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Review Articles Gene Therapy For Adenosine Deaminase Deficiency: Successes and Limitations Karen Born*
Since childbirth is a core aspect of the human experience and a dramatic life cycle event, the practices associated with it can become quite contentious. The protest and celebration that accompanied the emergence and increasingly visible role of midwives in the Canadian health care system is understandable, considering the issues and context. The contradictory reactions of Canadians towards midwifery correlated with the many fears and misconceptions about the nature of birth, as well as the scope and role of midwives in the entire experience, from pregnancy to delivery and beyond. Many of these misconceptions influenced politics and policy makers, and entrenched oppositional view points of midwifery through powerful lobbies and interest groups. The historical forces and movements of the twentieth century, however, empowered the midwife lobby to propagate midwifery as a viable alternative to childbirth, stirred women to demand access to midwifery and enabled a greater acceptance of midwifery as a practice and profession within the health care system. Extensive studies and inquiries in the past thirty years suggest that midwifery may be a cost-effective, efficient alternative to obstetric, physician services. Midwifery as Integrated into the Health Care System There are growing concerns that Canada is facing a crisis in maternity care because of looming shortages in professionals available to provide newborn and maternity care. The proportion of family physicians providing obstetric services has decreased from 36% in 1982 to 18% in 2000 (3). Moreover, due to increased lengths in postgraduate training and medical school enrollment limits, there has been a shortage of younger physicians, upon whom obstetrics traditionally relies for staffing (4). Midwives, as the only health professionals educated specifically to care for normal childbearing and newborns, are prepared to alleviate the burden of physician shortages in the future. Canada's current health care reforms and visions of complete community health would be greatly enhanced by further integration of midwifery into family medicine and women's health. Canada is the last industrialized country to formally legalize midwifes as health care practitioners. In all other industrialized countries, with the exception of the United States (U.S.), most babies are delivered by professional midwifes who are integrated into the health care system (5). The World Health Organization defines a midwife as a person who is qualified to practice midwifery: She is trained to give the necessary care and advice to women during pregnancy, labour and the post natal period, to conduct normal deliveries on her own responsibility, and to care for the newly born infant. At all times she must be able to recognize the signs of abnormal or potentially abnormal conditions which necessitate referral to a doctor, and to carry out emergency measures in the absence of medical help. She may practice in hospitals, health units or domiciliary services. In any one of these situations she has an important task in health education within the family and community. In some countries, her work extends into the fields of gynecology, family planning or child care (6). Midwives, as the deliverers of primary care in low risk pregnancies, can alleviate some of the current pressures on obstetricians, hospitals, physicians and nurses through taking on more cases, and developing collaborative relationships with other health care practitioners. In order for midwifery to become a legal, cost effective, and medically-sound practice uniformly across Canada, legal recognition, standardization of education, and funding would be required. A History of Midwifery in Canada: Practice on the Periphery The trajectory of midwifery in Canada reveals how the practice was marginalized and regenerated due to various influences, including the medical profession, state-imposed legal regulations and changes in cultural perspectives of childbirth. Midwifery was formally legislated out of medical practice in 1895 when the parliament, under pressure from the physician lobby, passed a law placing childbirth under the sole jurisdiction of physicians (7). Midwifery had been particularly prevalent in smaller, remote and indigenous communities, however, it became increasingly difficult for midwives to maintain the profession's viability due to this legislation. Midwives left the profession in fear of legal prosecution, and hence the technical skills and culture of midwifery was not transmitted to the next generation, though in some districts of Canada, the profession of the nurse-midwife began to form to counter the decline of traditional midwifery (8). Furthermore, the advent of insured medicine in Canada reinforced the abandonment of the midwife profession, due to a lack of clients and social support, as most Canadian women knew of no alternatives to birth attended by a physician. The absence of formalized midwifery-training programs, coupled with the dwindling number of practicing midwives, forced this once-mainstream practice to the periphery of health care. Midwifery persisted during these difficult years in a few, isolated communities because of socio-cultural, geographical and historical factors. Many of these communities where midwifery was practiced lacked access to physicians and hospital facilities. This occurred mostly in isolated Northern and rural regions, such as Rankin Inlet in Northwest Territories. Unlike the rest of Canada, where maternal and infant care was and still is under provincial legislation, midwifery was self-regulated in these indigenous communities (7). The marginalization of midwifery by the Canadian political and medical mainstream was a manifestation of the aversion towards midwifery by the Canadian health care establishment. The Canadian Medical Association, as well as Provincial Colleges of Physicians and Surgeons, opposed midwifery, citing studies deeming it inferior and unsafe in comparison to medicine's approach to childbirth. They strongly opposed homebirth, which they asserted constituted an inherent, unavoidable risk, and punitive measures were imposed on physicians in Alberta and Ontario to deter them from attending home births or providing backup support for planned home births (9,11). The Canadian Nurses Association, though not as oppositional, was quite cautious since it perceived midwifery as encroaching on nursing interests and jurisdiction (7). Some Canadian nurses advocated an increased role for nursing professionals in maternal care, citing the U.S. model of the nurse-midwife as being amenable to their potential role in the Canadian system (7). Historical currents during the World Wars slowly fostered resurgence in interest and support for midwifery in urban areas and in the political arena, as groups of women organized for increased access to midwifery, since many male physicians were on the front (8). This small lobby persisted and was strengthened exponentially with the advent of feminism and advances in perceptions of women's health. Despite the wider acceptance of midwifery, there was no standardization of midwife training and education in that era. Midwifery was a private practice, remunerated directly by the patient. Standards governing midwifery were not clearly defined and the practice was still considered outside of the usual legal modalities of health care. Acquiescing to this lobby, government commissions to investigate midwifery were initiated in the late 1960s and 1970s in order to determine a possible role for nurse-midwives in both urban and rural settings. These committees were often politically motivated, and an opportunistic method for governments to consolidate votes and support from women and feminists. The Committee on