blood cells incapable of carrying out normal immuno-logic responses. The approach to treating SCIDS with gene therapy involved taking a bacterium carrying a plasmid that had the normal human ADA gene incorporated in it. The cloned ADA gene was transferred from the bacterium to an inactivated retrovirus. Bone marrow from the patient with SCIDS was then harvested and infected with the retrovirus, thus transferring a functional copy of the ADA gene into the T cells. The genetically altered T cells were then transplanted back into the patient (Figure 14-1). Using this approach, patients with SCIDS were effectively “cured” of their disease. As these patients have been followed, limitations in this treatment modality have been noted including a low level of the retroviral transduction (<1%) and difficulty in maintaining transformed cells in the periphery. Unanticipated “side effects” like an increased risk of developing cancer also complicate such therapies.
Figure 14-1. Schematic of gene therapy trials for severe combined immunodeficiency (SCID). (From Klug WS, Cummings MR, Spencer CA, et al: Concepts of Genetics, 10th ed. Benjamin Cummings, 2011.)
There is thus a balance between optimism and realism that must be communicated to patients and to the public at large. The potential of gene therapy literally to cure human disease cannot be overstated. However, as noted earlier, there are practical and technical issues that continue to impede the translation of preclinical studies into effective clinical protocols. There are also critical issues of safety and regulation. When discussing gene therapy as a possible treatment option for patients, the clinician must be honest about the practical reality of gene therapy.
Despite these limitations the science of gene therapy continues to advance. In recent years, gene therapy has emerged as a truly independent discipline. There are now even clinicians who work solely within this field. In fact, many clinical trials with gene therapy are currently underway (Table 14-7).
Table 14-7. Clinical Trials with Gene Therapy
Adenosine deaminase deficiency
AIDS/HIV
Cancer
Coronary artery disease
Cystic fibrosis
Duchenne muscular dystophy
Growth hormone deficiency
Hemoglobinopathies
Hemophilia B
Hypercholesterolemia
Inborn errors of metabolism (multiple)
Parkinson disease
Cloning
As we noted earlier, people react emotionally to the term “cloning.” Just the overall consideration of making a duplicate of one’s self reaches down to some of the most basic edicts of humanity. Unfortunately, these initial reactions have greatly limited the public from an accurate understanding of the concept. Cloning simply means making an identical copy of something. It is important to emphasize that cloning in the medical arena can occur at any of several different levels—cells, tissues, organs, or organisms. The tremendous ethical concerns that are typically raised are usually focused on the latter. These concerns have likewise overshadowed the tremendous potential that cloning has for the treatment of human disease. At the level of cells, tissues, and organs, the potential benefits are staggering—and largely noncontroversial. Some specific examples might include:
1. Cloning of an individual’s neuronal cells could generate therapies for problems like spinal cord injuries or neurodegenerative conditions (including potentially even normal aging).
2. Cloning of organs for auto-transplantation. For instance a person with 80% to 90% of total body surface area burns will be in need of large amounts of tissue for grafting. Using cloning techniques from the small amounts of non-affected skin could generate adequate supplies of the patient’s own skin (which would also alleviate issues with graft rejection). In conditions such as hepatic or renal failure, cloning an entire replacement organ from an individual’s own cells would again alleviate graft issues and also eliminate the need for cadaver-source donors.
3. Cloning of a specific anatomic structure would aid in reconstructive options for problems such as injury or congenital anomalies. For instance, cloning of an entire ear appears to be a reasonable expectation in the near future.
In a very real sense, all of these examples would fit our definition of “genetic therapies.” Also, while these may seem somewhat dramatic and maybe a little too amazing to be true, they are none-the-less on the horizon. Despite the limitless potential that such interventions promise, the huge ethical issues associated with the cloning of individuals has largely overshadowed such promise in the eyes of the public. Deep concerns exist over the moral and ethical questions of cloning people—and even other animals. While final resolution on such issues will need careful consideration and discussions among all interested disciplines (ethics, politics, religion, law), certain principles are straightforward enough to discuss here.
One of the most misunderstood concepts of the cloning of individuals is the idea of making an exact duplicate of one’s self. It is critical to recognize that our genetic code is not the sole determinant of who we are as individuals. As individuals we are products of not only our genetic make-up, but of environmental influences, experience and chance as well. One only has to think about the practical example of monozygotic (MZ) twins. Almost everyone has had the chance to know a set of siblings who are monozygous twins. Simple observation will quickly highlight the fact that those two persons, while similar, are not exactly the same. Simply put, although they are genetically identical they are not developmentally identical. Even the concept of being genetically identical is an oversimplification. While monozygotic twins start off genetically identical, genetic differences likely happen throughout gestation (see Chapter 7, Mutation).
