Pomb Genetic Therapy

Genetic therapy

• Gene therapy: treatment that involves the transfer of genetic material into cells of organism to treat disease or mark cell populations.
- currently only somatic changes are considered so modification does not pass to future generation
- intensely regulated field due to risk of genome manipulation
• Diseases treated with gene therapy:
- Immunodeficiencies
- Cystic fibrosis
- Familial hypercholesterolaemia
- Haemophilias (deficient in clotting factor VIII)
- Sickle cell and beta thalassaemia
- Cancer (lymphoma)
- Vascular disease
- Neurological disorder (Parkinson’s disease)
• Criteria of gene therapy disease:
- Life threatening condition with no effective treatment
- Single gene causality and has been cloned
- Regulation of gene not needed to be precise
- Technical problems of gene delivery and expression resolvable
• Gene delivery strategies: ex vivo involves removal of gene from cell, changed in labs and returned to patients while in vivo requires direct targeting to correct cells
- Physical: electroporation (shocking the cell to absorb nucleus), microinjection (micropipette the material), lipofection (liposome fusion)
- Viral: retrovirus, adeno-associated virus, lentivirus, adenovirus, HSV-1 (virus integrate modified genes into the host genome)
• Target cells:
- Haemopoietic stem cells
- Lymphocytes
- Respiratory epithelium
- Hepatocytes
- Fibroblast skin cells
- Skeletal muscles
• Benefit of recombinant pharmaceutical:
- Produced by expression cloning in micro-organisms/mammalian cell lines or in transgenic livestock
- Large amount of protein generated
- Reduced risk of pathogen contamination such as HIV and Hep C for treatment of haemophilia
- Avoid side-effects/immunogenicity of closely related but not identical animal protein
• Examples of recombinant protein:
- Factor VIII and IX for haemophilia A and B
- Insulin for diabetes
- Growth hormone for GH deficiency
- Erythropoietin for anaemia
- Granulocyte colony-stimulating factor for neutropenia
- Tissue plasminogen activator for thrombotic disorders
- Interferon in leukaemia and chronic hepatitis
• Genetically engineered antibodies: artificially produced therapeutic antibodies designed to recognize specific disease-associated antigens, leading to killing of disease cells.
- Monoclonal antibodies made in animal have limited use due to production of unwanted immune response in patients
- Generation of human monoclonal antibodies is difficult
- Design of artificial combination of immunoglobulin segments to clone
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Stem Cells and Regenerative Medicine

• Developmental genetics: the study that examines the genetic processes in which one embryo give rise to an entire organism.
- Processes such as proliferation are recapitulated in adult life and are the cause of diseases such as cancer
- Understand normal development is important to design treatment for human birth defects
• Stem cells: self-renewing progenitor cells that can generate one or more specialized cell types
- Embryonic stem cells: derived from inner cell mass of blastocyst and have the capacity to differentiate into all cell type in body (pluripotent)
- Adult stem cells: produce cells of only one lineage
• Embryonic stem cells:
- A mouse model: ES cells from mice with mutations (knocked out genes) are extracted and a gene construct is introduced into the endogenous gene locus. The modified cells are then reintroduced into the developing blastocysts and contribute to the rest of the body
• Human therapeutic cloning:
- Somatic cell from the patient is biopsied and the nucleus transferred to an enucleated donor oocyte
- The embryonic stem cells are then cultured on specific mediums to induce development into different cells.
- These include pancreatic islet, haematopoietic, neural cells etc which are all immunologically compatible with the patient
- Tissues are transplanted back into the patients
- Potential benefits: new neuron for Parkinson’s disease, learning molecular events that drive tumour
• Adult stem cells: plasticity of the stem cells is an important interest. Ability of the cells to cross-differentiate lineages can widen the clinical utility.
- With MI, blood stem cells may be introduced through a catheter to form cardiomyocytes and contribute to vascular tissue
• Advantage of Zebrafish study:
- Optical clarity
- Development of body within 24 hours
- High fecundity
- Short generation time
- Maintained at high density

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