Healing Arts, set up in 1966 at the advent of universal medical care insurance in Ontario, recommended the integration of the nurse-midwife into the health care system (8). However, there was significant pressure by nursing associations, which did not wish to incorporate midwifery into their practice. These nursing professional groups suggested that Canada adopt the British model of midwifery as an independent and separate profession (8). Societal demands for homebirth and natural births flowed from the counter-cultural center of Canada-British Columbia-in the 1970s. Midwifery became increasingly prevalent but was strictly relegated to the home setting. Midwives practicing at that time faced potential liability as they were providing medical care and services without formal recognition or uniform standards, and were thus vulnerable to the legal charge of practicing medicine without a license (8). Subsequent high profile trials led to increased attention to this issue, both by medical practitioners and the public, and fostered a number of government inquiries into the practice. This attention aided in the genesis of provincial midwifery coalitions and organizations to lobby the government and represent the position of midwives in several provinces. A high profile death in 1985 of an Ontario baby, delivered at home by a midwife, brought the issue to public debate, media attention and scrutiny (8). The Crown was supported by medical professionals, who blamed the midwife for the death, whereas the midwife's defense was that the death was unavoidable. Both sides, nonetheless, concluded that regulation of midwifery was needed in Ontario. The trial and subsequent inquests evolved into a public inquiry into the state of midwifery in Ontario, and was crucial to the genesis of the Midwifery Task Force of Ontario (MTFO). The MFTO advocated the implementation of midwifery as a self-regulating profession with its own college, independent of both medicine and nursing. The MTFO also recommended that midwives have the option to practice in the home, or in an institutional setting, and that a nursing background should not be a prerequisite to midwifery education (8). When this legislation passed in Ontario in the early 1990s, and midwifery became a service reimbursed by the government, Canada joined the ranks of other countries that had already accepted midwifery and integrated the practice into their health care system (10). Government support for the midwifery initiatives were forthcoming for two main reasons: i) midwifery was seen as a cost effective form of care, and ii) midwifery support positioned governments as publicly supporting women's issues and promoting women's rights (8). Governments in British Columbia, Manitoba, Ontario and Quebec followed quickly and implemented midwifery-oriented health policy including legalization of the profession, standardization of training and fees remunerated through the public, provincial insurance plan. However, Saskatchewan and the Atlantic provinces have not legalized nor formalized midwifery practice at this time. Policy and Practice of Midwifery in Canada Despite the legalization of midwifery in some provinces, controversy persists in the medical community about the medical efficacy of midwife care, and there are disagreements about who provides the least expensive care to women with low risk pregnancy. In terms of optimal care for low risk pregnancy and normal vaginal delivery, studies have shown nearly congruent mortality and morbidity rates whether attended by midwives or physicians (12). In a study by Janssen et al. labour interventions in comparable midwife-attended homebirth births, midwife-attended hospital births and physician-attended hospital births were analyzed. The study showed that the home birth group displayed less frequent use of analgesia, electronic fetal monitoring, augmentation or induction of labour, and episiotomy, as well as fewer caesarian sections among women in the home birth group (6.4%) compared with the midwife hospital group (11.9%) and the physician hospital group (18.2%) (12). Obstetricians are trained with a surgical orientation and some have a tendency to utilize interventional techniques to speed up labour (12). The majority of births are low risk and can proceed without interventional, surgical techniques (12i). Therefore, midwives are critical of this surgical medical training and practice, though necessary in complicated births, for its application in low-risk births (1). The methodologies of teaching birth in medical school, and the charge that students and residents rarely witness a normal, spontaneous, unanaesthetized birth are some of the more extreme criticisms by midwives of the medical establishment (1). The midwifery lobby advocates an increased role for themselves in natural, uncomplicated, spontaneous birth. As defined by the Ontario Midwifery Act in 1991, "the practice of midwifery is the assessment and monitoring of women during pregnancy, labour and the postpartum period and of their newborn babies, the provision of care during normal pregnancy, labour and postpartum period and the conducting of spontaneous normal vaginal deliveries."(13) Midwife advocates assert that midwifery training includes the ability to foresee complications and appropriately call for physician assistance. These precautions reduce potential problems and encourage referral for complicated births to obstetric specialists. The differing courses of treatment of medical and midwife professionals for uncomplicated birth explain the different approaches to care and methodologies employed. The obstetrician tends to see the patient for short checkups preceding birth, and then will attend to the woman while she is giving birth for short periods of time in a hospital, assisted by nurses and working in shifts. The midwife, however, develops a more consultative, collaborative relationship with the woman in the weeks leading up to birth, coaches the woman through the duration of delivery, and gives continued, postpartum maternal and newborn consultation. Policy perspectives regarding cost efficiency often cite midwifery as a less costly alternative to physician care (11). There are a number of important variables that must be applied to fully balance the cost comparisons of midwife and physician deliveries. These include the reduced complications in midwife-attended births, the absence of technical equipment and drugs, and less support staff. Moreover, the midwifery option is often advantageous from a subjective client perspective, as their birth experiences are generally quite positive (11). A study by Harvey et al. confirmed this by indicating "women experiencing low risk pregnancies were more satisfied with care by midwives that with care provided by doctors." (14) Physician shortages, particularly of obstetricians and family physicians trained to provide obstetrical care, has been a major concern to decision makers since the mid-1990's. Many family physicians (who traditionally delivered babies in non-urban areas) decline or withdraw from obstetric practice due to fears of litigation, insufficient training or lifestyle concerns (3). The inclusion of midwives as the providers of primary maternal and newborn care has compensated for obstetrician and physician shortages in rural regions. However, midwives are not universally welcomed by obstetricians, physicians and hospitals since midwives deal primarily with uncomplicated cases, which siphon billings of easier, quicker deliveries from physicians, relegating more difficult, intense, and problematic patients to physicians. This is known as 'cream-skimming' or 'cherry picking.' Home birth implies less income to hospitals, and since they require a certain level of funds to properly care for complicated births that generate massive expenses of personnel time, and resources, this is seen as a problem. The issue of 'cream skimming' has