Current Pharmacogenomics

ISSN: 1570-1603

Current Pharmacogenomics
Volume 4, Number 2, June 2006

Contents


Gene Therapy by Liver Transplantation and Single Stranded Oligonucleotides (SSOs) in Familial Amyloidotic Polyneuropathy (FAP) Pp. 79-85
Y. Ando and M. Nakamura
[Abstract]


Information of ADME-Associated Proteins and Potential Application for Pharmacogenetic Prediction of Drug Responses Pp. 87-103
C.J. Zheng, L.Y. Han, X. Chen, Z.W. Cao, J. Cui, H.H. Lin, H.L. Zhang, H. Li and Y.Z. Chen
[Abstract]


Pharmacogenetics, Target Molecules, and Biological Anti Rheumatic Drugs in Autoimmune/Chronic Inflammatory Rheumatic Diseases Pp. 105-111
G. Ferraccioli, B. Tolusso and M. De Santis
[Abstract]


Pharmacogenetic Aspects of Neuroleptic Malignant Syndrome Pp. 113-119
C. Kawanishi, I. Kishida, T. Furuno, D. Kato and L. Bertilsson
[Abstract]


Detection of Known Mutations with DNA Polymerases: Its Pharmacogenetic Applications Pp. 121-131
J. Zhang, C. Zhou, Y. Yin, L. Chen, J.R. Pardinas, T. Liu, H. Gao, J.-S. Saldivar and K. Li
[Abstract]


Genetic Variation at the Human MGMT Locus and its Biological Consequences Pp. 133-144
G.P. Margison, A.C. Povey and M. Santibáñez-Koref
[Abstract]


Fish Pharming: Identifying Gene Function and Therapeutic Targets Using Pharmacologic Treatment of Zebrafish Embryos Pp. 145-152
M. Kamkar, M.A. Steggles and C.C. Martin
[Abstract]


Clinical Importance of Calcium-Sensing Receptor Gene Polymorphism Arg⁹⁹⁹Gly in the Age of Calcimimetic Therapy
H. Rothe and G. Mayer
[Abstract]


Prospect of Individualized Medicine in Chronic Hepatitis C Therapy by Pharmacogenomics Pp. 157-167
Y. Hwang, C. Su, D.-S. Chen and P.-J. Chen
[Abstract]


Effect of Brain Derived Neurotrophic Factor (BDNF) Gene Variants on Therapeutic Response and the Risk for Schizophrenia Pp. 169-175
S.-J. Tsai and C.-J. Hong
[Abstract]




Abstracts

[Back to top]
Gene Therapy by Liver Transplantation and Single Stranded Oligonucleotides (SSOs) in Familial Amyloidotic Polyneuropathy (FAP)
Y. Ando and M. Nakamura

Liver transplantation has been considered as a promising therapy to halt the progression of clinical symptoms of progression in familial amyloidotic polyneuropathy (FAP) because most of transthyretin (TTR) is produced by the liver. In addition, domino liver transplantation using an FAP patient’s liver has been performed because of shortage of domor livers. However, the use of liver transplantation as therapy for familial amyloidotic polyneuropathy (FAP) has given rise to several problems, an alternative treatment is needed. We have tried several other approaches: To suppress production of variant transthyretin (TTR) in the liver, we injected purified normal human TTR into patients with FAP. Production of variant TTR levels decreased significantly for 48 h. However, 1 week after the injection, production returned to levels that were almost the same as those before injection. TTR has a rapid turnover, so this method cannot be used to suppress production of the harmful protein for an extended time. An RNA/DNA chimera and single-stranded oligonucleotides (SSOs) were tested in vitro and in vivo in an attempt to repair the amyloidogenic TTR gene in the liver and retina. On the basis of results achieved so far, SSOs is a promising tool for gene therapy.


[Back to top]
Information of ADME-Associated Proteins and Potential Application for Pharmacogenetic Prediction of Drug Responses
C.J. Zheng, L.Y. Han, X. Chen, Z.W. Cao, J. Cui, H.H. Lin, H.L. Zhang, H. Li and Y.Z. Chen

Pharmacogenetic prediction and mechanistic elucidation of individual variations of drug response is important for facilitating the development of personalized medicines and optimum therapeutic dosages. One of the keys to pharmacogenetic studies is the knowledge about proteins responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. This article describes the web-resources of ADME-associated proteins, assesses the usefulness of the relevant information for facilitating pharmacogenetic prediction of drug responses, and discusses computational methods that explore the relevant information for predicting individual variations of drug response from the polymorphisms of ADME-associated proteins.


