Measuring The Impact Of Given Hrm Strategy Commerce Essay

Measuring The Impact Of Given Hrm Strategy Commerce Essay Human resource is seen as one of the most critical differentiators contributes to the organizations competitive advantages. All the other assets, such as products, markets, cash, buildings and equipment are passive require human application to generate value (Caliskan, 2010). It is the manpower that plays the key factor to sustaining the productivity for the organizations. How people being managed effectively and the behaviours of theirs can tell an organizations performance. In other words, the organizational performance can be explained by productivity, efficiency, effectiveness and competitiveness made by the employees. INTRODUCTION This essay will discuss why work ethic principles and values are part of the human resources strategy, how training and further education can enhance employees behaviours therefore to offer more to the organizations performance, and how human resources impacts on corporate performance. THE FACTORS INVOLVED IN MEASURING THE IMPACT OF GIVEN HRM STRATEGY Every organization is powered by its people. And the organizational effectiveness is viewed by the quality of services deliver to their customers who develop the organizations reputation. HR strategies play to role to help to organizations to delivery excellent services. Successful organizations see HR strategy formulation and execution as a continuous and dynamic process. In fact, effective HR strategies are essential to ensure productivity and maximum success for organizations. Effectiveness is one way of measuring the impact of HRM strategy implantation. The true success of the human resources management could not be just measured by the organizations financial targets. We should not treat strategies isolated, they need to be bundled. Therefore, to measure the effectiveness of strategic contribution of human resource management should focus on the overall contribution to the success of the organization, in terms of added value, competitive advantage and the impact on business performance (The Association of Business Executives , 2008). And typically, ways in which this contribution has been made will include: Develop a positive and healthy working environment Enhance positive motivations and commitment Increase employee skills and extended the skills base Provide employees with extended responsibilities so they can make full use of their skills and abilities Provide career opportunities and define competence requirements Provide career development and job security to employees Instituting processes of performance management and continuous development Use reward management system to convey messages about what the organization believes to be important. Share information and management transparent. Provide employees with invoice. Treat employees as partners instead of team players. (The Association of Business Executives , 2008) THE AVAILABLE TOOLS USED FOR MEASURING THE EFFECTIVENESS OF HRM STRATEGY Organizations need to have a complete system for the followings: Identify what process should achieve (i.e. its objectives), then measure what is actually being achieved, compare what is actually being achieved against what should have been achieved, then provide required corrective actions if necessary, last implement new actions. By doing all these can measure weather the HRM strategy being effective or not. The popular concept for measuring the effectiveness of human resources strategy these days are: Balance scorecard and Benchmarking. Balance scorecard is comprehensive management tools to measure and share the organizations progress towards its achievement of the strategic goals. More specifically, the balance scorecard is a strategic planning management system that consists of people, strategy, process and technology to align the organization to share a version of achieving its success and getting the people working on the right tracks. Added value, it is people who develop visions, define and set goals, develop strategic plans and implement them (The Association of Business Executives , 2008).This right organization structure is to develop employees being motivate and managed effectively, gain their commitment therefore to deploy them effectively, productively. For example, traditional measures of performance such as value of sales per salesperson, With this strategic management scorecard system, the organizations operational performance such as financial status, customer results, operational efficiency and capacity building can be measured and valued. The balance scorecard is also a communication system through the whole organization to provide better aligning strategic objectives with resources. It sets goals and drives all the employees to adopt and adjust their attitudes and behaviours/actions to achieve them. The balance scorecard helps people within the organization to come to a better understanding regards the interrelationships between different organizational functions. Therefore the top management can avoid the functional barriers and improve decision-making and problem solving. Ultimately enhance the organizations performance. Last but not least, the balanced scorecard helps the organization focus on the future not simply the past or present. Another popular tool of measuring organizations performance is Benchmarking. In fact benchmarking has long been recognized in industry as an effective means of improving business performance. Benchmarking is frequently cited as the second most popular global technique (after business planning) for performance improvement (Bencharmarking, 2006). The shortest definitions of benchmarking is Finding and implanting best practice (Camp, 1995). It means searching for industry best practice that lead to superior performance. Benchmarking is the process of comparing ones business process and/or best practices from other industries. Organizations benchmark themselves in quality, time and cost etc. against their real peers therefore to improve their performance. Benchmarking process diagram (Bencharmarking, 2006) There are two types of benchmarking: Informal and Formal benchmarking. Here I would only talk about formal benchmarking, which consists: Performance and best practice benchmarking. Performance benchmarking involves comparison of the organizations financial status (such as expenditure, cost of labour, adherence to budget, cash flow, revenue collected etc.) and non-financial measures (such as staff turnover, budget processing time, complaints etc.). Through benchmarking, the organization can recognize whether is being a leader or it is far behind in the market. For example, by comparing the income with the organization itself to the industry, the organization can know whether it is making too small profits or there is still more rooms to grab more profits. These processes involve identifying, capturing, analysing and comparing, the organization gains knowledge to know its status well enough which leads to better business strategies and responding human resources practices. The CONNECTION BETWEEN HRM STRATEGY AND ORGANIZATIONAL PERFORMANCE Human resource is considered the most important factors to gain and sustain competitive advantages for organizations. In order to achieve this, the human resource management practices need to be aligned within themselves (internal fit). The human resource management also need to be aligned with the organizations strategy (strategic fit) (Lamboij, Sanders, Koster and Zwiers, 2006). Human resources strategy should always match the business strategy. It should be flexible, compatible, adoptive, integrated, and effective to the organizational changes. The goals of HR strategy process are strictly concerned with the managing people effectively which can assist in the achievement of organizational objectives. The best fit human resource strategies that help the organizations to gain and sustain competitive advantages should be: Invest in people to increase capability and align skills to the organizational needs through on-the job and off-the job training and further educations. Providing training and development, job security and satisfaction are key human resource techniques essential for high performance. Acknowledge the organizations identifies and the knowledge/attitudes that require to meet the organizational goals and satisfy the customers. Define and promote the behaviours and positive attitudes required for organizational success and encouraged, valued and rewarded them. The better employees know what to expect from them, the more they behave cooperatively towards their co-workers and their supervisors. HRM provides professional conduct guides that apply to from hourly employees up to top management to determine business related acts or behaviours are right or wrong. Appoint right employees with the right skills/abilities to do the right jobs to let them feel fulfilled and challenged. Gain employees commitment and loyalty to the achieve organizations missions and goals. ETHICAL CODES OF CONDUCT/BEHAVIOUR IN HRM STRATEGY There are a number of reasons why developing a workplace code of ethics is crucial. Workplace ethics is the moral conducts of behaviours developed by a place of business to determine what is expected of employees in a particular settings. Managers play the key role to take responsibility for determining and enforcing the acceptable and expected standards within their organizations. Workplace ethics set the rules of conduct for everyone at a particular business environment. It helps everyone to know what is encouraged/expected or inappropriate at work. If everyone is clear on what kind of behaviours are expected and what is unacceptable, employees are able to be point out when there are some actions are out of