Tumor necrosis factor alpha

Abstract

The present disclosure describes the use of genetic variance information for genes involved in inflammatory or immunologic disease, disorder, or dysfunction. The variance information is indicative of the expected response of a patient to a method of treatment. Methods of determining relevant variance information and additional methods of using such variance information are also described.

Description

RELATED APPLICATIONS [0001] This application is a Stanton, U.S. application Ser. No. 09 / 590,749, filed Jun. 8, 2000, which is a continuation in part of Stanton, U.S. application Ser. No. 09 / 495,780, filed Feb. 1, 2000, entitled GENE SEQUENCE VARIATIONS WITH UTILITY IN DETERMINING THE TREATMENT OF INFLAMMATORY OR IMMUNOLOGIC DISEASE, which is a continuation in part of Stanton, U.S. application Ser. No. 09 / 492,712, filed Jan. 27, 2000, entitled GENE SEQUENCE VARIATIONS WITH UTILITY IN DETERMINING THE TREATMENT OF INFLAMMATORY OR IMMUNOLOGIC DISEASE, which is a continuation-in-part of Stanton, International Application No. PCT / US00 / 01392, filed Jan. 20, 2000, entitled GENE SEQUENCE VARIATIONS WITH UTILITY IN DETERMINING THE TREATMENT OF DISEASE, Stanton, U.S. application Ser. No. 09 / 427,835, filed Oct. 26, 1999, entitled GENE SEQUENCE VARIATIONS WITH UTILITY IN DETERMINING THE TREATMENT OF DISEASE, and Stanton and Adams, U.S. application Ser. No. 09 / 300,747, filed Apr. 26, 1999, entitl...

AI Technical Summary

Benefits of technology

[0010] In connection with the methods of this invention, unless otherwise indicated, the term “suffering from a disease or condition” means that a person is either presently subject to the signs and symptoms, or is more likely to develop such signs and symptoms than a normal person in the population. Thus, for example, a person suffering from a condition can include a developing fetus, a person subject to a treatment or environmental condition which enhances the likelihood of developing the signs or symptoms of a condition, or a person who is being given or will be given a treatment which increase the likelihood of the person developing a particular condition. For example, tardive dyskinesia is associated with long-term use of anti-psychotics; dyskinesias, paranoid ideation, psychotic episodes and depression have been associated with use of L-dopa in Parkinson's disease; and dizziness, diplopia, ataxia, sedation, impaired mentation, weight gain, and other undesired effects have been described for various anticonvulsant therapies. Thus, methods of the present invention which relate to treatments of patients (e.g., methods for selecting a treatment, selecting a patient for a treatment, and methods of treating a disease or condition in a patient) can include primary treatments directed to a presently active disease or condition, secondary treatments which are intended to cause a biological effect relevant to a primary treatment, and prophylactic treatments intended to delay, reduce, or prevent the development of a disease or condition, as well as treatments intended to cause the development of a condition different from that which would have been likely to develop in the absence of the treatment.

[0116] The invention also provides a method for improving the safety of candidate therapies for the identification of an inflammatory or immunological disease or dysfunction. The method includes the step of comparing the relative safety of the candidate therapeutic intervention in patients having different alleles in one or more than one of the genes listed in Tables 1 and 3. Preferably, administration of the drug is preferentially provided to those patients with an allele type associated with increased efficacy. In a preferred embodiment, the alleles of identified gene or genes used are wild-type and those associated with reduced biological activity.

Problems solved by technology

In OA, the cartilage that covers the ends of the bones within joints deteriorates and causing pain and loss of movement as bone begins to rub against bone.

However, because these drugs are limited in their efficacy in advanced or more severe stages of arthritis, these agents are usually add-on therapies.

These agents are known to interfere with the actions of these cytokines.

The therapies discussed above are limited to the slowing or retarding the progression of arthritis.

As joint degeneration progresses and result in irreversible damage, options become limited.

Slow clinical relevance of these therapies limits determination of optimal therapy for individuals with arthritis and makes it difficult to select optimal therapy for any given stage of the disease.