[Back to top]
Pharmacogenetics, Target Molecules, and Biological Anti Rheumatic Drugs in Autoimmune/Chronic Inflammatory Rheumatic Diseases
G. Ferraccioli, B. Tolusso and M. De Santis

Autoimmune chronic rheumatic inflammatory diseases are polygenic illnesses in which the inflammatory process mainly occurs in the synovial tissue, surrounding the joints. Dozens of inflammatory genes are upregulated or downregulated in each rheumatic disease. The genes of several of the molecules synthesized are often polymorphic and some of these polymorphisms have clearly been shown to be functionally relevant. In recent years monoclonal antibodies directed against some of the molecular targets have been developed, the first ones being the monoclonals against a key driver of synovial inflammation namely tumor necrosis factor α, followed by interleukin 1β, then interleukin 6 receptor and others. According to the background, the clinical benefits could be either partially driven by the pathobiological milieu, or by the polymorphisms of the genes encoding the target molecules. In this article the complex heterogeneity of the inflammatory genes regulating key molecules, which are targets of the therapeutic intervention with specific monoclonal antibodies is reviewed, along with the crucial data that could be obtained also on the inflammatory process by the ongoing clinical trials in which pharmacogenetics is mandatory.


[Back to top]
Pharmacogenetic Aspects of Neuroleptic Malignant Syndrome
C. Kawanishi, I. Kishida, T. Furuno, D. Kato and L. Bertilsson

Neuroleptic malignant syndrome (NMS), a potentially life-threatening adverse reaction to neuroleptic drugs, is characterized by hyperthermia, extrapyramidal signs, altered consciousness, and autonomic disturbances. Even atypical antipsychotic drugs, considered to carry less risk of adverse reactions than conventional agents, nonetheless can cause NMS. While central dopaminergic pathways have been regarded as pivotal in NMS onset, mechanisms underlying NMS generally remain unclear -rendering prediction or prevention of NMS impossible.

Genetic factors predisposing to NMS have been suggested in addition to acquired risk factors, and recent progress in pharmacogenetics and pharmacogenomics permits molecular genetic investigation of adverse drug reactions. Case-control association studies of functional polymorphisms of the dopamine D2 receptor gene have suggested putative mutation sites and a haplotype possibly influencing susceptibility to NMS. Polymorphic alleles of cytochrome P450 2D6 that encode defective enzymes permitting accumulation of excessive plasma neuroleptic drug concentrations also have been examined in relation to NMS susceptibility. Several genes or polymorphisms may contribute to NMS occurrence to a certain extent. Additionally, NMS may represent multiple conditions with shared symptoms but different causative mechanisms. Genetic studies are difficult in NMS because of its low incidence. However, accumulation of genetic information correlated with clinical information for individual patients, as well as more extensive genetic studies, are needed for better understanding of NMS and safer psychopharmacotherapy.


[Back to top]
Detection of Known Mutations with DNA Polymerases: Its Pharmacogenetic Applications
J. Zhang, C. Zhou, Y. Yin, L. Chen, J.R. Pardinas, T. Liu, H. Gao, J.-S. Saldivar and K. Li

The changes in physical and chemical characteristics derived from genetic alteration are the basis for the development of mutation assays. Among the ever-increasing number of mutation assays available, most are variants of allele-specific primer extension targeting single nucleotide polymorphism (SNP) and point mutations. Conventional allele-specific primer extension was designed to work using exo- polymerases exclusively, regardless that the fidelity of DNA polymerases has been recognized for more than three decades depending on the presence of proofreading activity provided by its internal 3’ exonuclease. Recently, exo⁺ polymerase with proofreading activity has been applied in mutation detection. The application of proofreading activity by DNA polymerase with 3’ to 5’ exonuclease provides two significant advantages: elimination of false positives and applicability to both real-time PCR as well as microarray platforms. Technologically, the high fidelity DNA polymerases offer a variety of applications in genetic analyses, including mutation detection, high fidelity expression profiling, and de novo sequencing. Some of these applications can be immediately applied in pharmacogenetics studies, particularly in the filed of somatic Pharmacogenetics.


[Back to top]
Genetic Variation at the Human MGMT Locus and its Biological Consequences
G.P. Margison, A.C. Povey and M. Santibáñez-Koref

O⁶-alkylguanine-DNA alkyltransferase (MGMT) repairs DNA adducts that result from alkylation at the O⁶ position of guanine. These lesions are mutagenic and toxic and can be produced by a variety of agents ranging from carcinogens present in cigarette smoke to drugs used in cancer chemotherapy. There is a considerable amount of interindividual variation of MGMT activity and recent work has uncovered a series of polymorphisms that affect protein activity or are associated with differences in expression levels. On the other hand, current evidence for an association with cancer risk is tenuous: while some studies find such associations, others fail to support them. However, all published studies are based on small sample numbers. Not yet addressed are issues such as the relationship between sequence variation and the extent of the side effects of chemotherapy involving O⁶-alkylating agents. This review summarises the current state of knowledge in these areas.