the lines. Workplace ethics also ensures that employees are treated equally and they always have rights to speak for themselves. Workplace ethics helps to enhance reputation by gaining consumers to think that the organizations are somehow better than their competitors. More impo rtantly, the ethical standards/values are shared and known within the organizations by the entire staff, the environment will be conductive to values-driven behaviours, such as values that can guide decision making and discussion and information sharing; values can help to enhance a sense of commitment to the organizations and therefore, are an important part of high commitment management. Values can improve the all the relationships within and outside the organizations. For example, within the organization, between the organization and its workforce, values and ethics codes identify the attitudes towards equal opportunities and diversity; Between management and employees, value and code ethics guide the managers to maintain a professional relationships with employees, and to identify the importance of trust, respect and equality; Between employees, values and ethics codes identify what sort of behaviours are expected among employees. Outside the organization, values and ethics and make an organization stand out among other competitors to its customers and consumers (The Association of Business Executives , 2008). Indeed an organization that has good value and ethics code can impress its customers with their attitudes, the responsibilities they have towards the social responsibility and the views of the environment, etc. THE ETHICAL IMPLICATIONS OF STRATEGIC HUMAN RESOURCE MANAGEMENT Human resource managers are in a key position to ensure that ethics codes management is applied through the whole organization. Communications and training programmes are essential. And managers need to make decisions ethically to determine business-related acts or behaviours are right or wrong. Business ethics can provide businesses with moral guidelines in conducting their affairs. Managers often face ethical dilemmas in the workplace but they may not aware of it. On reason is the manager is not trained in ethics so it is difficult to know when an ethical issue exists (Mintz, 2011). The first step in making ethical decisions is to be sensitive to identify the unethical signposts in question. Determine whether your decision harms one or more parties while benefiting others. Managers need to be aware that ethical decision making causes the consequences of the actions on others the stakeholders in the specific situation. The next step is to identify alternative choices and actions to evaluate them in the ethical way. Be sure to follow the laws, regulations, practices and company policy including the code of conducts. From an ethical perspective certain guidelines apply such as dont violate anyones rights; be fair-mined in deciding how best to resolve the dilemma, always follow basic virtues including honesty, integrity, reliability and being responsible and accountable for ones actions (Mintz, 2011). After evaluating the alternatives from the ethical perspective, managers need to know for certain how the potential decision might affect the stakeholders. It should create trusting or even legal problems/reputation damage among employees and top management. The last step in ethical decision-making is the most difficult one. It takes a lot to carry out an ethical decision with ethical action. It could be the case that the ethical decision and ethical action would actually do harm to the company reputatio n or other employees image among the organization. For example, if sales A found out that sales B, one of the top sales in the company, misleading customers a bit regarding the product (not a serious mistake) in order to get more sales. In this case, should sales A reports to the top management straight away or just pretend nothing happen? If reports to the top management, they may likely not do anything. Or they would think sales A is just getting jealous with sales B, which will lead them to think that sales A is not the type of guy that they want to keep for long term. Or the top management invest in the detail and find out the truth and they have to fire sales B, which the consequence will be the company lost a top sale and some big customers therefore it effects the organizations reputation and selling targets. One of the the rational way to deal with this unethical issue will be whistle-blowing. Sales A could make an anonymous complain or letter to report this unethical behavi our explain the behaviour or issue in detail as well as how the issue should be resolved. Nowadays organizations have employees from different culture background. One thing managers need to ensure that they do not discriminate unfairly in their decisions or actions towards employees, either before or during the employment. Organization should provide equal opportunities to everyone within the organization. Managing cultural diversity is never easy. Recognising the behaviours of discrimination is the first step towards establishing equal treatment working environment. All in all, the responsibilities of good managers in making ethical decisions are: Be sensitive with the ethical issues in working environment Be clear with the responding consequence followed by the ethical decisions/actions Identify company policy, code of ethics conducts and carry out the ethical actions TRAINING METHOD IN WORK PLACE Training in an organization can be divided to two broad types. They are on-the-job trainings and off-the job trainings. With on-the-job trainings, employees receive trainings while they are at work. In this way, employees are conducting and learning when they are working. On-the-job training gives employees motivation to start the job. Some reports indicate that people learn more efficiently if they learn hands on rather than just listening to the instructors. Example: New engineers could work with experienced engineers. They could ask questions about the machines and the tools they are operating on, the problems they may come across the usual solutions to them etc. Instructors need to make the plan for what should be taught, and how much time spend on it, and after the trainings employees will informed about their progress. The main methods of on-the-job/off-the-job training included: Demonstration / Instruction Showing on site to the trainers specifically how to get the job done. Coaching a more detailed and intensive method of training that involves a close working relationship between the experienced trainers and the trainees. Coaching gives trainees the chance to ask questions and receive honest answers. Lectures Lectures usually take place in a classroom-format. Giving lectures supply huge amount of information to a lot of people in a short amount of time. But lectures could get boring and trainees lose interest in it. Group discussion Group discussion is most likely to take place in a classroom where a group of people discuss issues. Group discussion can allow employees to ask questions and provide ideas for the management. Comparing to lecture, it gets more involvement from the employees, and managers can heave the voice from the employees. Role playing Role playing allows employees to act out issues that could occur in the work place. Role playing can be effective in connecting theory and practice. There are many methods of trainings. The key is to find the best training method to suit the actual situation. Assess each training method implemented in the organization and get feedbacks from trainees. Then decide to adopt the most effective method to specify the training programme (Silva, 2011) FURTHER TRAINING AND DEVELOPMENT These days for every business their goal is to stay competitive in the market. And highly skilled, motived and committed staff is the key factor to achieve that goal. Further-training widens employees skills and acknowledge, and therefore enable their personal advancement to contribute more to the organizations performance. Providing career development helps to motive employees and gain their commitment. In details, firstly, training and development helps in maximizing the human resource which further helps the organization to achieve organization goals as well as their personal goals. Secondly, training and development helps to provide opportunities to broaden employees knowledge, increase their skills, improve their personality even. Thirdly, training and development helps in increasing the productivity of the employees that helps the organization further to achieve its long-term success. Fourthly, training and development helps building the positive attitudes, good team spirits, and friendly working environment among the organization. It also helps improving the quality of work and work-life. Last but not least, training and development helps in the organization development. For example, the organization gets more effective decision making and problem solving with dedicated and skilled staff. Training and development helps in developing leadership skills, employee motivation, loya lty, positive attitudes, good perceptions between managers and employees. CONCLUSION Human resource is the most valuable resource to gain and maintain competitive advantage for organizations. From above we know that HRM impacts greatly on organizational performance. There are available tools such as balanced scorecards and benchmarking to measure the effectiveness of HRM. In workplace, unethical issues are inevitable and ethical codes of principles are necessary for every company. Mangers need to make ethical decisions and act on them ethically. Training and further education improves employees skills and abilities therefore enhance the organizations performance greatly.