Drugs used to treat arthritis may cause death, disability, disease, and pose risks to an unborn child.

Further this product was associated with site of injection reactions, infections, and headache.

The overall cost of these illnesses to society is enormous due to the extent of the number of individuals afflicted with COPD.

The high morbidity and mortality rates associated with COPD are linked to the failure to identify at-risk patients for intervention.

Large reserves of pulmonary function in lungs and the slow progressive nature of the disease can often delay the clinical diagnosis and therapeutic intervention.

Repeated exposure to bronchiole irritants in individuals with hyperactive or sensitive airways can lead to bronchospasm, i.e. bronchial smooth muscle constriction, that is frequently accompanied by excess mucous production and edema of the bronchial walls.

These changes result in a reduction of elastic recoil permitting excessive airway collapse upon expiration and leads to irreversible airway flow obstruction.

In emphysema, there is a loss of elastic recoil leading to pulmonary hyperinflation.

The hyperinflation reaches a limit when the diaphragm is pushed flat and no longer functions effectively.

These anatomical changes alter inspiration to the point that exertion is nearly impossible.

In these individuals there is a marked alveolar wall destruction with a non-uniform pattern of air space enlargement.

In these patients there may be excessive formation of thick mucous and is often accompanied by persistent cough.

However, it has been determined that systemic corticosteroids are beneficial for acute exacerbations of COPD but are not used for long-term treatment and have not been proven to retard the progression of the disease.

Dyspnea may be severely disabling despite aggressive therapy.

Unfortunately, opiates can have a respiratory depressant effect and care should be taken to deliver the appropriate therapeutic dose.

Many patients with COPD find themselves anxious or depressed or both.

This expensive and aggressive approach is usually reserved for younger patients, particularly those who are alpha 1-antitrypsin deficient.

The most common limitations for the use of bronchodilators is the mistaken use of inhalants and inadequate patient education.

Beta-adrenergic agonists can cause tremor, reflex tachycardia, tachyphylaxis, cardiomyopathy, and other cardiac toxic effects.

Tachycardia is particularly problematic in the elderly or for those individuals who are at cardiac risk.

Further, β-adrenergic agonists have been shown to cause hyperkalemia.

Anticholinergics as bronchodilators have been associated with systemic side effects.

Ipratropium has a slow onset of action and a longer duration of action than β-adrenergic agonists which can be deleterious for acute bronchodilation because patients continue to administer the drug without effect and overdose.

Theophylline continues to be a controversial treatment due to misconceptions of its role as a bronchodilator, drug delivery problems, and conflicting results of comparative studies during acute exacerbations.

Further, theophylline has a limited therapeutic window, i.e. the dose needed to achieve bronchodilation is close to the dose associated with undesirable or adverse side effects including convulsions, cardiac arrhythmias, tachycardia, vasodilation, and diuresis.

Only 20-30% of these patients experience therapeutic benefit for long-term use and indiscriminate use often leads to adverse effects without benefits.

Unfortunately there have not been identified predictors of responders or nonresponders to long term steroid use in patients with COPD.

Unfortunately, those patients in which long-term steroid use results in no benefit are subjected to potential adverse effects or toxicities.

So far, there is little evidence to suggest that these agents render clinical improvement.

Further cough suppressants may impair secretion clearance and possibly increase risk of pulmonary infection.

Since many autoreactive clones of T and B cells exist and are normally regulated by homeostatic mechanisms, loss or breakdown of this system of checks and balances can lead to activation or enhancement of these autoreactive clones and ultimately lead to autoimmune disease.

The estimated cost of MS is $5 billion dollars.

Further, a nonrelapsing-nonremitting form is characterized by a gradual progression and steady worsening of neurological function without any recovery or improvement.

Although ultimately renal impairment and failure is a common endpoint, therapy affecting the hypertensive phase or renal involvement has changed the mortality rate.

In 80% of the cases, sarcoidosis is self-limiting and results in minimal symptomology, discomfort, or debilitation.

However in the remaining 20%, sarcoidosis patients face potentially serious debilitation, disfigurement, and can be life threatening.