not yet become critical in the midwifery debate, however, with the anticipated growth of midwifery, it will become an increasingly contentious issue in terms of allocation of government funds. Physicians who deal predominantly with complex cases confront premature personal burn-out and also reduced financial income and billings. These are among the main factors cited by physicians and hospital lobby groups to oppose greater roles for midwifery. Nevertheless, as policies evolve, there has been more impetus to include midwives in group practices to compensate for physician shortages and hospital overcrowding. Trained, regulated and integrated midwives can potentially decrease stress on family physicians and obstetricians by attending the large number of uncomplicated births and counseling patients on mothering and lifestyle. Midwifery similarly addresses issues of determinants of health and focuses on health promotion by discussing nutrition, early breastfeeding and child care as part of the midwife repertoire of a dynamic patient-based approach focusing on interpersonal relationships and continuity of care (3). Provincial Perspectives: Midwifery Policy in Ontario and Alberta Much debate, particularly between different interest groups of health care practitioners and policymakers, has accompanied the implementation of midwifery into the health care system. Since each province has autonomy in health care, midwifery has been legalized and promoted to different degrees, reflecting the unique social, political and economic needs and citizen demands of each province. A comparison of the course of legalization of midwifery in Ontario and Alberta illustrates how these differences are accommodated and reflected in law. Policies of legalization and recognition tend to address midwife-training, ranges of responsibility, methods of payment, degree of autonomy and relations to other health care providers and institutions (16). Ontario The Ontario Midwifery Act of 1993 regulated midwifery as an autonomous health profession, established university programs for midwifery training, created the regulating body of the College of Midwives of Ontario, and additionally organized a system of provincial financial billing for midwifery services. This legislation established that midwives could be the primary practitioners of care, with the responsibilities of admission, direction of care, and discharge, and that midwives can practice at homes, hospitals, or birthing centers. This option of delivery of care validated midwifery and allowed midwives in Ontario to become increasingly familiar with other health professionals and participate more actively in research, education and policymaking regarding maternal and newborn care (17). The practice of midwifery is growing in Ontario. There are three provincial universities (McMaster, Ryerson Polytechnic and Laurentian), which offer the Ontario Midwifery Training Programme, a four-year degree including intensive clinical exposure and training. There is also the College of Midwives, which offers the Prior Learning and Assessment Program. These programmes register approximately thirty-five new midwives each year (17). Arguably, this progressive policy and strong government support has facilitated the remarkable success and growth of midwifery in Ontario, with nearly 3,800 births in 1999 attended by midwives, and an anticipated 12,000 births in 2004 (10). The Ontario legislation is the foundation upon which the four provinces that subsequently legalized midwifery look to for precedent and policy directives. Patients increasingly demand midwifery, and midwives are anticipated to deliver 30% of all babies in Ontario and British Columbia by 2020 (10). Physicians in some regions have maintained strong efforts to retain their labour and delivery caseloads, and often the admission privileges of midwives are not respected (9). These physician interests are driven by various factors including a desire to preserve billing privileges and delivery priority. Midwives, however, are entrenched as part of the health care system spectrum, as their presence was implemented in an incremental and organized manner and the future evolution of the profession is assured through policy mechanisms facilitating greater patient choice and services. Alberta The legalization and inclusion of midwifery in Alberta differs dramatically from Ontario. The legislation granting legal recognition and professional status to midwifery does not allocate funds, educational initiatives or institutions for the growth of midwifery. The failure to pay midwives from the provincial budget, and trivial government support of midwifery led to a stagnation of development, and precipitated an exodus of trained midwives from Alberta despite recognition. The conservative fiscal stance of the Albertan government illustrates the power of government policy to facilitate or hinder shifts in health care. The government justified its actions by citing unnecessary competition between practitioners and "overlapping, nonexclusive scopes of practice" as specific criticisms of midwifery (9). Consequently, with no provisions to ensure that the supply of midwives would increase through education and training, Alberta experienced a crisis in midwifery. Widespread shortages of physicians delivering acute primary care, combined with the strong midwife and feminist lobby, enabled the politicization of midwifery, with the midwife lobby utilizing the argument of consumer choice to galvanize the public and induce government action in order to sustain the profession in the province (9). Midwifery remains politicized in Alberta, as it is currently part of the provincial government's initiative to reduce government health care costs through privatization of services of choice. That policy allows Albertans to have access to regulated midwifery and trained professionals, however, they must remunerate midwives directly for their services. Although women in Alberta can no choose to have a physician or midwife for their birth experience, only the physician fees are fully covered by Medicare. With midwife-attended births comprising 6.6% of all births in British Columbia, and 4.5% in Ontario, Alberta remains at the low rate of 1%. In Alberta, the midwife-attended births occur mainly in the home and are only available to women who can afford this service. This discrepancy is directly attributed to a lack of government funds (18). This illustrates the decisiveness and impact of government support and policy, and how inclusion of midwifery services in the health care system facilitates greater access for women who choose such services. Midwifery and the Future of Health Care in Canada Midwifery is becoming increasingly important to future visions of health care in Canada, and is a strong political tool and issue to garner public interest and support. Despite its political salience, midwifery as a health care service and alternative to physician-assisted birth has garnered support for practical purposes so that the challenges and shortages of maternal care can be remedied by further integrating midwifery into the changing health care system as a cost effective, medically sound alternative to physician delivery. According to Monique Begin, the former Minister of Health and Welfare, the health care system must evolve to create health care providers who will be able to operate in the dynamic system of the future (19). This system must be increasingly responsive to patient needs, and linkages need to be forged between the various participants in the health care world, between traditional medicine, health promotion advocates, as well as the social and environmental determinants of health (19). The model of care offered by midwifery is compatible
with these principles, as midwifery is based
upon standards such as continuity of care, informed
choice and consent,
and choice of birthplace.