Song of Roland

The textbook displays Charlemagne as an astounding and great military leader but examines a few of his flaws as well. The Song of Roland creates the image of Charlemagne that is an extraordinary, legendary leader. They both tell about what great things he accomplished in his life, the many wars he won and how his bravery carried him through everything. The Song of Roland praised him in such a legendary way to create the impression of a heroic leader.By doing this it establishes a strong positive view of the Frankish Empire. In the ninth chapter of the Making of the West, the authors describe the Carolingian king, Charlemagne and the various views of his life that historians have. While admiring his greatness the authors analyze a few negatives about Charlemagne. For example, he liked the Pope but hated that the Pope crowned him emperor. He liked being king and calling himself king but at first didn’t want the title of Emperor.Another criticism to Charlemagne’s great wor k as a military leader is that he did all of his work winning wars and conquering lands that he destroyed the states surrounding his original empire and gaining control of them but by doing that, he lost his buffer. So soon after all the wars were finally over for Charlemagne, hew invasions started occurring on the borders of his new kingdoms. One more concern historians claim he did was what he had done when he arrived at the Saragossa Town after the winning the war with the Saxons.Apparently when he got to the city, the citizens were resisting conversion to Christianity and he wasn’t happy about it. He forced mass conversion of the Muslim citizens with the threat of his sword. This act goes against the whole idea of Christianity to be accepting of other faiths and tolerant of them. These examples only demonstrate a few criticisms to Charlemagne’s leadership but still explain that he was a great emperor overall. The Song of Roland describes Charlemagne as an amazing m ilitary leader.He had Counts and Bishops in charge of leading wars to gain lands for the Franks in every direction and he was successful in doing so. He was a very emotional man, he wept over the deaths of fellow comrades and warriors, friends and relatives. Charlemagne was also a spiritual man in that he prayed everyday and asked for God to protect the bodies of the fallen soldiers and keep them safe. The angel St. Gabriel came down to him many times to give Charlemagne advice or to encourage him to continue his missions and to fight.He fought with courage and bravery, he was afraid of nothing. After his victory against Emir, he still felt the need to serve God and all his kingdom respected him for that and obeyed his power. Charlemagne is described as a courageous, spiritual, loyal and extraordinary emperor and leader full of pride for his kingdom. All of the words Charlemagne can be indentified with help bring about the view of the Frankish Empire. Because of the things Charlemag ne did and more importantly they way he went about them, the Frankish kingdoms were viewed as prestigious and in control.They gave off the impression of high power and other kingdoms were going to have a challenge if they wanted to fight the Franks. The Making of the West textbook and the book The Song of Roland discuss how great Charlemagne was and how what he did made a difference in the view of the Frankish Empire. Although he had some flaws or contradictory actions, he was still an astounding emperor. He expanded his kingdoms and defeated many enemies. He had become a heroic military leader for the Franks and the Frankish Empire.

The Treatment of Cystic Fibrosis using gene therapy, in particular Adeno-Associated Viruses

Sample details Pages: 25 Words: 7507 Downloads: 4 Date added: 2017/06/26 Category Statistics Essay Did you like this example? In this dissertation we shall consider the field of gene therapy in specific relation to cystic fibrosis. We examine the different delivery vector mechanisms that have already been explored and concentrate primarily on the adeno-associated vectors. We examine the current state of research and consider the advantages and drawbacks of the various methods considered. Don’t waste time! Our writers will create an original "The Treatment of Cystic Fibrosis using gene therapy, in particular Adeno-Associated Viruses | Physics" essay for you Create order We conclude with a discussion and analysis of our findings and make anumber of assumptions relating to the future direction of the researchin the field. The rate of progress in the field of gene therapy has been enormous. We must remind ourselves that the first clinical gene transfer experiment took place in 1989 when a patient with malignant melanoma received genetically modified auto logous T cells. (Rosenberg SA et al1990) Gene therapy encompasses two major areas. The in vivo field, where genes are incorporated into the target cells of the living body and the ex-vivo field where the target cells themselves are genetically modified outside the body and then re-implanted. Medical science has been using the basic techniques of gene transfer for a long time. The technique has been exploited when viral genes are introduced to human cells when a viral vaccine is administered. The key technologies that allowed the transition from vaccination to gene therapy were the evolution of methods that allowed the genes to be isolated and replicated (cloned) and manipulated (engineered) prior to transfer into human cells (Freeman SM et al 1996) The key principle in this process is the efficient transfer of the manipulated therapeutic genes into the nuclei of target cells usually be means of various vectors. This dissertation will be considering the utilisation of these vectors in some detail. In broad terms, the new or modified genetic material is able to produce new proteins which can restore deficient or abnormal functions of genetically diseased tissues, to generate tissues that have entirely new properties or to create transplantable tissues for the controlled release of therapeutic proteins. (Russell SJ1997) In terms of viral vectors, prior to 1996 science was dependent on the use of modified retroviral vectors (eg.MMLV) to effect gene transfer into the chromosomes of a target cell and the adenovirus vectors when such integration was not needed. Neither vector was particularly successful as the intact nuclear membrane (in then on-dividing state) was a major barrier for chromosomal gene integration. (Sikorski R et al 1998). A breakthrough came with the realisation that lentiviruses (e.g. HIV) have the same ability to transfer genetic coding into the cellular genome but could do this in the non-dividing or dormant phase cells. (Amado R G et al 1999) In vitro, lentiviruses have been shown to change the target cells expression of proteins for up to six months. importantly, they can be used for terminally differentiated cells such as respiratory epithelium. The only cells that the lentivirus cannot penetrate the nucleus are those in the quiescent (G0) state as this blocks the reverse transcription stages of protein synthesis. (Amado R G et al1999) Cystic fibrosis Cystic fibrosis is the most commonly lethal inherited recessive inthe caucasian population. It affects about 1 per 2,500 livebirths. Thetreatment of cystic fibrosis has improved enormously in the last fiftyyears with the life expectancy increasing from an average 10 years to30-40 years now. The prime cause of death in affected individuals is the repeatedcycle of infection, inflammation and fibrosis of the respiratory tractwhich eventually culminates in respiratory failure and death. The disease itself is caused by mutations in the single gene forthe cystic fibrosis transmembrane conductance regulator (CFTR) whichproduces a protein found in sweat and pancreatic ducts, gut,seminiferous tubules, lungs and many other tissues. The mutationsresult in an abnormal protein which, when expressed in the lungs,produces thick viscous and dehydrated secretions. This does not allow for the efficient expulsion of bacterial pathogensfrom the lungs and a number of highly resistant forms of bacteria arecommonly found in cystic fibrosis (viz pseudomonas aeruginosa)(Porteous DJ et al 1997). An individual must receive a defective copy of the cystic fibrosisgene from each parent in order to develop the clinical picture ofcystic fibrosis. Following normal genetic principles, if two carriersconceive a child, there is a 25% chance that it will have cysticfibrosis, a 50% chance that it will be a carrier and a 25% chance thatit will have two normal cystic fibrosis genes. Viral and non viral vectors Viruses have an ability to enter a host cell and combine their owngenetic material with that of the host cell. This is the basicrationale behind the science of gene transfer therapy. As we shalldiscuss in some detail in this dissertation, there are a number ofpotential viral vectors that have been explored, evaluated andexploited in the search for an efficient and safe form of therapy.Viruses are not the only vector that can be utilised . Simply placingDNA in the nasal mucosa will produce some incorporation into theepithelial cells (Knowles MR et al 1998). This absorption can bedemonstrably enhanced further by the combination of the DNA withvarious plasmid or lipid complexes(Zabner et al 1997) The advantages of lipid or plasmid assisted transfer mechanisms arethat they do not appear to generate the immunological responses thatare seen with the viral vectors. They can also be used to facilitatethe transport of much larger pieces of DNA which would otherwise belimited by the packaging consideration incumbent on the viral vectors.