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Organelle Involvement
Almost every cell organelle has been involved in the genesis of various diseases
Genetic Diseases
Many disease are determined genetically
Three major classes: (1) chromosomal disorders, (2) monogenic disorders (classic Mendelian), and (3) multifactorial disorders (product of multiple genetic and environmental factors)
Genetic Diseases
Polygenic denotes disorder caused by multiple genetic factors independently of environmental influences Somatic disorders - mutations occur in somatic cells (as in many types of cancer) Mitochondrial disorders - due to mutations in mitochondrial genome
Chromosomal Disorders
Excess or loss of chromosomes, deletion of part of a chromosome, or translocation
e.g., Trisomy 21 (Down syndrome)
Recognized by analysis of karyotype (chromosomal pattern) of individual (if alterations are large enough to be visualized) Translocations important in activating oncogenes
e.g., Philadelphia chromosome - bcr/abl)
Monogenic Disorders
Involve single mutant genes Classification: (1) autosomal dominant - clinically evident if one chromosome affected (heterozygote)
e.g., Familial hypercholesterolemia
Multifactorial Disorders
Interplay of number of genes and environmental factors
pattern of inheritance does not conform to classic Mendelian genetic principles due to complex genetics, harder to identify affected genes; thus, less is known about this category of disease e.g., Essential hypertension
If structural gene for noncatalytic protein affected by mutation can have serious pathologic consequences (e.g., hemoglobin S)
Ethical Issues
Once genetic defect identified, no treatment options may be available
Will patients want to know? Is prenatal screening appropriate? Will identification of disease gene affect insurability?
e.g., Hungtingtons disease - mutation due to trinucleotide (CAG) repeat expansion (microsatellite instability)
normal individual (10 to 30 repeats) affected individual (38 to 120) - increasing length of polyglutamine extension appears to correlate with toxicity
Molecular Medicine
Knowledge of human genome will aid in the development of molecular diagnostics, gene therapy, and drug therapy
Gene Therapy
Only somatic gene therapy is permissible in humans at present Three theoretical types of gene therapy
replacement - mutant gene removed and replace with a normal gene correction - mutated area of affected gene would be corrected and remainder left unchanged augmentation - introduction of foreign genetic material into cell to compensate for defective product of mutant gene (only gene therapy currently available)
Gene Therapy
Three major routes of delivery of genes into humans
(1) retroviruses
foreign gene integrates at random sites on chromosomes, may interrupt (insertional mutagenesis) the expression of host cell genes replication-deficient recipient cells must be actively growing for integration into genome usually performed ex vivo
Gene Therapy
(2) adenoviruses
replication-deficient does not integrate into host cell genome disadvantage: expression of transgene gradually declines requiring additional treatments (may develop immune response to vector) treatment in vivo, vector can be introduced into upper respiratory tract in aerosolized form
Gene Therapy
Conclusions based on recent gene therapy trials
gene therapy is feasible (i.e., evidence for expression of transgene, and transient improvements in clinical condition in some cases so far it has proved safe (only inflammatory or immune reactions directed toward vector or some aspect of administration method rather than toward transgene no genetic disease cured by this method major problem is efficacy, levels of transgene product expression often low or transient
Genetic Medicines
Antisense oligonucleotides
complementary to specific mRNA sequence block translation or promote nuclease degradation of mRNA, thereby inhibit synthesis of protein products of specific genes e.g., block HIV-1 replication by targeting gag gene