Midwives are not just trained to deliver babies,
but rather to offer a range of
care such as maternity care, breastfeeding instruction
and
support (19). The midwife-patient relationship
is based upon trust,
longevity and encouragement
as midwifery mandates personalized, intimate
care and relationships. Furthermore, within maternal
care, midwifery acts as an
interface between family physicians,
specialists and other traditional modalities
of health care. The loss of the basic maternal and neonatal care
services has the potential to undermine the
overall health of
a community. Maternity and neonatal services
are necessary for a community that wants to
grow, and the development of a flexible, well-integrated
community health care system with a wide variety
of basic services is critical to serve the
health care needs of the increasingly diverse
population in Canada. For example, the presence
of regulated midwifery in Rankin Inlet has resolved
some social problems associated with moving
an expectant mother away from her family and community
in the
weeks preceding
and following birth (7). References Gene Therapy For Adenosine Deaminase Deficiency: Successes and Limitations Michael Ga-Hong Woo, B.Sc.*† INTRODUCTION Severe combined immunodeficiency disease (SCID), often dubbed the "baby in a bubble" syndrome, represents the most severe type of primary immunodeficiencies (1). It is a heterogeneous group of congenital disorders caused by a number of different defects of the lymphoid lineages (2) and the estimated incidence is 1 in 100,000 live births (3). Several natural mutants have been characterized in humans, all of which involve complete block of T-cell development, and will directly or indirectly impair B-cell immunity (1, 4). This leads to devastating clinical symptoms as a result of predisposition to infections from many opportunistic pathogens (4). In many cases, severe infections starting at 1 to 3 months of age will lead to death if untreated (5, 6, 7). This disease received worldwide recognition in the 1970s when the story of David Vetter, who lived all of his 12 years of life inside a sealed plastic bubble designed to protect him from infections was brought to light. Subsequently, his life story and the unique strategies used to treat David, received widespread media attention, being the subject of movies and television shows . The adenosine deaminase (ADA) deficient variant of SCID is an autosomal recessive disorder and accounts for approximately 20% of all SCIDs (8). This inherited deficiency results in decreased enzymatic activity or the lack of production of adenosine deaminase a housekeeping enzyme of the purine salvage pathway (9, 10). ADA was the first gene associated with a SCID condition to be identified (11), and was the focus of the first gene therapy trial in 1990 (12). ADA-SCID is a lethal disorder that is now treated with either allogeneic bone marrow transplantation or enzyme replacement therapy (2, 13). Gene therapy of this disease is in clinical trials and has produced the most promising clinical experience thus far of all the genetic diseases. ADA-SCID patients have been transplanted with transduced autologous T lymphocytes and hematopoietic stem cells (HSC) (4, 7). The progress made in the attempt to treat this disease reflects both the successes of gene therapy and the limitations of it that have to be overcome before it can be a reliable and realistic treatment for ADA deficiency and other genetic diseases. The past, present and future therapies of ADASCID will be examined to demonstrate this progress. WHAT IS ADENOSINE DEAMINASE? Adenosine deaminase (ADA) is an important deaminating enzyme of the purine salvage pathway that converts adenosine and 2'-deoxyadenosine to inosine and 2'-deoxyinosine respectively (2, 11, 12, 14). ADA allows for the conversion of adenosine into other purines to be recycled and removed by formation of uric acid, which is the end product of purine metabolism in humans (14). ADA is especially critical for cells such as lymphocytes and erythrocytes that lack or have very low activity of the de novo purine synthetic pathway (2). In humans, there are two isoforms of the ADA enzyme, adenosine deaminase1 (ADA1) and adenosine deaminase 2 (ADA2). Intracellular ADA activity is mainly mediated by ADA1, while ADA2 is the predominant isoform in human plasma and serum (14). The cellular source of the latter has been linked to the monocyte-macrophage cell system, although it is widely accepted that ADA2 activity represents T-cell function, and measurements of ADA2 activity has been used to evaluate the disease severity of patients with acquired immunodeficiency syndrome (14). The importance of maintaining normal levels of ADA activity can be seen in patients with a genetic deficiency of this enzyme. Lack of ADA activity, which is important in T-cell development, is associated with a form of severe combined immunodeficiency disease referred to as ADA-SCID (11, 14). In terms of biochemistry, the lymphospecific toxicity associated with this disease is thought to be the result of the accumulation of 2'-deoxyadenosine (a substrate of ADA) and its conversion to the phosphorylated form (deoxyadenosine triphosphate, dATP), which is an inhibitor of ribonucleotide reductase, a key enzyme in DNA synthesis and DNA repair in dividing T cells (15). This leads to cell death in non-dividing T cells (1, 14). A second mechanism contributing to the pathology of ADA-SCID involves the methylation reactions of Sadenosylmethionine to S-adenosylhomocysteine (AdoHcy) (14). AdoHcy is hydrolyzed to adenosine and homocysteine by AdoHcy hydrolase. In patients with ADA-SCID, accumulating 2'-deoxyadenosine inhibits AdoHcy hydrolase resulting in the accumulation of AdoHcy. AdoHcy then functions as a competitive inhibitor of many transmethylation reactions critical to cellular functions (14). CLINICAL AND PATHOLOGIC FEATURES OF ADA-SCID Classically, SCID is defined as a fatal infantile syndrome with symptoms resulting from the absence of cellular and humoral immunity. Most infants suffering from ADA-SCID have shown the same clinical and immunological manifestations as patients with non-ADA-SCID (16, 17). Although these infants suffer from lymphopenia and absence of non-maternally derived immunoglobulin, symptoms may not appear until several weeks to several months of life (2). The