(Felgner P 1997). The use of retroviral vectors is far from straightforward. The heavilypublicised case in April 2000 brought some of the problems to theattention of the media. A retroviral manipulation of a case of X-SCID(X linked severe combined immunodeficiency) was treated by gene therapywith an apparent degree of success (BBC 2002). This particular diseaseprocess is caused by a mutation on the gene which codes for the C chainof the cytokine receptors which is situated on the X chromosome andvital for the functional development of T Killer lymphocytes which aretherefore completely absent in the condition A multinational team used a retroviral vector to insert a functionalcopy of the gene into bone marrow stem cells which were thenre-transfused back into the patient. (Cavazzana-Calvo M et al 2000).This particular case resulted in a return to normal levels of T cellsin a comparatively short period of time. This was hailed in both thepopular media and the peer reviewed journals as a major success and itcan indeed be considered a landmark as it pioneered the successful useof an ex-vivo procedure that avoided direct in vivo transfer of thevector. The reason for specifically highlighting this particular case isthat following the initial optimism of the clinical team, two of thefirst ten patients with this condition who were treated in the same waysubsequently developed a leukaemia-like illness. Genetic analysis ofthe malignant cells suggested that the retroviral vector used in thetransfer had also activated an oncogene LIM-only2 (LMO2) which is knownto be associated with some forms of leukaemia. The clinicians reviewingthe situation felt that, although it was not the only cause of themalignancy it was one of the events that triggered it. Similar concernshave been raised in respect of other clinical trials. (Lehrman S 1999) The prime reason for presenting these events is to demonstrate thefact that there is both a theoretical and practical risk of insertionalmutagenesis. Reduction of the risk requires greater specificity of thetargeting of the genetic deficit perhaps by directing the expressionof the therapeutic genes to various specific tissues utilising bothtransductional and transcriptional targeting. Relph K et al 2004), In terms of specific considerations of the arguments in favour of theuse of retroviral vectors, one can cite the fact that they have ahighly efficient mechanism of gene transfer together with lowimmunogenicity. It is a well researched and well studied system and isknown to selectively infect actively dividing cells. The conversearguments reflect their disadvantages including their ability todisturb or activate oncogenes, the fact that they are difficulty tospecifically target and it is difficult to obtain high titres in theclinical situation (after Olsen, J. C. 1998). In broad terms, the principles behind the use of retroviral vectorsare that they must be modified in order not to be able to transmit anyovertly pathological coding. This involves the deletion of viral helpergenes such as gag, pol and env to render the replication processinvalid. This is done by utilisation of a producer or packaging cellline. (Nichols, E. K 1998). An example of a commonly utilised and extensively researched vector isthe MoMuLV. It is an engineered vector which can store 8 kb of RNAwithout compromising packaging efficiency. It is a hybrid cell lineeasily grown in mouse fibroblast cells There is a subdivision of the retroviral vectors known as thelentivirus, which is the only retroviral vector capable of integratinginto the chromosomes of non-dividing cells. This has been effectivelydemonstrated in vitro (Naldini L et al 1996). The biggest problem with the lentivirus vectors is that theyappeared to only produce very low titres. Some recent researchsuggested that a modification to a amphotropic envelope protien wascapable of allowing higher titre levels. (Rolls M et al 1999) At about the same time that the scientific press was learning aboutthe problems with retroviral transfer (see above) other investigatorswere working with adeno-associated viruses (AAVs). A similar processwas invoked using adeno-associated viruses to correct a genetic defectinvolving coagulation factor IX. The adeno-associated viruses were usedas they were considered to be amongst the safest candidates for genetransfer. They do not naturally cause disease processes in humans andhave only rarely been found to incorporate in a random fashion into thehuman genome. Although it is noted that adenoviruses do cause oncogeneactivation in rodents although it has not been found in humans(Blacklow NR 1988). The trial had a very positive outcome. (Kay MA et al 2000), but thetrial author (in later research work) published a study which suggestedthat, in study mice, the vector used in the trials actually integrateditself into gene containing regions of DNA more frequently that it didinto non-coding regions (Kay MA et al 2003). The findings were reportedas the fact that new genetic material was randomly distributed amongstall of the chromosomes particularly at sites of gene activity. On thisbasis, there appears to be at least a theoretical basis for thepossibility of similar cellular defects such as occurred in the X-SCIDpatients. Adenoviruses are comparatively simple structures. They arecategorised as double stranded DNA viruses. They have icosahedralcapsids with twelve vertices and seven surface proteins. The virionitself is spherical and non-enveloped and in the region of 70-90 nm insize. Their natural history is that they are spread easily in the naturalstate by the faeco-oral route and also by respiratory inhalation whichclearly has great implications for the treatment of cystic fibrosis. A theoretical analysis would immediately suggest that the adenovirus should be a suitable candidate for gene therapy as they can codefor specific proteins and they do not produce infection pathogenicviral offspring. The early trials into this particular area were reviewed by Griesenbach(Griesenbach U et al 2002) who pointed out that the cystic fibrosisgene was first cloned in 1989 and in the subsequent years, 18different trials were carried out, all with rather low degrees ofsuccess. They collectively trialed three different vectors, namelyadenoviruses, adeno-associated viruses 2 and cationic liposomes, andalmost universally found that each vector had a very low rate ofclinically significant gene transfer and none was sufficient to achieveclinical benefit Plasmid Complexes At its most basic level, a plasmid is a small accessory collection ofDNA which is found in the cytoplasm outside of the nucleus. They arecapable of independent replication and can be manipulated with rathermore ease than nuclear DNA. Early investigations into the field of gene transfer explored thepossibility of plasmid vectors and demonstrated the feasibility of themethod to effect CFTR gene transfer in vitro (Alton EW 1993). Otherteams had demonstrated the fact that, in clinical use theplasmid-liposome is both nontoxic and non-immunogenic (Hyde,SC et al1993). This appeared to raise the possibility that many of theimmunological problems encountered by teams working with