Misdiagnosis is frequent and can limit appropriate therapeutic intervention.

Inflammation of the kidneys results in impaired renal function.

Membranous nephropathy may develop and lead to impairment of glomerular filtration rate.

However, because these drugs are limited in their efficacy in advanced or more severe stages of autoimmune disease, these agents are add-on therapies.

These agents are known to interfere with the actions of these cytokines.

As immune response tissue damage occurs, degeneration of the function progresses, irreversible damage occurs, and therapeutic options become limited.

The slow clinical relevance of these therapies limits the clinician to determine optimal therapy for individuals with autoimmune disease, and provides a risk for selection of optimal therapy for any given stage of the disease.

Furthermore, there may be delays in identifying those patients that have an autoimmune hyperreactivity, and this can delay therapeutic intervention.

There are toxicities and undesired side effects associated with the above current therapies for autoimmune disease that require monitoring.

Drugs used to treat autoimmune disease may cause death, disability, disease, and place an unborn child at risk.

Since the majority of autoimmune disease patients are women in their reproductive years, the level and extent the agents used to treat autoimmune disease affects or has a potential to affect the mother during pregnancy, cross the placenta, affect the developing fetus, or be excreted in breast milk during lactation are important issues facing the skilled practitioner.

In acute rejection, infiltration of lymphocytes and macrophages recognize the foreign antigen on the graft cells, and initiate a cascade of intragraft events that ultimately leads to host cellular and humoral mediated destruction of the grafted tissue and if unchecked will result in irreversible loss of the graft.

Delayed or chronic rejection occurs in a slower process than acute rejection and ultimately leads to a gradual loss of function in the grafted tissues.

If damage to the tissue is extensive, very little can be done to save the graft.

All too often, this balance is not achieved and on one end the patient succumbs to infections or on the other the graft is rejected.

Specifically, cyclophosphamide has been associated with fluid retention, hemorrhagic cystitis, and cardiac toxicity.

Radiation is associated with higher incidence of infections and chromosomal breakage and mutations.

In addition to the above listed toxicities and undesirable side effects, potent immunosuppression as required in the transplantation setting leads to prolonged immune compromise and predisposes the patient to infections (80% of the patients) and cancer (ranging between 10-40% of the patients).

This risk has been proposed to result from impaired immune surveillance mechanisms, chronic antigenic stimulation, reactivation of latent oncogenic viruses and the direct oncogenic effects of the immunosuppressive agents.

However, because these drugs are limited in their efficacy in advanced or more severe stages of arthritis, these agents are add-on therapies.

The therapies discussed above are limited to the slowing or retarding the progression of arthritis.

As degeneration of the joints progresses, and irreversible damage occurs, the options become limited.

These activated molecules transfer their energy to form cytotoxic singlet oxygen leading to lethal alteration of cellular membranes and subsequent tissue destruction.

The main limitation of the current therapies for psoriasis is that the drugs are only efficacious during the administration.

Further, periods of remission and outbreaks are difficult to impossible to predict.

This can lead to missed schedules and requires patient education.

Lastly, for all the listed therapies there is unreliable efficacy in their ability to stop proliferation and inflammation of the lesions.

Toxicities of the current therapies include the following: phototherapy can lead to other skin lesions and sunburn.

If the stimulating agent is maintained, i.e. hyperlipidemia, hypercholesterolemia, or other risk factor, then the protective inflammatory response will also persist and they may become deleterious to the cells lining the arterial wall.

This may lead to an inflammatory reactions participating in the destabilization of the fibrous cap.

These LDL immunocomplexes can induce numerous metabolic and functional changes which can directly or indirectly damage the endothelial cells leading to the progressin of the atherosclerotic lesion.

Despite the evidence of the involvement of the immune system in atherogenesis, the complexity of the immune reactions and response impairs the clarification of the involvement of these machanisms at the various stages of athersclerosis.

It is widely recognized that preclinical data is imperfect in predicting response to a compound in man.

In such cases, the procedure for using the drug is restricted or limited on the basis of a diagnostic test for determining the presence of a variance or variant form of a gene.