full-blown syndrome includes overwhelming fungal, viral and bacterial infections and failure to thrive (10). While the underlying immunodeficiency in ADASCID appears early in life, there is a progressive worsening of the condition as toxic metabolites accumulate (due to the absence of ADA) and continue to interfere with normal T-cell and B-cell function. Although 15% of ADA-SCID patients show a slightly later onset and a slower progression of symptoms, it is still fatal. The variability of disease progression may be partly a result of environmental factors and undoubtedly of genetic origin. If left untreated, ADA-SCID is fatal by 1-2 years of age; however, it is more common for death to occur during the first few months of life (2). In addition to infantile-onset ADA-SCID, cases of later onset immunodeficiency have also been reported (2). In one of the earliest cases of ADA deficiency, clinical symptoms did not appear until two years of age and the only detectable abnormality suggestive of an immunodeficient phenotype, prior to disease onset, was a phasic appearance of lymphopenia and eosinophilia (18). Since then, other cases have been reported and reviews of patient medical history and laboratory findings reveal common features. At the time of diagnosis, all had diminished T cell counts with low mitogen responses; however, several showed normal total Ig and antibody responses to some antigens (19, 20, 21). They had substantially high IgE and/or eosinophilia, a history of recurring sinopulmonary bacterial infections including pneumococcal pneumonia and septicemia, and inability to produce antibody to some antigens such as pneumococcus (19, 20, 21). An interesting feature seen in two cases was the diagnosis of "autoimmune" hypothyroidism (20, 21), which could directly reflect toxicity to the thyroid or autoimmune disease due to abnormal regulation of the immune response. These later onset ADA-SCID patients would show more residual ADA activity than those with the infantile-onset disease (2). CURRENT TREATMENTS FOR ADA-SCID Bone Marrow Transplantation The current curative treatment of choice for all SCID patients including ADA-SCID is bone marrow transplantation (BMT) from an HLA-identical sibling (11, 12, 13). HLA, an abbreviation of human leukocyte antigen, is the major histocompatibility antigen occurring on human nucleated cells, including lymphocytes. This form of treatment results in a long-term cure rate of 95-100% (22), however, less than one third of patients have access to an HLA-identical donor (11, 12). In the absence of an HLA-identical sibling donor, T-cell depleted parental bone marrow (haploidentical donor) is preferred over an unrelated donor. This alternative has provided less encouraging results and reports have shown that treatment success rates of BMT for ADA-SCID patients lacking an HLA-genotypically identical donor have not improved over the last 20 years (12). Significant side effects can result due to the need for conditioning cytoreduction and immunosuppression with systemic chemotherapy and total body irradiation, which increases the risk of both short and long term complications. Complications include life-threatening infections, acute cardiomyopathy, progressive pulmonary fibrosis, irreversible sterility and secondary malignancies (10). For all these reasons, BMT is not a useful treatment for all SCID patients, especially those who are too sick to tolerate cytoreductive therapy or where the risks associated with this treatment is felt to be too high (10). Polyethylene Glycol-modified Bovine ADA (PEGADA) For patients with ADA-SCID who are lacking an HLA-identical bone marrow donor, an alternative treatment would be enzyme replacement therapy using polyethylene glycol-modified bovine ADA (PEG-ADA) (23). Because the toxic substrates of ADA (adenosine and deoxyadenosine) diffuses freely throughout the body, injecting this enzyme into ADA-deficient patients can replace the function of the missing enzyme (24). Infusions of purified bovine ADA linked to polyethylene glycol have been successful in decreasing the number of infections by increasing lymphocyte count and by restoring partial T-cell function. However, the formation of inactivating antibodies against the bovine ADA has been observed, and full immune reconstitution is less regularly achieved with this therapy (4, 8, 25). This treatment is also very expensive, costing an estimated US $250,000/yr./patient (11, 26). In a study by Bordignon et al. (1993), two children suffering form ADA-SCID were treated with PEG enzyme replacement therapy and showed very promising initial results (10). Weekly doses of 20 U/kg body weight resulted in a therapeutically constant plasma level abolishing all the tested biochemical abnormalities associated with ADA deficiency. Improvements included the absence of infections and restored weight and height gain, and after three months of therapy, the patients did not require isolation or hospitalization. During these three months, their absolute lymphocyte counts normalized, as well as percentages of CD3+, CD4+, CD8+ T cell populations, and lymphocyte proliferative responses to PHA and IL2, indicating an improved immune system. One patient, upon receiving vaccination from tetanus toxoid and FSME virus one year after initial PEG-ADA treatment, developed specific antibodies and produced specific T-cells to both antigens. Unfortunately, these improvements did not persist after discontinuation of i.v. immunoglobulin prophylaxis, with the appearanceof decreased total lymphocyte counts, reduction of TCR repertoire and antigen specific responses. In addition, results indicated that intracellular production of ADA activity would be more efficient in promoting lymphocyte survival and immune functions rather than extracellular detoxification as in the case with PEGADA replacement therapy. RATIONALE FOR THE GENE THERAPY OF SEVERE COMBINED IMMUNODEFICIENCIES (SCID) Over the past 3 decades, advances in molecular biology have demonstrated
the usefulness of gene therapy as a new tool to correct patient cell function
and to alleviate disease. The first successful gene transfer with a retroviral
vector to murine hematopoietic cells was reported in 1983 (27), and since
then, numerous studies using murine hematopoietic stem cells have been
done to assess the potential use for human stem cell gene therapy (12).