viral mediatedgene transfer mechanisms might be circumvented. In vivo work (Yoshimura,K et al. 1992) had demonstrated that genescould be transferred into the cytoplasm by this method and Stribling, R(et al 1992) demonstrated that, once there, they would then replicatenormally. Alton experimented with a CFTR-plasmid preparation in miceand demonstrated that it was capable of correcting the chloride levelsin cystic fibrosis mice back to normal levels (Alton EW 1993) Although the initial results were encouraging, clinical trials weredisappointing as the plasmid complex could not easily penetrate thethick mucous residues in the diseased lungs of patients with cysticfibrosis. (Erickson,R 1993) The plasmids typically have a positively charged head-group which isable to bind to the DNA strand and a hydrophobic tail group whichfacilitates the transfer of the complex across the cellular membranes.Initial studies suggest that between 100-1000 times more DNA isrequired to effect successful gene transfer when this method iscompared to viral vectors. (Santis,G et al 1994). One alternative adaptation has been reported by Stern M (et al 2003)who points out that one of the solution of delivery is to ensure thatthe respiratory epithelium is exposed to the DNA over a long period.Their solution was to encapsulate the CFTR-plasmid in a slow releasebiocompatible polymer. Clinical trials are underway but not yetreported. The adeno-associated vectors appear to have (at least on atheoretical basis) a number of advantages over the vectors that we havealready discussed. They are based on a virus vector that is alreadynon-pathogenic (Berns, KI et al 1995) and has a mechanism that allowsit to be a long-term persistent entity in human cells (Blacklow, NR etal 1989). The adeno-associated vectors are particularly useful indealing with disease process that involve single gene mutations. This,therefore makes it particularly suitable for single gene disorderssuch as cystic fibrosis and alpha 1 antitrypsin deficiency. (Flotte, TRet al 1998). In addition, some workers have also developed vectors which are capableof producing either inducible or constitutive expression of thecytokine, interlukin-10 (IL-10) which is an importantanti-inflammatory protein which, on a theoretical basis, could beuseful not only in cystic fibrosis but in other disease process whichhave chronic inflammation as their prime manifestation (viz Type Idiabetes mellitus or inflammatory bowel disease) (Egan, M et al 1992).These manifestations have been studied and have now reached the stageof early clinical trials (Wagner J et al 2002). With specific reference to the implications of cystic fibrosis, wecan point to trials which have resulted in the expression of cysticfibrosis transmembrane conductance regulator (CFTR) from rAAV(recombinant adeno-associated vectors) in cell cultures (Flotte, TR etal 1993), in animal models (primates) (Afione, SA et al 1996), andagain in early phase I clinical trials (Wagner, J et al 1998) The rAAV-IL-10 model has been studied in bronchial cell culturesfrom cystic fibrosis patients, to determine the functional consequencesof CFTR complementation. This has not yet been demonstrated in vivowith humans but in both mice (Song, S et al 1998), and monkeys (Conrad,CK et al 1996) The overall results of these (and other) studies have shown that itis possible to achieve long term gene transfer and functionalexpression of the replaced gene (some studies for as long as 18 months)without any overt pathological findings. The histological findings are something of a surprise however, as,at least in both primate and mouse studies, the vector-introduced DNAin this form does not appear to be assimilated into the geneticmaterial of the chromosome, but persists in log strings or concatemersthat are episomal, which is in complete contrast to what happens whenthe naturally occurring agent infects the cell. There is some evidenceto suggest that host cell intrinsic factors such as DNA-dependentprotein kinase play some role in this process (Song, S 2001). The significance of this finding could be that the exclusion of thefunctional, newly introduced DNA from the rest of the nuclear gene poolmay be less likely to produce effects that could be either potentiallydisruptive to the host cell and less likely to activate oncogenes.Phase I trials have demonstrated significant rises of CFTR levels inboth sinus and lung tissue with no evidence of vector-related toxicity.(Wagner, JA et al 1999) The adeno-associated vectors are constructed from proviraladeno-associated vectors plasmids, which have the Rep and Cap proteinsdeleted and substituting the appropriate gene (CFTR or equivalent)between the rAAV2 inverted terminal repeats together with other signalsequences such as promoter and polyadenylation sequences (Flotte, TR etal 1994) The packaging processes allows for about 5 kb of rAAV genomes to becarried in the vectors which are prepared using a cotransfectiontechnique utilising human embryonic kidney cells (HEK-293) where thevector plasmid is cotransfected into the cells with helper agents(plasmid pDG) being used to encode the rAAV2-rep and -cap genestogether with the adenovirus helper functions (Grimm, D et al 1998).These are incubated for between 48 and 72 hrs. The cells are then lysedand the resultant agents are then separated by ultracentrifugationagainst a density gradient and affinity chromatography (Zolotukhin, Set al 1999). The vectors are thereby amenable to being separated by both theirphysical characteristics and also their biological characteristics(infectious units). They are carefully screened to ensure the absenceof any possible contamination from non-modified (replication competentAAVs) prior to clinical usage. (Muzyczka N 1994) The comparatively small payload of the adeno-associated vectorsis proving to be a significant problem. The vector itself is small whencompared to the comparatively large size of the CFTR gene. (Flotte TRet al 1993) It does not leave any room to manoeuvre to manipulate thevector-specific sequences in the way that we have described with theretroviral and adenoviral groups. (Flotte TR et al 2001). A number of authors have characterised the problem with theobservation that the rAAV is typically about 20 nm across which allowspackaging of about 4.7 kb (kilobases) of transferable modified gene(exogenous DNA). (Dong JY et al 1996), If it is combined with otherenhancers such as the promoter, the polyadenylation signal, thisclearly reduces the capacity for the DNA component. (Duan D et al2000). The Yan paper (Yan Z et al 2000) has outlined a novelexploitation of the unique ability of the rAAV genomes to link togetherin strings which appears to have the ability to bypass this particularlimitation.( Flotte TR 2000). The mechanism itself is the capacity of two distinct rAAV genomes thathappen to simultaneously infect the same target cell to undergo anintermolecular recombination insider the transduced nucleus of thetarget cell. This was a chance finding which arose from work involvingrAAV-derived episomes (Kearns WG et al 1996) in primate airways. It wasfound that some of these episomes were configured as circular head totail concatemers (Duan D et al 1999). This could have been either froma rolling circle replication from a single vector or alternatively,from an intermolecular recombination of material from multiple cellularpenetrations which combined within the palindromic inverted terminalrepeat sequences that are an intrinsic part of the AAV genomestructure. The authors were of the opinion that it was likely to be thelatter eventuality (Duan D et al 1998) It was a logical progression to try to exploit this phenomenon andthereby bypass the limitations imposed by the relatively smallpackaging capacity of rAAV. The adeno-associated vectors capsid onlyhas a capacity of about 5 kb. If we consider that the 145 nucleotidestretch of the AAV-ITR (inverted terminal repeat) sequence has to be inplace at both ends of the single-strand DNA for the vector DNA to beboth replicated and packaged, this only leaves in the region of 4.7 kbof genetically active material in each rAAV particle. As we have cited earlier in relation to the Dong paper (Dong JY et al1996) the CFTR gene accounts for about 4.5 kb which leaves very littlespace for other enhancing material. Because of this, the actual CFTRvector that has been used in the clinical trials to date uses only theminimal