Because of the rate of spontaneous mutations, MZ twins will almost certainly have several acquired genetic difference even by the time of birth. Likewise, MZ twins do not even share an identical in uteroenvironment. Twins differ in their position in the womb and in blood flow in the womb. Clinical geneticists have long observed the not infrequent occurrence of discordant phenotypes in MZ twins (we refer you to similar discussions in Chapter 10 on “Concordance” and to Figure 10-5).
At the present time, the bulk of international law and consensus is on the side of extreme caution. A legal moratorium currently exists in the United States on the cloning of individual humans. Before this would ever become a sanctioned practice, many ethical and legal issues will have to be resolved. Several practical issues will have to be ironed out as well. For instance, the famous sheep Dolly (Figure 14-2) was conceived by a nuclear transplantation of the nucleus from a donor cell of an adult sheep. Thus even at the time of birth, Dolly possessed a mature genome and actually died a premature aging death. Thus, it is clear that careful oversight is needed in this realm. However, such caution should not stymie efforts for less controversial interventions that could greatly benefit our patients.
Figure 14-2. Dolly, the famous sheep (right) that was ‘conceived’ by nuclear transplantation producing a literal clone of the donor. (Courtesy of the Roslin Institute, The University of Edinburgh.)
Personalized Medicine
The concept of personalized medicine was introduced in the Clinical Correlation section of Chapter 1 of this book. Personalized medicine may be defined as health care targeted to the inherent biology and physiology of an individual leading to improvements in their medical care. Simply, this is medicine tailored to the individual with direction coming from the person’s own unique situation. As we have emphasized a number of times, a large contributor to individual diversity is one’s own genomic constitution. Thus, the ultimate “genetic therapy” is that in which knowledge of an individual’s genome directs their medical care. Personalized medicine can occur at several levels. In its simplest form it may be using the person’s family history information to identify specific risks that warrant testing, screening or interventions hopefully to prevent disease. In Chapter 9 we emphasized the importance of having family history information on every patient. The well-trained modern health care professional should have a working knowledge of genetics to be able to review and accurately respond to a patient’s family history. Even in this era of modern genetic diagnostics, the family history remains equally effective in identifying and diagnosing conditions in a family. This is indeed personalized medicine at its classic best!
Using any number of the remarkable molecular tools discussed in Chapter 11, personalized medicine can now be taken to the molecular level. The next 10 years will see the era of molecular-based personalized medicine ushered in. Currently there are just a few logistical hurdles, such as reimbursement and regulation, that need to be addressed. However, there is no question that direct clinical utility of such science will occur in the very near future (Table 1-5).
Part 3: Clinical Correlation
One of the many areas in which exciting advances have been made in genetic therapeutics is in the treatment of the lyso-somal storage disorders. The lysosomal storage disorders (LSDs) are a group of conditions that share a common pathogenic mechanism. All of these conditions are problems with enzymatic catabolic processes (see Chapter 8). The different LSDs are characterized by which biochemical accumulates abnormally within the cells (see Chapter 13). The progressive accumulation of substances within the lysosomes eventually disrupts cell function. As such, the typical LSD patient has a normal phenotype at birth. Over time, an abnormal phenotype emerges that is characterized by the type and degree of accumulation of abnormally stored compounds.
Hurler syndrome is an example of a lysosomal storage disorder. It was described in 1919 by a German physician, Dr. Gertrude Hurler. It is caused by a deficiency of an enzyme called alpha-L-iduronidase. As with most inborn errors of metabolism, it is inherited as an autosomal recessive trait. The enzyme alpha-L-iduronidase cleaves the alpha-L-iduronic acid residues off of the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate. Another term for GAGs is “mucopolysaccharides.” Thus Hurler syndrome and other related conditions are collectively referred to as the “mucopolysaccharide storage disorders” (MPSs). Hurler syndrome has been designated type I MPS.
Infants with Hurler syndrome are phenotypically normal at birth. Growth and development usually proceed normally for the first couple of years of life. Early symptoms may include repeated ear infections and enlarged tonsils. Eventually, the abnormal accumulation of GAGs will lead to other phenotypic changes. Accumulation of the GAGs in the bones will lead to a pattern of changes known as dysostosis multiplex. This can include an enlarged skull with shallow orbits. The cranial bone is thick and the cranial sutures may initially be widened, but eventually close prematurely. The ribs are narrow where they attach to the vertebrae and widen as they approach the sternum—sometimes described as being “oar-shaped.” The clavicles are short, thickened, and have irregular margins. The vertebral bodies show a hook-shaped configuration of vertebral bodies. The pelvis is malformed with small femoral heads and flaring of the iliac wings. The long bones have diaphyseal splaying and the epiphyses are dysplastic. The phalangeal bones are widened and tapered—described as being “bullet-shaped” (Figure 14-3 a-c). Progressive accumulation of GAGs in other tissues leads to hepato-splenomegaly, clouded cornea, the development of hernias, and a progressive coarsening of facial features (Figure 14-3d). The most serious complication is a progressive neurodegeneration due to abnormal storage of GAGs in the central nervous system. The natural history of Hurler syndrome is neurologic regression and worsening behaviors with an early demise typically in the teenage years.