[Back to top]
Fish Pharming: Identifying Gene Function and Therapeutic Targets Using Pharmacologic Treatment of Zebrafish Embryos
M. Kamkar, M.A. Steggles and C.C. Martin

One of the remaining challenges for the post-genomic era researcher is the systematic assignment of gene function to a sequenced genome. The zebrafish is an effective model organism for conducting comparative analyses of the human genome. The ability to obtain large numbers of zebrafish embryos, grow them in a 96-well dish, and then expose them to molecules dissolved in their water, underline the valuable characteristics of this organism that is currently being explored by academic and private researchers. This high throughput strategy is being applied to evaluate the specificity and the cellular toxicity of environmental toxins and new drug therapies. Similarly, small molecules, metabolic inhibitors, enzyme antagonist and agonist or receptor/ligand substitutes have been used to enhance our understanding of developmental and physiological pathways and gene cascades. These studies also introduce valuable systems that can be employed to investigate the pathologies that can occur when these pathways are disrupted. Pharmacologics act primarily at the post-translational level, the proteome. These results are further supported by comparative genomic studies using the numerous zebrafish mutants that are available or by targeted gene knockdowns using antisense morpholino oligonucleotides. The conservation of genetic mechanisms across a wide range of phyla ensures that the results obtained from fish can be directly transferred to humans.


[Back to top]
Clinical Importance of Calcium-Sensing Receptor Gene Polymorphism Arg ⁹⁹⁹Gly in the Age of Calcimimetic Therapy
H. Rothe and G. Mayer

Cinacalcet HCl is the first calcimimetic agent available for the therapy of secondary hyperparathyroidism (sHPT) and palliative treatment of parathyroid carcinoma. It acts on the extracellular calcium-sensing receptor (CaSR) as an allosteric activator, i.e. it leads to responses as if hypercalcaemia was present, in the face of normal or even low serum calcium levels. Its most important effect is the suppression of PTH secretion from the parathyroid chief cells.

A reduction of PTH levels by 30-40% could be achieved in about 70% of patients with sHPT and maintained for at least two years in clinical studies. Doses required to meet the treatment goal range from 30mg to 180mg per day. There is evidence that one reason for the variability in the response to cinacalcet is a polymorphism (Arg ⁹⁹⁹Gly) in the intracellular tail of the CaSR molecule. It is one of three SNP’s in exon 7 of the CaSR gene, the other two being Ala ⁹⁸⁶Ser and Glu ¹⁰¹¹Gln. Arg ⁹⁹⁰Gly CaSR molecules (with glycine in position 990) appear to be more sensitive to cinacalcet HCl than those with arginine in this position. They are also more sensitive to calcium ions and therefore, more effective than the arginine variant in suppressing PTH secretion at hypercalcaemic levels. In primary hyperparathyroidism, the presence of Arg⁹⁹⁰Gly leads to less severe clinical courses.


[Back to top]
Prospect of Individualized Medicine in Chronic Hepatitis C Therapy by Pharmacogenomics
Y. Hwang, C. Su, D.-S. Chen and P.-J. Chen

Interferon-α and ribavirin combination therapy has been the current choice for treating chronic hepatitis C (CHC) patients. The treatment takes 6 to 12 months but the overall sustained response rate is only around 50% and often brings significant adverse effects to some patients. The treatment outcome has been shown to be associated with various viral factors, such as viral loads before and during treatment and, most importantly, viral genotypes and quasispecies. Host factors that may affect drug response include age, gender, ethnicity, HLA alleles and stage of liver fibrosis. Recent studies have further indicated an association between patients’ genotypes and their treatment efficacy.

In this review article, we evaluate and summarize factors that may contribute to the treatment outcome of CHC. The content is divided into four categories: 1. viral factors: viral load, viral genotype and early viral response; 2. general host factors: gender, age, treatment period/dosage and kinds of IFN; 3. host genetic polymorphisms, particularly single nucleotide polymorphism (SNP) association studies; and 4. gene expression profiles in hepatitis C liver tissues.

In summary, recent advances in pharmacogenomics have demonstrated the potential applications of genetic polymorphisms and expression patterns in determining treatment responsiveness in chronic hepatitis C. By combining both human and viral genotypes and their expression, it becomes plausible to satisfactorily assess the clinical outcomes prior to interferon combination treatment for CHC patients.


[Back to top]
Effect of Brain Derived Neurotrophic Factor (BDNF) Gene Variants on Therapeutic Response and the Risk for Schizophrenia
S.-J. Tsai and C.-J. Hong

Early maldevelopment of brain tissue has been postulated as a crucial factor in the pathogenesis of schizophrenia. The neurotrophin brain-derived neurotrophic factor (BDNF) is widely and abundantly expressed in mammalian brain. BDNF plays important role in the development of brain and has critical effects on the differentiation of monoaminergic neurons. In rodents, antipsychotic treatments have been shown to alter the expression of brain BDNF. Furthermore, schizophrenia is associated with a decrease in central as well as peripheral BDNF protein concentration. Thus, in light of this evidence, the BDNF gene is considered as an attractive candidate gene for predicting schizophrenia or antipsychotic therapeutic response. In this review, we summarize the investigations of BDNF levels and the BDNF genetic effects on therapeutic response and the risk for schizophrenia, proposing several recommendations for future genetic studies of BDNF signaling pathways in schizophrenia.