promoter activity of the AAVs-ITR itself to actually activateand drive the CFTR expression (Flotte TR et al. 1993). To look at this potentially important development in a little moredetail we can consider Duans original paper (et al 2000) and theauthors describe what they call a superenhancer. They describe acombination of a potent simian virus (SV40) and CMV immediate earlyenhancer elements as being packaged in one rAAV vector and a luciferasegene assisted by a small minima;l promoter in another rAAV vector. Invitro experiments suggested that either the SV40 or the intrinsicpromoter activity of the AAV-ITR was sufficient for this purpose. Theintermolecular recombination described above, was found to occur inboth vitro and in vivo experiments and was found to be sufficient tohave a greater than additive effect. Initial results from these varying methods are encouraging insofaras they are producing results of transgene expression which are 100-600times greater than with the unenhanced vector alone. (Yan, Z et al2000) Although not directly referable to our considerations of cysticfibrosis, we should note that Yans group and other workers have doneexperimental work which has culminated in the long term expression offunctional levels of erythropoetin with this two vector method in micein vivo. (Naffakh N et al 1995), This basic principle has been further enhanced by Sun (Sun L et al2000) with an ingenious manipulation of the system. They triedinserting the promoter and the first half of the coding sequence in onerAAV vector, immediately followed by a splice donor and then theupstream half of an intron. In the other rAAV vector was the downstreamhalf of the intron, the splice acceptor, the second half of the geneand the polyadenylation signal. To quote the author verbatim: This strategy is efficient enough to mediate high-level expressionand the intermolecular junctions are apparently stable enough tomediate expression for several months in vivo. Although this is clearly an ingenious augmentation of the sameprinciple , we should note that there are both advantages anddisadvantages to both pathways. The strategy that adopts the superenhancer takes its strengths fromthe fact that the recombination mechanisms optimise theposition-independent and orientation-independent functions of theenhancers. Consideration of the options would suggest that there arefour potential recombination outcomes from the process described.Either of the two vectors could be on the 5 end of the heterodimericmolecule and clearly either molecule could be in either orientation. With the superenhancer option, all four of these possibleintermolecular recombination outcomes should be functional fortransgene expression whereas if compared to the split intron strategy,by using the same reasoning, it is clear that only one out of the fourcould work. On the other side of the argument, the superenhancer option has thedisadvantage that the actual coding sequence of the gene to betransferred must still fall within the packaging capacity of the vectoritself whereas the split intron allows for a greater functionalexpansion of the packaging capacity. (after Flotte TR et al 2000) In either event it can be seen that these ingenious modificationseffectively eliminate the main size limitation of the rAAV deliverysystem. Although initial pre-clinical work is encouraging it appearsthat there is still some potential for a degree of immune responseparticularly if the host organism has not experienced the newlyproduced protein before. A number of studies have been done on animal (vertebrate andprimate) with only minimal success. Different administration methodshave been studied including direct administration into the lung (WagnerJ et al 1999), IM injection (Song, S et al 2001 B) and hepatic portalvein infusion (Song, S et al 2001 A) Human clinical trials have taken place with these vectors (Flotte T etal 1996)(Wagner J et al 1998) (Virella-Lowell, I et al 2000). Thestudies were done on adult male and female patients (18-47 yrs) whowere pseudomonas free and had recently been hospitalised for IVantibiotic infusions The disappointing results were probably a reflection of the factthat the CFTR defect is also interconnected in some way with aproinflammatory phenotype which appears to be triggered by the abnormalprotein via an unfolded protein response. The authors were able to showevidence that the rAAV-CFTR mechanism was able to correct the proteinproduction defect, they found it clinically difficult to transduce asufficient number of cells in the airway to reverse the inflammatoryresponse. It is proposed to run further experimental work which combines theCFTR expression with an anti inflammatory gene such as the IL-10.There is some in vitro work to suggest that this may be a possibleworkable approach (Teramoto, S et al 1998). Other work on ways ofenhancing the phenotypic expression of the modified genotype hassuggested that the use of various promoters and the rAAV-CMV/beta-actinhybrid promoter (CB-AAT) was found to be tone of the most efficient, atleast when it was compared to the other tested options such as the CMV,E1, U1a and U1b promoter constructs (Teramoto, S et al 1998) Overall, the initial results appear to be encouraging. A singleinjection of an rAAV-CB-AAT vector in animal studies has resulted inhigh level, stable transgene expression which has persisted over thelife span of the experimental animals and that there was no detectableinflammatory response in the animals who had received this form oftreatment (Flotte TR 2002) Flotte (et al 2002) reports that four human clinical trials at bothPhase I and Phase II level are currently underway examining the effectsof the rAAV-CFTR vector. They had an entry cohort of seven patientswith the vector being applied to the nasal lining, the maxillary sinusand the bronchus. The authors report no adverse effects being found andthat they have observed transgene expression at doses of 6 x 108 drp inthe sinus or 1 x 1013 drp in the lung. There are no reported interimfindings from the Phase II trials as yet. There is clearly a potential for clinical benefit on the basis of theresults found to date if one can extrapolate from in vitro and animalexperiments. The authors comment that, in contrast to the adenovirusvectors there is a marked lack of inflammatory toxicity with the rAAVvectors. Despite these positive comments, we should not, however, overlook thepotential limitations of this particular delivery system. These havebeen identified by various authors as: The inhibitory effect of preexisting airway inflammation on rAAV transduction in the lungs (Virella-Lowell, I et al 2000) A relative paucity of receptors on the apical surface of airway epithelial cells (Summerford, C et al 1998), The relatively weak nature of the minimal promoters used in the first-generation rAAV-CFTR vectors(Flotte, TR et al 1993), The potential for adverse long-term effects from rAAV vector DNA persistence. (Wu, P et al 2000) The Flotte group are currently investigating this problem by examiningthe hypothesis that the barriers in the airways of the cystic fibrosissufferer are primarily due to the neutrophil-derived -defensins (HNP1and HNP2) and are actually reversible by the mechanism of AAT proteindelivery (Virella-Lowell, I 2000) Wu and his co-workers have been looking at ways of manipulating thegenetic make up of the rAAV2 capsid and thereby trying to enhance thetargeting ability so that the vector specifically targets the serpinenzyme complex receptor on IB31 cells which is virtually specificfor the Cystic fibrosis bronchial cells Zabner, J (et al 2000), have considered alternative rAAV serotypesin the hope of finding one that will bind more specifically to thebronchial cells Other peripheral adjuncts have also been explored includingpromoters to enhance the effects of complementation and superenhancerswhich have been shown to improve the ability of the rAAV toconcatermerise with the help of smaller amounts of promoter agents(Duan, D et al 2000). Perhaps it is appropriate to conclude this section on considerationof adeno-associated vectors with a critical analysis of a very recentmulticentre, double-blind, placebo-controlled trial (Moss RB et al2004) This was a well constructed, fully statistically significant anddouble blinded trial which considered both the safety and thetolerability of repeated doses of adeno-associated serotype 2 vectorrepeatedly given