gene therapy - a novel approch in medical treatment
TRANSCRIPT
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Gene Therapy
Department of Pharmacology; GCTS 1
By – Subhajit Hazra (1st Year, 1st Semester)
Roll no- 03 Department of Pharmacology
(Masters of Pharmacy) Gupta College of Technological Sciences (GCTS); Asansol
Guided By –
Mr. Avik Das; MS (US) Gupta College of Technological Sciences (GCTS); Asansol
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After discussion we would be able to appreciate :
The Basic Concept of Gene Therapy
The Central Dogma
Barrier to Gene Therapy and its resolution
Types of Vectors
Concept of RNA Virus Vectors
Concept of DNA Virus Vectors
Other Vectors
Clinical Trials of Gene Therapy
Conclusion
Department of Pharmacology; GCTS 2
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Introduction to the Gene Therapy and its Basic Concept
Gene therapy Experimental technique
Uses Gene to cure diseases
Thus the basic concept of gene therapy is :
To introduce into target cells a piece of genetic material that will result in either a cure for the
disease or a slowdown in the progression of the disease.
Department of Pharmacology; GCTS 3
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4Department of Pharmacology; GCTS4
The “Central Dogma”
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Central Dogma of Molecular Biology :
Replacing a mutated gene that causes disease with a healthy copy of the gene.
Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
Introducing a new gene into the body to help fight a disease.
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“Carrier” – The Primary Stumble
One of the biggest stumbling blocks to successful widespread
application of such genetic treatments is the development of
safe and effective vectors with which to ferry genetic material
into a cell.
Department of Pharmacology; GCTS 5
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Features of an “Ideal Carrier Vector”
The important attributes of an ideal vector are –
Efficient and easy production
Safety aspects
Sustained and regulated transgene expression
Targeting of the viral vectors and Site-specific integration
Department of Pharmacology; GCTS 6
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Types of VectorsVectors are of 2 types – viz : * A Viral Vector * A Non-Viral
Vector
Department of Pharmacology; GCTS 7
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Viral Vectors Viral Vectors : The basic concept of viral vectors is to harness
the innate ability of viruses to deliver genetic material into the infected cell.
Types of Viral Vectors :
RNA Virus Vector
DNA Virus Vectors
Department of Pharmacology; GCTS 8
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Basic Principle of Viral Vector Design
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Fig 1 - (a) Converting a virus into a recombinant vector. (b) The packaging and vector constructs are introduced into the packaging cell by transfection.Both “Packaging Constructs” and “Vector Constructs” express their particular proteins. These expressed proteins are the n encapsulated in into virus particles to generate the recombinant viral vector.
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RNA Virus VectorsThe viral RNA contains three essential genes, gag, pol, and env, and
is flanked by long terminal repeats (LTR)
The gag gene encodes for the core proteinscapsid, matrix, and nucleocapsid, which are generated by proteolytic
cleavage of the gag precursor protein.
The pol gene encodes for the viral enzymes protease,reverse transcriptase, and integrase, which are usually derived from
the gag-pol precursor.
The env gene encodes for the envelope glycoproteins, which mediatevirus entry.
Department of Pharmacology; GCTS 10
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RNA Virus Vectors (Cont.)
Department of Pharmacology; GCTS 11
Fig 2 - The colored boxes indicate genes elements that are eitheressential [and therefore retained in vectors (red) or supplied by packaging constructs or cell lines (green)] or that are nonessential and often deleted
(blue).
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DNA Virus VectorsThe currently prominent DNA virus vectors are :
Adeno-associated viruses (AAV) and Adenoviruses.
Adeno-associated viruses (AAVs) contain a single stranded, relatively small (»4.7 kb) genome.
Adenoviruses contain a double-stranded DNA genome .
The basic principals of vector design same as that of RNA virus vectors.
Department of Pharmacology; GCTS 12
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AdenovirusesAdenoviruses are medium-sized DNA
viruses and have been isolated from avian and mammalian species.
The human adenovirus (Ad) family consists
of more than 50 serotypes that can infect and replicate in a wide range of organs.
Department of Pharmacology; GCTS 13
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Types of Adenoviruses Generation of Adenoviruses
Gene/s Targeted Modification Implications
First Generation E1 Viral replication and activation of the
expression of other Ad transcription units
prevented.
Up to 3.2 kb of the E1 region of the viral
vector can be replaced
by trans-genes. Second Generation E2 and/or E4 Viral replication
Prevented (E2). Viral replication as
well as protein synthesis prevented
(E4)
Toxicity of E2 gene expressed protein
prevented. E4 - Viral DNA replication andlate protein synthesis
prevented Third Generation - Development
of high-capacity, helper-dependent
vector
Activity regulation Possible
Department of Pharmacology; GCTS 14
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Adeno-Associated Viruses (AAV)
Adeno-associated viruses are nonpathogenic viruses. They contain a
single stranded DNA genome of only 4.7 kb.
Department of Pharmacology; GCTS 15
AAV requires co-infection with of helper viruses for efficient, site-specific integration. It binds to human chromosome 19, a highly desirable feature of a gene therapy vector .
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Other VectorsVectors derived from Herpes Simplex
Viruses (HSVs) are among the most promising because of the size and
complexity of its »150-kb genome.
Department of Pharmacology; GCTS 16
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Clinical trialsWorldwide, over 400 clinical trials have been conducted,
with enrolment of over 6000 patients. A substantial portion of these clinical trials (over 70%) are cancer related and often carried out on terminal patients.
The most commonly used vectors are retroviral vectors, which were the first viral vectors to be used in a gene
therapy trial.
The targets of that first clinical trial were the T-lymphocytes of two children suffering from severe
combined immunodeficiency (SCID).
Department of Pharmacology; GCTS 17
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Conclusion Geneticists must identify target genes that contribute to specific
diseases or that can influence the disease course.
The task for the virologists is to develop efficient and safe vectors that are able to deliver the genes of interest to the target cells and assure the proper expression of the transferred genetic material.
Clinicians will carry out clinical trials with vectors optimized for the disease and the medical requirements of the patients.
Department of Pharmacology; GCTS 18
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Selected Bibliography’s GENE THERAPY: Promises and
Problems; Alexander Pfeifer and Inder M.Verma.
GENE THERAPY: Twenty-First Century Medicine; Inder M. Verma and Matthew D.Weitzman.
Department of Pharmacology; GCTS 19
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Department of Pharmacology; GCTS
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Thank You