Treatment of Genetic Diseases Flashcards
Coenzyme supplementation
- ex: homocystinuria
- apoenzyme binds to the coenzyme to form the vitamin”active enzyme”
- cystathione B-synthase + large dose of VitB6 (pyridoxine) will improve condition of Homocystinuria
Dietary restriction of substrate
- ex: PKU “defic of Phe hydroxylase”
- Tx of PKU-I: restriction of phe in diet, low phe diet (supplement w/ Tyr), doses of BH4 (sapropterin) in some pts, PAH enzymeRT.
- Tx for PKU-II: prognosis is worse, BH4 needed in brain for catecholamine synthesis. Challenge: BH4 supplement doesn’t cross BBB
- Urea cycle disorder: dietary restriction and chemical diversion.
- high level of NH3 causes neurological probs.
- maintain a low protein diet.
- Administration of sodium benzoate diverts NH3 to glycine synthesis and is excreted as hippurate.
Hemophilia A
-tx w/ F8 replacement therapy is effective (direct injection of F8, Cryoprecipitate/F8).
Polyethylene glycol derivatization: PEGylation
- attaching a PEG group to a protein.
- may protect protein from rapid degradation by increasing 1/2 life.
- reduce clearance by kidney
- reduce the chance of immune response
AR SCID Tx
- ADA defic
- BM transplant (HLA matched pt)
- Protein RT
- Gene therapy
- PEG-ADA is superior to unmodified ADA in restoring immune function.
Gaucher disease
- treated w/ ERT PEGylation of recombinant B-glucocerebrosidase protein which improves Hb levels.
- PEG-B-glucocerebrosidase target to macrophage lysosomes.
- exposure of mannose residue allows lysosomal uptake.
Signal transduction pathway
- HER2 Abs: Herceptin inhibits growth signal of Her2+
- CML: Philadelphia chrom; Imanitib mesylate “Tyr kinase inhibitor”
Epigenetic modifications
- HbF inducers used in HbS
- Drugs that increase expression of fetal globins (y) are 5-azacytidine (Decitabine; demethylating agent), Hydroxyurea, Butyrate compounds (inhibit histone deacetylation).These drug based interventions alter epigenetic generegulatory mechanisms.
Gene Therapy
- providing a gene function to pt suffering from a genetic disorder in order to counteract the effects of a non-functional one.
- can only be done on somatic tissue
- appropriate for gene therapy: disorders of single gene defect, affected tissue accessible for gene delivery and disorders for which genes are identified and cloned.
In Vivo and Ex Vivo therapy
-In Vivo: attempts to get genetically modified cells directly into pt. Not limited to stem cells. ex: X-SCID, CFTR
- Ex Vivo: remove of pts cell -> gene transfer of cloned gene -> culture cells _> select cells w/ cloned gene -> return back to pt
- may use stem cells or differentiated cells. ex: tx of fibroblast from pt w/ Hemophilia B
Gene therapy delivery systems
- able to target correct cell type
- effective at getting gene into number of cells
- able to get gene into nucleus where it can be expressed
Delivery methods
- Adenovirus (able to get to nucleus and genetic material exists as separate entity)
- Retrovirus (insert genetic materia into the genome)
- DNA approaches as liposome (fatty shell; can fuse w/ phospolipid layer of cells
Problem w/ Gene therapy
- Immune response: example; pt died after receiving OTC gene
- Tumor formation: pts developed leukemia after gene therapy for X-SCIDS
- temporary fixes problem
- Phenotoxicity: from overexpression of transgene
- Immunotoxicity
- horizontal transmission: vector becomes infectious and enters envir
- vertical transmission: germline transmission
Gendicine
- uses an adenovirus as a vector for p53.
- virus injected into tumor, reinstating endogenous production of p53 from cell that lost it during cancer progression
- will not integrate into human host cell genome
Embryonic stem cells
- derived from the inner cell mass form all the somatic and germ tissue of fetus.
- cultured stem cells can be driven to form any tissue type
Induced pluripotent stem cells (iPSCs)
- -mature cells can be reprogrammed to become pluripotent (an embryonic stem cell-like state)
- differentiated cells reverted back to undifferentiated state
RNA
Primary microRNA transriptis processed into small interfering RNA (siRNA) species which are able to regulate mRNA stability or translation.
-siRNA binds to mRNA for regulation either destruction or translational silencing. “anti-sense therapy”
-miRNA involved in regulation of cell prolif. It acts to reduce exp of genes by targeting specific mRNAs.