Figure 14-3. Hurler syndrome. (a-c) X-rays demonstrating dysostosis multiplex (see text for details). (d) Young male with Hurler syndrome prior to the advent of therapeutic options. This patient has advanced signs and symptoms of his disease.
Early attempts (1960s and 1970s) at treating Hurler syndrome included the surgical placement of pregnancy membranes (i.e., amnion) into the abdomen of these patients. This treatment actually provided some relief—albeit temporary—from the progression of the disorder. Over the past several years, modern approaches to the treatment of Hurler syndrome have emerged (Figure 14-4). Genetically engineered enzyme replacement therapy became available in 2003. Patients treated with this modality receive intravenous infusions every 1 to 2 weeks of the manufactured human enzyme. Thus far the treatment seems to be effective in reducing the accumulation of the GAGs in peripheral tissues. One significant barrier to effective therapy is the delivery of the enzyme across the blood brain barrier. Current clinical trials are underway looking at the effectiveness of intrathecal administration of the drug.
Figure 14-4. Siblings with Hurler syndrome (mucopolysaccharidosis type I). (a) A 2½-year-old male post stem cell transplantation. He is doing well and is developmentally normal. (b) The younger female sibling of the boy in (a), diagnosed in utero also having Hurler syndrome, with confirmation at birth. She has been on enzyme replacement therapy since the first few weeks of life, and is posttransplantation herself. She has neither physical stigmata nor imaging changes seen in untreated mucopolysaccharide storage disorders.
Another method of correcting the enzymatic defect is tissue transplantation. Several centers in the United States and Europe offer stem cell transplantation as another method of providing the missing enzyme for Hurler syndrome and other LSDs. Transplantation has the advantage of being a “permanent” method of providing enzyme, but it carries with it the high risk of transplantation and the long-term issues of immune suppression. As with enzyme infusion, the problem with enzyme transfer across the blood-brain barrier remains a complicated issue.
Until the above therapies were developed, the “treatment” of children with Hurler syndrome was largely supportive. The condition was invariably progressive, and the most the geneticist could do was to help the family through the difficult time of watching their child continually get worse. Because Hurler syndrome is progressive, earlier institution of therapy is ideal. Since effective treatments now exist, there is a strong interest in whether effective newborn screening of the condition can be accomplished.
Board-Format Practice Questions
1. A child is born with a cleft lip and palate, a congenital heart malformation, and a missing radius. The parents ask you (the attending physician) if gene therapy is an option available for their child. You would answer:
A. You can refer them now for gene therapy to correct the defects.
B. Gene therapy is not quite available, but should be available in a couple of years to fix the problems.
C. Gene therapy is not currently available, but even if it were, it would be unlikely to correct congenital malformations.
D. Gene therapy is available but cost prohibitive.
E. Gene therapy is ethically wrong, and you would discourage them from even considering it.
2. You are asked to speak to a civic group in your home community. They want information about “cloning.” What would be good information to share with them?
A. All forms of cloning are morally repugnant and should be outlawed.
B. Everyone should have a clone of themselves made and preserved in case organ donation is needed in the future.
C. The exact cloning of an individual is something that will not happen as we are more than just our genes.
D. The cloning of Dolly the sheep was accomplished with no unexpected complications.
E. Cloning should not be considered a controversial issue–all major religious and legal organizations have endorsed it.
3. You see a 13-year-old boy in your clinic. He is deeply upset over his size. After you assess the family you note that he has familial short stature, i.e., he is “normally” short. He and his parents ask that he be placed on growth hormone. You would tell them:
A. Growth hormone is not licensed for normal variant short stature and you cannot treat him.
B. They should not be worried about his size. It could be worse; he could have a bad disease.
C. You would be glad to treat him, it is cheap, effective, and can be used for anyone who asks.
D. It is a good idea to treat him, as it will improve his self-esteem once he gets taller.
E. Although growth hormone has FDA approval for normal variant short stature, it is expensive, unlikely to be covered by insurance, and may not improve his self-esteem.
4. Case management has always been a part of the service that is provided by geneticists. Which of the following is a true statement about case management for persons with genetic disorders?
A. Geneticists are the only physicians that can perform such services.
B. In general the genetics specialist should stay out of case management and leave this function to the primary care provider.
C. Case management is often improved by the use of interdisciplinary services.
D. An example of case management would include performing surgery on a patient with a congenital anomaly.
E. Case management would probably be better if it were handled by insurance companies and their medical reviewers.
5. Options available for the treatment of lysosomal storage disorders, such as Hurler syndrome, would include:
A. Enzyme replacement therapy.
B. Chelation of the stored glycosaminoglycans.
C. Newborn screening.
D. Dietary reduction of glycosaminoglycans.
E. Gene correction.