15 - March 7, 2013.docx

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Molecular Genetics and Microbiology
Johanna Rommens

March 7, 2013 Gene therapy – from last day continued Duchenne – large number of exons – exons in frame – if skip over exon, maintain polypeptide in frame – alleviate point of mutation – in that scenario, directly gene based option but in most diseases, do not always have that situation where able to devise a mutation-specific Strategies and examples of cancer gene therapy Currently most investigation with respect to gene therapy – so for example, Cancer tumour – whether clonal or not? Gene therapy trials – changed over the last decade Use for genetic disease – become more applied Despite all promise of gene therapy, clogged up in phase trials – most in phase 1, not looking at efficacy Correct endogenous genes – Zinc finger nucleases – ZFN – engineered products – take advantage of proteins that are able to bind to DNA – simply incorporate some type of restriction enzyme with zinc finger – giving dual requirement for specificity – cleave in middle – induce double-stranded breaks in DNA and with various repair processes that exist in cells, use those to exploit idea to repair Make double strand break, introduce wild-type sequence, repair by recombination – theoretically BUT side effects due to multiple repair mechanisms in some cells TALENS uses the same idea of zinc fingers except the component used to bind to protein works on different principal – type of enzyme that cleaves DNA and some domains of proteins that recognize specific DNA – one advantage of TALENS: can be more diverse in the binding site – wider potential for TALENS than zinc fingers nuclease Correcting mutation with respect to genetic disease – get ribozymes to not only edit but change sequence – exploit for therapy – ex., viruses can edit and change RNA MARCH 7 LECTURE Last day was about gene therapy Gene-BASED therapy for today Ex. Insulin from animals – successful Recombinant proteins Neutropenia – concern about causing leukemia Careful use – giving artificial dose – do not always know what arises from the dose Other types of therapy – slick and cool monoclonal type antibodies – intrabodies – derivatives of antibodies – Only work if there is amplification of this gene Antibodies and small molecule based – continued If knows structure and thinks about biology of disease – target various kinds of situations – can block HIV infection by knowing the receptor Gleevec – treats CML – leukemia patients have translocation – this forms fusion protein that now acquires – protein is fusion product so gain of function Gleevec is antibody designed against fusion protein – it is very effective Gene-based so potential to be specific to the gene of interest Alternate ways to treat patients – if know there is defect in metabolic pathway and appreciate what the outcome and steps are to generate the metabolite, way to alleviate symptoms – ex. Dietery treatment in PKU – the problem in this disease is processing of phenylalanine – the problem that cuases toxicity – brain is particularly sensitive – but if restrict diet with protein supplements – can alleviate tremendously the side effects – treatment – suspected PKU can start diet in utero – tremendously useful – Or alternate pathway – for a lot of metabolic pathways there are side pathways – may exploit them Lack of vitamin B – use high dose – can get some through due to neighbouring or related pathways Still need to know the metabolic pathway that is needed to develop/sort out best route for particular pathology In contrast to idea of gene-based therapy, there is basis for thinking of genes
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