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Gene Therapy and it’s application in Cancer, HIV and Hereditary diseases BY: Md. Monirul Islam Pharmacy Discipline Khulna University Khulna.

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Page 1: Gene theapy

Gene Therapy and it’s application

in Cancer, HIV and Hereditary

diseasesBY:Md. Monirul IslamPharmacy DisciplineKhulna UniversityKhulna.

Page 2: Gene theapy

Gene Therapy An Overview

Background

Gene therapy is “the use of genes as medicine”. It involves the

transfer of a therapeutic or correct gene into specific cells of an

individual in order to repair a faulty gene.

1980• Advances in sequence & cloning of human gene.

1990• Ashanti De Silva, 4 yrs, treated for SCID.

1999• Death of Jesse Gelsinger in a gene-therapy experiment

Current Status

Research is still ongoing. Although no gene therapies have been

approved by the FDA for sale, some diseases have been

experimentally successful:

– Melanoma , SCID, Hereditary Blindness, Sickle Cell Anemia

Page 3: Gene theapy

How does gene therapy work?

A vector delivers the therapeutic gene into a patient’s target cell

The target cells become infected with the viral vector

The vector’s genetic material is inserted into the target cell

Functional proteins are created from therapeutic gene causing cell to return to a normal state

Page 4: Gene theapy

Gene Therapy For CancerWhat is cancer?

Cancer, known medically as a malignant neoplasm, is a broad group of various

diseases, all involving unregulated cell growth.

Gene therapy is the latest and a new approach for cancer treatment.

Chemotherapy for cancer patients often kills healthy cells as well as cancer cells.

Gene Therapy VS Chemotherapy

Page 5: Gene theapy

Gene Therapy For Cancer (contd…)

Strategies

Enhancing the immunogenicity of the tumor.

Enhancing immune cells to increase anti-tumor activity.

Inserting a "sensitivity" or suicide' gene into the tumor.

Blocking the expression of oncogenes.

Inserting a wild-type tumor suppressor gene.

Protecting stem cells from the toxic effects of chemotherapy.

Blocking mechanisms which tumors evade immunological destruction

Killing tumor cells by inserting toxin genes under the control of a tumor-specific promoter,

Page 6: Gene theapy

Cytokine Genes

Introduction of genes encoding for proinflammatory

cytokines e.g. IL-12 and IFN-g:

– Induce local inflammation– Tumor destruction– Induction of cell mediated immunity

Gene Therapy For Cancer (contd…)

Prominent Strategies

Suicide Genes

HSV-tk– Phosphorylation of Ganciclovir– Bystander effect

*HSV-tk: Herpes simplex virus- thymidine kinase

Page 7: Gene theapy

Introduction of p53 gene:

– Usually mutated in most

cancers

– Antioncogene

Introduction of MDR-I gene in HSC:

– Increases HSC tolerance to

chemotherapy

– Allows more aggressive treatment

Gene Therapy For Cancer (contd…)

Prominent Strategies (continued)

Tumor Suppressor Genes

Protection of HSC* *HSC: Hematopoietic Stem Cells

Page 8: Gene theapy

Gene Therapy For Cancer (contd…)

Other Strategies

- by inserting toxic genes that encodes diphtheria A chain.

Enhanching immunogenecity

- by introducing genes that encode foreign antigens.

Blocking expression of oncogenes

- by introducing the gene that encodes antisense K-RAS message.

Blocking mechanisms by which tumors evade immunological destruction

- by introducing the gene that encodes antisense IGF-1 message.

Killing tumor cells

Page 9: Gene theapy

Gene Therapy For AIDSHuman immuno deficiency virus (HIV) is a lentivirus (a member of the retrovirus

family) that causes acquired immuno deficiency syndrome (AIDS), a condition in

humans in which progressive failure of the immune system allows life-threatening

opportunistic infections and cancers to thrive.

HIV

Contains two strands of (+) ssRNA.

Contains reverse transcriptase & integrase.

Integrase helps in the insertion of HIV DNA into host DNA.

Infects helper T cells and macrophages.

Page 10: Gene theapy

Gene Therapy For AIDS (contd…)

Gene therapy could be used to make immune cells resistant to HIV (the AIDS

virus). It could also be used to help patients destroy HIV and HIV-infected cells by

increasing the body's immune response to these elements.

Intracellular immunization

Ribozymes

Transdominant mutant

Trojan horse

Strategies

Page 11: Gene theapy

Gene Therapy For AIDS (contd…)

Details about Strategies

Intracellular immunization

An antibody is produced intracellulary by genetic engineering to make the

engineered cells resistant to viral infection.

Ribozymes

These are RNA molecules that contain antisense sequence for specific

recognition and a RNA-cleaing enzymatic activity.

Transdominant mutant

These are proteins that have altered amino acid that render the mutant

protein capable of disrupting the functions of the wild-type protein.

Trojan horse

This is an anti-HIV RNA that contains an HIV-packaging signal coupled to an anti-HIV nucleic acid.

Page 12: Gene theapy

Gene Therapy For Hereditary Diseases

Common Hereditary diseases

A hereditary disease is an illness caused by one or more abnormalities in the genome,

especially a condition that is present from birth (congenital). Most genetic disorders are quite

rare and affect one person in every several thousands or millions.

Single gene inheritance Multifactorial inheritance

Chromosome abnormalities

Mitochondrial inheritance

•Cystic fibrosis, •Sickle cell anemia, •Marfan syndrome, •Huntington's disease•hemochromatosis.

Heart disease, high blood pressure, Alzheimer's disease, Arthritis DiabetesCancer, and Obesity.

Turner syndrome (45,X),Klinefelter syndrome (47, XXY)

Eye disease called Leber's hereditary optic atrophy; a type of epilepsy called MERRF and a form of dementia called MELAS

Page 13: Gene theapy

Gene Therapy For Hereditary Diseases (contd…)

SCID affected children are born without an effective immune system. The

therapeutic gene called ADA was introduced into the bone marrow cells of such

patients in the laboratory, followed by transplantation of the genetically corrected

cells back to the same patients. 

Severe combined Immune Deficiency

Chronic Granulomatus Disease (CGD)

CGD leads to the patients' inability to fight off bacterial and fungal infections that

can be fatal. Using similar technologies as in the ADA-SCID trial, investigators in

Germany treated two patients with this disease.

Page 14: Gene theapy

Gene Therapy For Hereditary Diseases (contd…)

Hemophilia

Patients born with Hemophilia are not able to induce blood clots. The therapeutic

gene was introduced into the liver of patients, who then acquired the ability to have

normal blood clotting time.

Other Genetic Disorders

After many years of laboratory and preclinical research in appropriate animal models

of disease, a number of clinical trials will soon be launched for various genetic

disorders that include congenital blindness, lysosomal storage disease and muscular

dystrophy, among others.

Diabetes

Insulin gene therapy will be considered as including any approach that involves the

introduction of a foreign gene into any cell type in the body, allowing it to produce

insulin.