(Certain kinds of experiments—for example gene expression profiling and proteome analysis—may not only allow refinement of a candidate gene list but may also lead to identification of additional candidate genes.)

Therefore the marketing of one compound vs. other members of the class is a challenging problem for drug companies, and is reflected in the lesser success that late products typically achieve compared to the first and second approved products.

This approach reflects the current reality that biologists do not sufficiently understand gene regulation, gene expression and gene function to consistently make accurate inferences about the consequences of DNA sequence variances for pharmacological responses.

The fundamental objectives for each phase become increasingly complex as the stages of clinical development progress.

That is, if a dangerous toxic effect manifests itself predominantly or exclusively in a genetically defined subpopulation of the total treatment population it may be deemed inappropriate to continue treating that genetically defined subgroup.

(It generally will not be practical to segment patients by geographical origin in a standard clinical trial, due to loss of power.)

However, in the early stages of clinical testing, when the main goal is to reduce the large number of potential hypotheses that could be tested to a few that will be tested, based on limited data, it may be impractical to rigidly apply the multiple testing correction.

(It would also increase the cost of studies, however the type of data that can be obtained can not be duplicated with conventional approaches.)

For example, it is well known that Alzheimers trials are long and expensive, and most drugs are only effective in a fraction of patients.

Yet it may be serious adverse effects occurring in just such a small group that create problems in later stages of drug development.

This addresses a serious limitation of conventional clinical trials with respect to the investigation of polygenic traits or the effect of rare alleles.

Unfortunately even Phase III studies, as currently performed, are often barely powered to address simple one variance hypotheses about efficacy or toxicity.

The problem, of course, is that each time a new genetic variable is introduced the comparison groups are cut in halves or thirds (or even smaller groups if there are multiple haplotypes at each gene).

It is therefore a challenging problem to test the interaction of several genes in determining drug response.

As the number of genetically defined groups increases (e.g. as a result of multiple variances or haplotypes) there is a loss of statistical power due to multiple testing correction.

While it is optimal to initiate pharmacogenetic studies in phase I, as described above, it may be the case that pharmacogenetic studies are not considered until phase II, when problems relating either to efficacy or toxicity are first encountered.

The first, second and third drugs in the class will likely have a dominant market position (based on their earlier introduction into the marketplace) that is difficult to overcome, particularly in the absence of differentiating clinical effects.

Nearly half of patients receive virtually no benefit from alfa interferon, but may suffer significant side effects.

For many genes, only cDNA sequences have been published, therefore the analysis of those genes is, at least initially, at the cDNA level since the determination of intron-exon boundaries and the isolation of flanking sequences is a laborious process.

In some cases, variation in activity due to a single gene or a single genetic variance in a single gene may not be sufficient to account for a clinically significant fraction of the observed variation in patient response to a treatment, e.g., a drug, there may be other factors that account for some of the variation in patient response.

However there is no way to know in advance whether there are major phenotypic effects associated with single nucleotide changes and, even if there are, there is no way to be sure that the salient variance has been identified by screening cDNAs.

As a result there is a smaller probability of Type I errors, that is, false inferences that a particular variant is associated with a given phenotype.

If a heteroduplex contains only one mismatch, cleavage will result in the generation of two fragments.

However, if a single heteroduplex (allele) contains two mismatches, cleavage will occur at two different sites resulting in the generation of three fragments.

Because Taq polymerase is very inefficient at extending 3′ mismatches, the only samples which will be amplified will be the ones in which the two primers are perfectly matched for sequences on the same strand (allele).

Thus, it is expected that such a regulatory agency may indicate that the approved indications for use of a drug with a variance-related variable response or toleration include use only in patients in whom the drug will be effective, and / or for whom the administration of the drug will not have intolerable deleterious effects, such as excessive toxicity or unacceptable side-effects.

Thus, even though normal cells of the patient may contain a form of the gene which correlates with effective treatment response, the absence of that form in cancer cells will mean that the treatment would be less likely to be effective in that patient than in another patient who retained in cancer cells the form of the gene which correlated with effective treatment response.

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