Targets Clinical Trials

the precise role of gene transfer cannot be defined. 

In the relatively early phases of clinical trials, multiple groups of investigators began to study cystic fibrosis, and this is not surprising given that it is the 

One of the earlier studies that involved the ex vivo transduction of hepatocytes was the homozygous form of fiunilial hypercholesterolemia. In this particular disorder, there is an absence of low-density lipoprotein (LDL) receptors in the liver parenchyma. These patients are afflicted with extremely high levels of semm LDL cholesterol and they suffer the adult consequences of severe arteriosclerosis as early as the age of 5 years. Five research sulyeets participated in this particular study two of them exhibited significant reduction in LDL cholesterol levels and a third showed a measurable reduction (48). Again, the results of this study are difficult to interpret, because all the sul ects were on chronic maintenance with 3-hydroxy-3-methylglutaiyl-coenzyme A reductase inhibitors that are known to reduce cholesterol. 

Several other trials are in progress and await completion and reporting of the data. Diseasesunder study include alphaj-antitrypsin deficiency, Fanconi s anemia, Gaucher s disease. Hunter s syndrome, Canavan s disease, limb girdle muscular dystrophy, amyotrophic lateral sclerosis, ornithine transcarbamylase deficiency, and junctional epidermolysis bullosa. 

In one of the earlier trials of immunotherapy, a very iimovative approach involved the use of identical twins. CD8 T cells were removed from an uninfected identical twin, transduced with the gene encoding a universal chimeric T-cell receptor, and then infused into the HIV-infected twin. Since the twins were genetically identical, there were no problems related to histocompatibility, and one could assume that the transferred lymphocytes would survive without the danger of rejection. Preliminary data suggested evidence of a selective survival advantage for the transduced T cells that were introduced into a virus-positive environment. 

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Fig. 1. Targeted clinical trial design for evaluating a new experimental therapy. A biomarker classifier is developed for identifying those patients most likely to respond to the new treatment (E). Only those patients are randomized to E versus the control treatment. The patients predicted less likely to respond (marker negative) are off-study. The targeted design is most useful in cases where the biomarker classifier has a strong biological rationale for identifying responsive patients and where it may not be ethically advisable to expose marker negative patients to the new treatment.

The effect of this reversal of the trend toward individualization is likely to increase burdens on the clinical trial process and on the submissions of NDAs and ANDAs. If customization is not practical through physician-patient trial and error experimentation, the submission of clinical data that defines effects and side effects specific to interactive medical conditions, ethnicity, gender, age, and genetic characteristics becomes all the more important. Unless a developer is willing to settle for a high-restricted label, significantly expanded and targeted clinical trials are the most likely response to the need for customized medication. 

R.A. Kloner, M.T. Speakman, and K. Przyklenk, Ischemic preconditioning a plea for rationally targeted clinical trials, Cardiovasc Res 55, 526-533 (2002). 

Kennedy RE, Cutter GR, Schneider LS (2014) Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer s disease. Alzheimers Dement 10 349-359... 

Approaches to cytotoxic chemotherapy iaclude special emphasis on dmg targeting and toxicity alleviation. The directions ia which new dmg discovery strategies are moving and the criteria used for advanciag compounds iato clinical trials (2) are discussed hereia, as are all of the dmgs approved by the United States Food and Dmg Administration (FDA) for the treatment of cancer as of this writing and those compounds ia clinical trials. 

Toxicity Amelioration. Cancer researchers traditionally have not focused their attention on the question of toxicity amehoration. This is partiy attributed to the lack of predictive animal models for human toxicities. For example, the preclinical rat model, used as a predictor of myelosuppression, has failed to predict myelosuppression in humans in clinical trials. In addition, reduction of one toxicity may result in the emergence of another, more serious problem. Research efforts to address the problem of toxicity amelioration has progressed in several directions. The three most prominent areas are analogue synthesis, chemoprotection, and dmg targeting. 

Drugs can only be effective if enough is present at the target site and they can be harmful if too much is present so as to produce toxic side effects. Any attempt to draw conclusions about the clinical efficacy of a drug in a clinical trial without knowledge of the concentration at the target site is premature. The science of pharmacokinetics basically... 

Leptin has proved to be an efficient treatment for the rare form of obesity associated with leptin deficiency. By contrast, the results of the fust clinical trial with human leptin in obese patients (without leptin deficiency) were less promising. This may be explained by leptin resistance in a high proportion of these patients. However, the mechanisms involved in the development of leptin resistance could become new drug targets. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Most of the PKIs currently in clinical trials are small molecules that compete for the ATP-binding site [3,5]. They prevent the phosphate donor ATP to bind to the protein kinase, and hence the target protein will not become phosphorylated and the perturbed signalling can be terminated. 

The antisense oligonucleotide LErafAON against the serine/threonine kinase c-Raf has been tested in phase I clinical trials. The antisense oligonucleotides ISIS-5132, which also inhibits c-Raf, and ISIS-3521, which inhibits PKC, went through different phase clinical trials with solid tumour patients. Unfortunately, no objective responses occurred with these PKI. GEM-231, an oligonucleotide targeting the RIa subunit of protein kinase A is currently undergoing phase I/II clinical trials alone or in combination with traditional therapy for the treatment of solid cancers [3]. 

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