by aerosol inhalation. The vector contained cysticfibrosis transmembrane conductance regulator (CFTR) complementary DNA(cDNA) [tgAAVCF], an adeno-associated virus (AAV) vector encoding thecomplete human CFTR cDNA. The entry cohort was comparatively small with 42 patients, of whom20 received the active agent. A number of indices of airway functionwere measured. Of particular interest to our considerations in thisdissertation was the fact that vector shedding was found in alltreated subjects up to 90 days after inoculation. And that all subjectswho received the active agent exhibited at least a fourfold increase inthe serum AAV2 neutralising antibody levels. Of the 20 treated patients, six subsequently underwent bronchoscopy.Of those six, gene transfer but not gene expression was demonstrated inall of them. On this basis, it would appear that the actual transfermechanism is effective, but there are other factors present whichappear to interfere with the subsequent expression of the gene in termsof protein production. The study did not comment on the possiblereasons for this. The authors were able to conclude that the delivery system workedwell with no evidence of adverse effects and that treated patientsdemonstrated an encouraging trend in improvement in pulmonary functionin patients with CF and mild lung disease. Lipid 67 We have discussed the various shortcomings of the virus-associatedvectors and this has prompted researchers to explore and consider otheroptimising options for facilitating gene transfer. Zabner (J et al1997) considered the use of cationic lipids in this process and foundone GL-67:DOPE (colloquially known as lipid 67) which appeared to beparticularly helpful in the process. Cationic lipids appear to show a degree of promise as possible vectorsfor CFTR cDNA transfer into respiratory epithelial cells of cysticfibrosis patients. Zabners group developed a preparation of plasmidencoding CFTR (pCF1-CFTR) and cationic lipid (GL-67:DOPE) whichappeared to facilitate the gene transfer to a significantly greaterextent than previously tested lipid complexes. They performed in vivostudies which compared the gene transfer rate to the epithelial cellsof the nasal mucosa of DNA-lipid complex and DNA alone. In generalterms, their findings indicated that the DNA-lipid complex was far moreeffective in achieving gene transfer than was simply giving DNA. Theauthors felt able to conclude that: These results indicate that nonviral vectors can transfer CFTR cDNAto airway epithelia and at least partially restore the Cl- transportdefect characteristic of CF. However, improvements in the overallefficacy of gene transfer are required to develop a treatment for CF. In this dissertation we are primarily considering the issues ofgene therapy in direct relation to cystic fibrosis. Inevitably, thishas meant considering the issues on a wider front, as many areasoverlap on a theoretical or practical basis. The prime biochemical cellular defect in cystic fibrosis is anabnormality in the cystic fibrosis transmembrane conductance regulator(CFTR). From a theoretical perspective it should be obvious thatreplacement of the defective gene with a working alternative would bebest achieved in the neonatal period before the body had time todevelop substantial fibrotic changes in the lungs that were secondaryto repeated episodes of infection (Dark J et al 1996). If successful, this could be expected to reduce both morbidity andmortality for cystic fibrosis. We have been able to cite evidence thatgene transfer has been accomplished both in vitro and in vivo. We havediscussed the results of a number of research groups who haveinvestigated various delivery systems which, to varying extents, haveproved able to deliver at least a small quantity of functional respiteto the cystic fibrosis sufferer. It is also important to be fully aware of the possibility ofinadvertent side effects in the field of gene manipulation. We havehighlighted the problems with oncogene activation. But this appears tobe associated with some vectors more than others. In short, it wouldappear that the problems and limitations that appear with this type ofprocedure are a function of the parent virus. The initial work with adenoviruses appeared promising as genetransfer could be accomplished but the major drawback was the doselimiting inflammatory effects which arose primarily as a result of thelarge amount of viral protein which was required to achieve atherapeutic dose. The subsequent modifications which had a greaternumber of coding sequence deletions appeared to be more effective inanimal experiments as they generated a lesser response from the cellmediated immunity mechanisms and therefore had a greater duration ofaction. (Caplen NJ et al 1995). It seemed a logical step from there to produce vectors that had noviral genes at all. This did not produce any significant benefits orimprovements from the previous agents. A number of research teamsacross the world tried different subsidiary strategies including druginduced immunosuppression or modifications of various immunogenicepitopes. The plasmid-lipid complexes appeared to have a number of clinicallyimportant advantages insofar as they did not appear to generate anyimmunological response which is in distinct contrast to many viralvectors. Initial optimism did not appear to be translated intopractical application as the delivery systems explored appeared to beunable to deliver sufficiently large quantities through thepathological mucous layer that is the main feature of the cysticfibrosis patient. (Crystal RG 1992). The adeno-associated vectors have received a large amount of attentionwhen it became clear that alternative vectors were needed to optimisethe therapeutic effect. They have now reached the stage where animaltesting has lead to human Phase I and II clinical trials. As a group,they appear to have the advantage that they dont trigger theinflammatory reaction in the same way, or to the same extent as theadenovirus group. The major practical difficulty with this grouphowever, is the fact that because they are so small compared to thecomparatively large size of the CFTR gene it leaves no space forvector-specific sequences on which to base assays to help todistinguish the endogenous RNA from the vector-expressed RNA. (FlotteTR et al 2001) All the evidence that we have seen appears to suggest thatadeno-associated vectors have a satisfactory safety profile andcertainly appear to produce a longer duration of clinical effect thanthe other modalities. Another variable, and indeed challenge, in the field of genetherapy, is to find the optimum delivery vehicle. We have cited studiesthat have tried direct insufflation to the bronchial epithelium. Thisappears to be a superior mode of delivery to the aerosol which appearsto have the ability to cause agent specific reactions in the alveolarmembranes. There is continuing work which is currently looking at therelative merits of nebuliser delivery mechanisms as compared toconventional aerosol delivery systems. Others that have tried avoidingthe bronchial tree and utilising the respiratory epithelium byintroduction to the maxillary sinuses through intranasal antrostomies. Conclusion including future of gene therapy. In this dissertation we have presented evidence of from a number ofdifferent approaches to the problem of gene therapy in tacklingmonogenic conditions such as cystic fibrosis. As with most areas ofscientific exploration many blind alleys have to be explored beforean appropriate avenue of research becomes apparent. The initial enthusiasm the greeted the exploration of theplasmidDNA vector did not appear to be well founded although it isclear that further exploratory work is continuing in the field. The area of adeno-associated vectors appears to be currently themost promising with, at least in vitro, suggestions that many of thecurrent limiting problems may be on the verge of being solved. The major stumbling blocks at the moment are the difficulties ofproducing a high vector titre in the clinical situation and the longterm safety considerations, particularly those relating to mutagenesisof ongogenes. On this point the Flotte group are optimistic and feelable to make the comment: The data from our laboratory strongly indicate that the bulk of rAAVDNA in the lung, muscle, and liver is episomal and that rAAV genomesinteract with host cell proteins such as the DNA-dependent