Pharmakogenomik/Pharmakogenetik - Implikationen für die Behandlung neurologischer Erkrankungen

Zusammenfassung

Mit zunehmender Entzifferung des menschlichen Genoms und erweiterten Kenntnissen genetischer Informationen hat das Wissen um die genetischen Grundlagen krankheitsspezifischer Phänotypen in der Forschung, Diagnostik und Therapie erheblich zugenommen. Ebenso werden die bestehenden pharmakologischen Prinzipien durch neue Daten hinsichtlich der genetischen Einflüsse auf die Haupt- und Nebeneffekte medikamentöser Therapien ergänzt. Auch in der Behandlung neurologischer Krankheiten nimmt die Relevanz der Pharmakogenetik bzw. -genomik auf Basis eines erweiterten Verständnisses der Pathomechanismen von Krankheiten wie z. B. der Migräne und neurodegenerativer Erkrankungen (Morbus Parkinson, amyotrophe Lateralsklerose, Morbus Alzheimer) stetig zu. Die folgende Übersicht fasst das bestehende Wissen um die genetischen Grundlagen der pharmakologischen Therapieansätze ausgewählter neurologischer Erkrankungen zusammen und versucht einen Ausblick auf zukünftige Entwicklungen in diesem Gebiet zu geben.

Abstract

Increasing knowledge of the human genome regarding the genetic basis of diseases has provided more specific information regarding research, diagnostics and drug-therapy. Pharmacological principles with respect to genetic influences on drug effects and adverse events have been supplemented by recent genetic data. This is true for the treatment of neurological diseases, taking pharmacogenetics/pharmacogenomics into account based on the extended knowledge of the pathomechanism of migraine, and neurodegenerative diseases (Parkinson's disease, amyotrophic lateral sclerosis or Alzheimer's disease). This review summarizes current knowledge on selected neurologic diseases and discusses an outlook to future perspectives of this field.

Literatur

• 1 Lazarou J, Pomeranz B H, Corey P N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.  J Am Med Assoc. 1998;  279 1200-1205
• 2 Goettler M, Schneeweiss S, Hasford J. Adverse drug reaction monitoring - cost and benefit considerations. Preventability of adverse drug reactions leading to hospital admissions.  Pharmacoepidem Drug Safety. 1997;  6 (S3) S79-S90
• 3 Evans W E, Relling M V. Pharmacogenomics: translating functional genomics into rational therapeutics.  Science. 1999;  286 487-491
• 4 Martin E R, Scott W K, Nance M A. et al . Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.  JAMA. 2001;  286 2245-2250
• 5 Gasser T. Genetics of Parkinson's disease.  J Neurol. 2001;  248 833-840
• 6 Mouradian M M. Recent advances in the genetics and pathogenesis of Parkinson's disease.  Neurology. 2002;  58 179-185
• 7 Scott W K, Nance M A, Watts R L. et al . Complete genomic screen in Parkinson disease: evidence for multiple genes.  JAMA. 2001;  286 2239-2244
• 8 Tan E K, Khajavi M, Thronby J I. et al . Variability and validity of polymorphism association studies in Parkinson's disease.  Neurology. 2000;  55 533-538
• 9 Swerdlow R H, Parks J K, Miller S W. et al . Origin and functional consequences of the complex I defect in Parkinson's disease.  Ann Neurol. 1996;  40 663-671
• 10 Maimone D, Dominici R, Grimaldi L ME. Pharmacogenomics of neurodegenerative diseases.  Eur J Pharm. 2001;  413 11-29
• 11 Williams T L, Day N C, Ince P G. et al . Ca²⁺-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis.  Ann Neurol. 1997;  42 200-207
• 12 Takuma H, Kwak S, Yoshizawa T, Kanazawa I. Reduction of Glu2R RNA editing, a molecular change that increases Ca²⁺ influx through AMPA receptors, selective in the spinal ventral grey of patients with amyotrophic lateral sclerosis.  Ann Neurol. 1999;  46 806-815
• 13 Bensimon G, Lacomlez L, Meininger V. et al . For the ALS/Riluzole study group. A controlled trial of riluzole in amyotrophic lateral sclerosis.  New Engl J Med. 1994;  330 585-591
• 14 Selkoe D J. Translating cell biology into therapeutic advances in Alzheimer's disease.  Nature. 1999;  399 A23-A31
• 15 Rosenberg R N. The molecular and genetic basis of Alzheimer's disease: the end of the beginning.  Neurology. 2000;  54 2045-2054
• 16 Schenk D, Barbour R, Dunn W. et al . Immunization with amyloid β attenuates Alzheimer-disease-like pathology in the Parkinson's disease amyloid precursor protein mouse.  Nature. 1999;  400 173-177
• 17 Bard F, Cannon C, Barbour R. et al . Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse modell of Alzheimer disease.  Nat Med. 2000;  6 916-919
• 18 Saunders A M. Gene identification in Alzheimer's disease.  Pharmacogenomics. 2001;  2 239-249
• 19 Saunders A M, Trowers M K, Shimkets R A. et al . The role of apolipoprotein E in Alzheimer's disease: pharmacogenomic target selection.  Biochim Biophys Acta. 2000;  1502 85-94
• 20 Cacabelos R, Alvarez A, Fernandez-Novoa L, Lombardi V RM. A pharmacogenomic approach to Alzheimer's disease.  Acta Neurol Scan. 2000;  S176 12-19
• 21 Poirier J, Delisle M C, Quirion R. et al . Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment in Alzheimer's disease.  Proc Natl Acad Sci USA. 1995;  92 12260-12264
• 22 Goadsby P J, Lipton R B, Ferrari M D. Migraine - current understanding and treatment.  N Engl J Med. 2002;  346 257-270
• 23 Ophoff R A, Van den Maagdenberg A MJM, Roon K I. et al . The impact of pharmacogenomics for migraine.  Eur J Pharm. 2001;  413 1-10
• 24 Cannon S C. Voltage-gated ion channelopathies of the nervous system.  Clin Neurosci Res. 2001;  1 104-117
• 25 May A, Ophoff R A, Terwindt G M. et al . Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura.  Hum Genet. 1995;  96 604-608
• 26 Peroutka S J, Price S C, Wilhoit T L, Jones K W. Comorbid migraine with aura, anxiety and depression is associated with dopamine D2 receptor (DRD2) Nco I allels.  Mol Med. 1998;  4 14-21
• 27 Glover V, Littlewood J, Sandler M. et al . Biochemical predisposition to dietary migraine: the role of phenolsulfotransferase.  Headache. 1983;  23 53-58
• 28 Genomic Neurology.  Arch Neurol. 2001;  58 1739-1918