Encouraging murine in vivo studies in which recombinant murine retroviruses
infect murine hematopoietic stem cells, have demonstrated high efficiency
(28). More importantly, these cells had the ability to maintain long-term
expression of the transduced gene. These successes led to the belief that
human stem cell gene therapy could soon be a reliable treatment for various
congenital or acquired human diseases. GENE THERAPY FOR ADENOSINE DEAMINASE DEFICIENCY Gene therapy involves the introduction of exogenous genetic material to correct or modify the function of a cell. It is an emerging medical procedure where genetic diseases could be corrected by transfer of a normal version of a relevant gene into a patient's somatic cells. Gene transfer into a patient's hematopoietic stem cells followed by their autologous transplantation could provide the same benefits as allogenic transplantation without the immunological complications such as graft rejection, graft versus host disease, and post-transplantation immunosuppressive therapy. Although gene therapy to treat blood diseases seems logical, there are still more problems than successes, mainly from inadequate tools used for gene transfer and gene expression. However, despite bouts of successes and failures, techniques for gene transfer, gene expression and hematopoietic stem cell manipulation have steadily improved. To date, a number of clinical gene transfer trials using human hematopoietic stem cells (HSCs) have been performed worldwide to test the potential of human stem cell gene therapy to treat ADA-SCID (7, 36, 37). However, the results from these trials are somewhat disappointing, revealing that murine studies cannot always apply to humans. The transduction frequencies in human HSCs were low and clinical benefits were not apparent in all cases. In spite of these failures, many lessons were learned that could be applied to gene therapy of other genetic diseases. The lessons learnt from preclinical studies and subsequent early clinical trials for ADA-SCID demonstrate the advances in gene therapy made so far. Preclinical studies in the 1980's showed that murine hematopoietic stem cells (HSCs) could be transduced in vitro using the Moloney murine leukemia virus (MoMLV)-based retroviral vector, containing the human copy of the ADA gene (9, 38). These cells were subsequently transplanted into irradiated mice resulting in circulating lymphohematopoietic cells that carried and expressed the human ADA gene (9, 38). These preclinical results suggested that a similar strategy could be applied in humans to successfully treat patients with ADA deficiency. As a result, researchers proposed to harvest autologous bone marrow from ADA-SCID patients, to transduce these cells in vitro with a retroviral vector carrying the normal human ADA gene, and to infuse these cells into the respective patients without using pretransplant myeloablative chemotherapy. Although it was a good idea, researchers at the time lacked in vitro and in vivo systems to evaluate human HSC gene transduction, so preclinical research could not definitively conclude that human HSC could be transduced (9). Instead, many researchers turned their attention to the transduction of peripheral blood T lymphocytes of ADA-deficient patients who were receiving PEG-ADA enzyme replacement therapy. This different approach was a result of preclinical studies showing that in vitro transduction of peripheral blood T lymphocytes from ADA-SCID patients, using a retroviral vector, was possible (33). The genetically modified lymphocytes were transplanted intraperitoneally into immunodeficient mice, and were examined one month later. Results indicated that T lymphocytes, which had been transduced with the normal human ADA gene, persisted, while T lymphocytes transduced with a control vector did not (33). This indicated that transduction of the normal ADA gene into ADA-deficient T lymphocytes was a feasible approach to treating ADA-SCID (10, 24, 33). These preclinical experiments were very encouraging and led investigators at the National Institutes of Health (NIH) to use a similar strategy to treat humans. In 1990, the Blaese group at the NIH performed the first clinical gene therapy trial on 2 young female patients with ADA-SCID (4, 12). They targeted peripheral blood T lymphocytes from the patients with ADA-SCID on PEG-ADA therapy with a MoMLV-based retroviral vector containing the normal human ADA gene (LASN) (4). The patient's lymphocytes were harvested, genetically modified, expanded more than 50-fold, and given back by infusion (4). Over 2 years, the patients received a total of 11-12 infusions of autologous genetically corrected lymphocytes and as a result, immune functions of both patients were better than when only on PEG-ADA treatment alone (4, 12). Unfortunately, the transduction frequency of the infused T lymphocytes differed in the two patients (30% and <1%) and they also continued to receive PEG-ADA therapy throughout the procedure (4). These experiments were able to show that transduction of human peripheral blood T lymphocytes are possible and that their progeny could persist in vivo for many years. These experiments also raised many questions such as; what was the antigenic repertoire of the transduced cells? More importantly, could the transduced T-cells persist without the exogenous source of ADA that was coming from the PEG-ADA therapy? As a result of these questions, many groups had the ambitious goal to
permanently correct ADA deficiency by genetically correcting autologous
haematopoietic stem cells (HSC). If successful, they would avoid the possible
problem of defects in the antigenic repertoire of the mature T cell used
in previous transplantations, and only one infusion of genetically corrected
stem cells would be needed to restore the patient's immune functions (23).
Three clinical trials have been conducted examining the use of transduced
autologous HSC to treat ADA deficiency. One trial used only bone marrow
HSC, another used bone marrow HSC in addition to peripheral blood T lymphocytes,
and the last used umbilical cord blood HSC (9, 24). The third study used CD34+ cells from umbilical cord blood (9, 12, 36). Three neonates were diagnosed in utero with ADA deficiency and cells were transduced with the same LASN vector used in Bordignon's study (9). Transduction of progenitor cells was efficient and longitudinal evaluation of the patients for transduced leukocytes occurred. A year after transplantation, the group reported low but sustained levels of transduced cells in mononuclear cells and granulocytes and increased ADA activity in HSC (36). These patients started PEG-ADA therapy during their first week of life and showed characteristics of a normal functioning immune system. At age 2, PEG-ADA treatment doses were decreased, resulting in a significant decrease in circulating T lymphocytes and a 100-fold increase in the frequency of T lymphocyte transduction without change in myeloid cells or B cells (36). As the dose of PEGADA decreased, a selective advantage in survival of the transduced T cells originating from the transduced HSC occurred, but was nonexistent in B cells or other hematopoietic cells (24, 36). At age 5, PEG-ADA therapy was discontinued in one patient, and over a two-month period, plasma ADA levels of this patient became undetectable, levels of ADA substrates increased, and there was substantial decrease in percentage and absolute levels of natural killer (NK) cells and B