proteinkinase in the formation of stable high-molecular weight concatemers. It is the episomal situation of the gene that is currently thoughtto be the best insurance against inadvertent iatrogenic oncogenesis(Flotte et al 2002) but this is clearly no substitute for long termcareful and rigorous safety studies. It is often assumed, quite incorrectly, that the field of genetherapy is a discrete and academically isolated field. Progress in thisarea, as in so many other areas of research, is completely dependent ofdiscoveries and improvements in other areas of science. The future direction of research will be determined, to a degree,by improvements in our ability to manipulate cell types and cell linesoutside of the body as this will inevitably aid our ability to implantgenetically engineered agents. Reflection over the advances inknowledge from just the last decade indicates that new and innovativedelivery mechanisms will be developed, explored and evaluated. It islikely that the known short term problems of immunogenicity, low titredelivery and inefficient packaging will be addressed, very possiblywith new delivery vectors. It goes without saying that these investigations are hugelyexpensive in terms, not only of money, but of time, expertise andinvestment generally and therefore it is likely that the limitingfactor in terms of development will be the availability of resources(Russell S 1997) References Afione, SA, Conrad, CK, Kearns, WG, et al (1996) In vivo model of adeno-associated virus vector persistence and rescue. J Virol 70,3235-3241 Alton,EW et al. 1993 Nature Genetics. vol 5. 1993 Amado R G Chen YJS 1999 Lentiviral Vectorsthe Promise of Gene Therapy Within Reach? Science. 285 (5428): 674-76. BBC Online News. Bubble boy saved by gene therapy. 3 April 2002, Berns, KI, Linden, RM (1995) The cryptic life style of adeno-associated virus. Bioessays 17,237-245 Blacklow NR. 1988 Adeno-associated viruses of humans. In: Pattison JR, ed. 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How to Choose a Building Lot for Your New House

Youre building a house. Which do you do first? 1. Select a style and a plan OR 2. Select a building lot? Both approaches have merit. If your heart is set on a Spanish style adobe home, a heavily treed lot may not make sense for you. Having an idea of the architectural style you prefer will determine the size and characteristics of your building site. You may run into problems, however, if you select a specific floor plan too soon. You can always design a home to suit a landscape, but you may not be able to alter a landscape to accommodate the specifications of predetermined house plans. The configuration of rooms, the placement of windows, the location of the driveway and many other design elements will be affected by the land you build on. The land itself has long been the inspiration for truly great homes. Consider Frank Lloyd Wrights Fallingwater. Constructed of concrete slabs, the house is anchored to a rugged stone hill in Mill Run, Pennsylvania. Compare Fallingwater with Mies van der Rohes Farnsworth House. Made almost entirely of transparent glass, this unearthly structure seems to float above a grassy plain in Plano, Illinois. Would the Farnsworth House seem as graceful and serene perched on a rocky hill? Would Fallingwater make such a powerful statement if it sat in a grass field? Probably not. Questions to Ask About Your Building Lot Once you have located a promising building site for your new home, spend some time on the building site. Walk the full length of the building site at different times of the day. If you are a follower of feng shui, you may want to think about the land in terms of its chi, or energy. If you prefer a more down-to-earth evaluation, think about ways the building site will influence the shape and style of your home. Ask yourself: What are the general characteristics of the land? Is it green and woodsy? Rocky and gray? Or, is it a vast open stretch with a golden hue? Will the prevailing colors of the landscape change with the seasons? Will the home you imagine blend with the landscape? Does the landscape suggest particular colors or materials you might include in the design of your home?Can other structures be clearly seen from the building lot? What is the prevailing architectural style? Will your proposed home fit the overall context of the neighborhood?Will the size of your proposed house be proportionate to the size of the lot? (You dont want to squeeze a mansion onto a postage stamp!)Is there a street or road? Should the house face toward or away from the road?Where should the driveway be located? Will there be enough room for cars and delivery trucks to turn around?Where are the most pleasing views? Where does the sun rise and set? Which views would you like to see from the living areas? From the kitchen ? From the bedrooms? Where should windows and doors be placed?If you are in a northern climate, how important is it to face the south? Will a southern exposure help you save on heating costs?Is the site flat? Are there hills or streams? Are there any other geological conditions that might affect the design or placement of your home?How much landscaping will be required? Will preparing the land for building and planting trees and shrubbery add to your final costs? The waterfall views at Fallingwater may look idyllic, but for most of us, building on a rocky hillside isnt practical. You want the site of your new home to be beautiful, but it must also be safe... and affordable. Before you make a final decision, youll need to consider a mind-boggling list of technical details. Check Your Building Lot For Common Problems As you narrow your search for an ideal building site, dont scrimp on getting expert advice on home building. Your builder can put you in touch with consultants with the legal and scientific expertise to offer building advice. Your consultants will investigate the characteristics of the land and explore zoning, building codes and other factors. Land Conditions Soil. Has the property been a victim of hazardous waste? Are there pollutants that may not be apparent to an untrained observer?Land Stability. Is the property is subject to land slides or sinkages?Water Drainage. Is the property located near a river? Are there hills or low spots which may make your home subject to water runoff? Err on the side of caution. Even Mies van der Rohe made a grievous mistake. He placed the Farnsworth House too close to a stream, and his masterpiece suffered serious flood damage as a result.Noise. Is there a nearby airport, highway, or railroad? How disruptive is it? Zoning, Building Codes and More Zoning. In five years, your beautiful views may be replaced by a highway or a housing development. Zoning regulations will indicate what may be legally constructed in the surrounding area.Building Codes. A variety of ordinances will affect the placement of your new home on the lot. Regulations will specify how close you can build to the property line, roads, streams, and lakes.Easements. Easements for electrical and telephone poles will limit the space you have for building your home.Public Utilities. Unless the property is in a development of suburban tract homes, there may not be easy access to electricity, gas, telephone, cable television or public water lines. Sewers. If there are no municipal sewers, youll need to know where you may legally place your septic system. Costs You may be tempted to skimp on the cost of your land so that you can spend more money on building your house. Dont. The cost of altering an unsuitable lot is likely to be more expensive than purchasing land that is meets your needs and your dreams. How much should you spend on a building lot? There are exceptions, but in most communities your land will represent 20% to 25% of your total building costs. Advice From Frank Lloyd Wright Building a house is often the easy part. Making decisions is stressful. In Wrights book The Natural House (Horizon, 1954), the master architect gives this advice on where to build: When selecting a site for your house, there is always the question of how close to the city you should be, and that depends on what kind of slave you are. The best thing to do is go as far out as you can get. Avoid the suburbs—dormitory towns—by all means. Go way out into the country—what you regard as too far—and when others follow, as they will (if procreation keeps up), move on.~p. 134