lymphocytes although no changes in levels of T lymphocytes occurred (36). Again, results showed a selective advantage in survival of the transduced T cell progeny of the transduced HSC. In addition, analysis of T cell function revealed a loss of antigen-specific blastogenesis to tetanus toxoid and candida (9). Interestingly, results also showed that expression of the MoMLV-based retroviral vectors were low in resting human T cells but were relatively high in dividing T lymphocytes, indicating that LASN vector is expressed during thymopoiesis and not in resting peripheral blood T lymphocytes (9). Results suggest that cessation of PEG-ADA therapy resulted in the loss of both transduced and nontransduced antigen-specific peripheral blood T lymphocytes. Since the patient started to show clinical symptoms of immune deficiency such as weight loss, oral thrush and upper respiratory infection, the patient resumed PEG-ADA therapy, resulting in restoration of good health (9, 36). The results obtained from this trial suggest that cord blood provides a stem cell population more suitable for efficient retroviral-mediated gene transfer than does bone marrow, however, significant advances are still needed in this transfer technique before human HSCs can be used to restore effective immunity and to achieve clinical benefits (11). CONCLUSION The current clinical results of gene therapy for ADASCID are encouraging but also reveal current limitations of gene therapy for immunodeficiency disorders. Results have shown that transduction and transplantation of HSC from both bone marrow and cord blood is possible, and that transduction frequency in T lymphocytes can reach as high as 10-30% if a selection advantage existed in vivo. Unfortunately, when an exogenous source of ADA was removed, results showed a lack of gene expression in nondividing T lymphocytes, indicating the loss of both transduced and nontransduced antigen-specific peripheral blood T lymphocytes. Successful treatment of SCID or diseases involving lymphoid differentiation will ultimately require expression of vectors in mature, nondividing lymphoid cells. For this reason, many investigators are focusing on improving gene transfer technologies. Recent improvements have resulted in the development of better vectors, packaging cell lines and culture conditions for human HSC transduction. For example, use of certain cytokines and recombinant fibronectin has improved transduction efficiency of HSCs in baboon and rhesus monkeys (39, 40). These cytokines can induce cycling of immature CD34+ cells making them more receptive to transgene integration. Also, new packaging cell lines have been designed which enhances binding of retrovirus to hematopoietic cells by pseudotyping with the gibbon ape leukemia virus envelope resulting in increased rate of CD34+ cell transduction (41). To reduce risk of in vivo transgene silencing, deletion of silencing sequences from viral LTR has been examined. Design of lentiviral vectors have also provided encouraging results, being able to infect non-cycling cells. Although attempts to cure ADA-SCID with gene therapy have yet to prove successful, study of this disease has resulted, by far, in the most promising clinical experience by identifying current limitations and providing enough successes to encourage the pursuit of the solutions. References Comparison of Christensen Prosthesis System with Autogenous Costochondral Graft for Arthroplasty of Traumatic Temporomandibular Joint Dysfunction Aria Omrani* M.D. INTRODUCTION The temporomandibular joint (TMJ) is the only joint in the body that is both a hinge and a sliding joint. The TMJ is the most active joint of the body, moving up to 2000 times each day during talking, chewing, swallowing and snoring. Disorders of the TMJ can be referred biomechanically and neurologically to the upper cervical spine, due to the structural approximation and neuromuscular relationship of the TMJ area and occipitoatlantal area. When TMJ dysfunction occurs in children, it impairs mandibular growth and results in mandibular asymmetry or retrognathism. Temperomandibular joint meniscus malposition frequently produces neck pain, headaches and suboccipital muscle spasms.(1) In many cases TMJ dysfunction has a profoundly negative influence on the psychosocial development of the patient, because of the obvious facial deformity, which worsens with growth. Arthroplasty of the TMJ is an effective treatment for structural disorders. Various alloplastic materials, as well as autogenous grafts, have been used in arthroplasty of the TMJ. Because of the growing use of both autogenous Costochondral graft (CCG) and alloplastic Christensen prosthesis system, it is important that the potential benefits of both procedures be carefully weighed against their disadvantages in different circumstances. After outlining the anatomy of the normal TMJ and the causes and effects of TMJ dysfunction, this article compares CCG and alloplastic Christensen prostheses in terms of advantages, disadvantages and patient groups in which their use is most appropriate. TMJ DYSFUNCTION Anatomy of the TMJ The TMJ hinges within the glenoid fossa of the mandible and glides anteriorly to the eminentia during normal motion. The head of the condyle and the glenoid fossa are covered with fibroid cartilage which serves as a shock absorber (1). The meniscus of the TMJ divides the joint cavity into two parts. The lower part is used during gliding motion and the upper part is used for hinge movements. The two heads of the pterygoid muscle act asynchronously to open the joint. One head of the external pterygoid muscle pulls the meniscus forward while the second head opens the joint. Secondary assistance is provided by the mylohyoid, geniohyoid and digastric muscles. In closing the jaw, the temporal, masseter and internal pterygoid muscles are activated. Causes of TMJ dysfunction Temporomandibular joint dysfunction results from various agents including internal derangement, congenital malformation, arthrotic changes, avascular necrosis, rheumatoid arthritis and trauma (2,3,4,5,6,7). Local and systemic infections systemic diseases like rheumatoid arthritis, ankylosing spondylitis and psoriasis are factors which have been implicated in the etiopathogenesis of TMJ ankylosis (8,9,10,11). Trauma conditions have also often been implicated in the etiology of TMJ ankylosis (12,13,14), the presence of intra-articular hematoma with intra-articular damage leads to scarring and bone formation with resultant hypomobility and ankylosis (11,15). The reported proportion of cases of TMJ dysfunction due to traumas ranges from 26% to 100% (8,9,12,16). Physiology of traumatic TMJ dysfunction Trauma to the TMJ can be caused by a single, acute injury (such as blow
to the jaw or car accident) or more prolonged, minor, stress due to, for
example, clenching or grinding of the teeth. Temperomandibular trauma
results in displacement of the disk of cartilage that cushions the ball-and-socket
of the joint with possible resultant entrapment of the disc (17). Symptoms and signs of traumatic TMJ dysfunction Muscle fatigue and a severe dull facial ache that is often localized to an anterior area to the tragus of the ear are the major symptoms of TMJ dysfunction. Muscle spasm in pterygoid, masseter and temporalis; bruxism; tenderness at the proximal mandible; and typical facial neuralgia are some of local effects of TMJ dysfunction. TMJ RECONSTRUCTION In recent decades, TMJ reconstruction using an autogenous costochondral graft (CCG) has gained popularity, mainly because this graft provides a functional implant with growth potential and restores the joint as closely as possible to its normal anatomy. However, there is a significant proportion of patients, including patients who have had multiple surgery, in whom success rates with autogenous grafts are low. The Christensen TMJ prosthesis system offers a significant improvement in function and reduction in pain in most of these patients. This system involves covering the articulating surface of the temporal bone and replacing the meniscal disc with synthetic prostheses. Careful selection of the treatment modality employed in surgical reconstruction of the TMJ plays a significant role in increasing the success rate of TMJ reconstruction. AUTOGENOUS COSTOCHONDRAL GRAFT The most widely accepted autogenous reconstruction of the TMJ involves a costochondral graft. Ease in obtaining and adapting the graft, biological similarity to the mandibular condyle and regenerative potential are some of advantages of CCG (18,19,20,21,22,23). A CCG can also keep pace with the growth of the unaffected side to maintain mandibular symmetry during the growth period (20). Kaban et al. (1990) achieved a mean maximum postoperative interincisor opening at one year of 37.5mm using CCGs to reconstruct the mandibular ramus in treatment of TMJ ankylosis in their seven-step surgical plan. This treatment included aggressive resection of the ankylotic segment, ipsilateral and contralateral coronoidectomy, lining of the joint with temporalis fascia or cartilage reconstruction of the ramus with a CCG and rigid fixation of the graft.(18,24) However, current evidence suggests that CCGs tend to have more vertically directed condylar growth pattern and more laterally positioned condyles than native bone tissue leading to possible mandibular prognathism (18,25). In addition, in patients with arthropathy, long-term steroids can weaken a CCG which may cause ankylosis disease in the reconstructed joint (27,28). Clark and Britton (2001) reported a case of patient who had been operated on three times after a car motor vehicle accident. During the third operation, surgeons attempted to establish TMJ function with a bilateral CCG. This ultimately fused with heterotopic bone, causing diminishing ability to chew and function and progression from fibrous to complete and total bony ankylosis (29). CHRISTENSEN PROSTHESIS SYSTEM The option to use an alloplastic system, instead of an autogenous one, is determined on the basis of severity of disease. The Christensen TMJ fossa-eminence prosthesis system offers a treatment modality for severe TMJ dysfunction especially in patients who have had multiple surgery in whom autografts appear to have a very low success rate (17,33,34,35). Temporomandibular joint reconstruction with the use of the Christensen
alloplastic
joint system allows a close reproduction of the natural anatomy (19). The
Christensen TMJ fossa-eminence prosthesis systems provide a smooth surface
for articulation
with the natural condyle or with a Christensen TMJ condylar prosthesis in
the case of total joint replacement. The prosthesis is attached to underlying
bone
structure with Co-Cr bone screws. Christensen TMJ condylar protheses are
designed to sit against the Christensen TMJ fossa-eminence prosthesis
and are secured
to the ramus of the mandible. In the case of significant bone loss or trauma,
the surgeon may request that the prostheses are cast to fit the specific
patient's anatomical structure. In the case of Christensen TMJ condylar
prosthesis, the
flange portion is always adapted to the patient's anatomy. The Christensen alloplastic joint system decreases the chance of recurrent ankylosis (30). However, particles of alloplastic prostheses at articular surfaces can generate a giant cell foreign body reaction which may cause loosening of the implant, with resultant fracture or displacement (19,27,28 ,31,32). Lack of growth and complications related to dystrophic bone formation in children and implant fracture caused by the use of inappropriate alloplastic materials are some factors that precludes the use of alloplastic TMJ prostheses (20,28,30). One of the most important aspects of preoperative assessment is condylar disease. Christensen fossa-eminence prosthesis is not used alone where there is a condylar disease such as avascular necrosis, because the condyle will be less adaptable to the new articular surface opposing it. Speculand et al. (2000) studied outcomes in 62 patients who received total prosthetic replacement of the TMJ between 1988 and 1997 (26). The proportion of patients who could eat all food increased from 23% of the total group preoperatively to 77% postoperatively. According to this study, preoperatively, 63% reported severe pain but this number reduced to 5% postoperatively. Another study by Chase et al. (1995) indicated that 82% of 22 patients with severe TMJ disorders who underwent implant of a Christensen fossa-eminence prosthesis with retention of disc, showed significant improvement in the ability to eat. In addition, incisor opening improved in 77% of these patients. The rate of significant improvement in their ability to eat in 26 patients who underwent placement of Christensen fossa-eminence without retention of disc was reported to be 96%. In this group, incisor opening improved in 86% of patients. In both groups, all patients showed a significant decrease in pain post operatively. A further 21 patients underwent, surgical placement of Christensen fossa-eminence prosthesis along with a condylar prosthesis as part of this study. Eighty six percent of patients in this group showed a significant improvement in ability to eat, 96% showed a significant decrease in pain and 91% had significantly improved in incisor opening post operatively (17). Recurrence and relapse are the most common complications associated with release of TMJ ankylosis. Studies have reported that the incidence of re-ankylosis is between 4% and 31% (9,16,36). Recurrence is frequently associated with extent of lesion, the release of TMJ ankylosis and surgical technique employed (16,38,39). CONCLUSION Temporomandibular joint dysfunction creates not only functional and aesthetic problems but also interferes with adequate nutrition and oral hygiene measures. The Christensen prosthesis system and the CCG are both accepted arthroplastic methods of TMJ reconstruction in traumatic TMJ dysfunction. Although CCG has been the most popular treatment modality to date, mainly because of accessibility and its adaptability to the TMJ area, recent studies indicate that as surgery frequency goes up, the rate of success of autografts decreases. Technical workability, functional adaptability and regenerative potential are some of the advantages of autogenous CCG. The growth potential of CCG makes it a suitable implant in children whereas the lack of growth precludes the use of Christensen alloplastic joint system in this population. Long-term treatment with steroids for an arthroplasty may reduce the physical strength of a CCG and may cause further ankylosis decreasing the utility of CCGs in such patients. The use of Christensen alloplastic joint system is determined on the basis of severity of disease and is most helpful in patients with the most severe symptoms before surgery. This system also decreases the chance of recurrent ankylosis. References |
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