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 Submitted To-
 Dr- Priyanka
Kriplani
 Professor
GENE EXPRESSION SYSTEM
(VIRAL GENE THERAPY)
Submitted To-
Dr. Priyanka Kriplani
Professor
Submitted By-
Muskan (M-506)
M.Pharm (2nd sem)
GURU GOBIND SINGH COLEGE OF PHARMACY
Gene therapy
Gene Transfer
Gene Transfer Techniques
Viral delivery systems
Reference
Contents
Gene therapy can be broadly defined as the transfer of genetic
material to cure a disease or at least to improve the clinical status of
a patient.
One of the basic concepts of gene therapy is to transform viruses
into genetic shuttles, which will deliver the gene of interest into the
target cells.
 Safe methods have been devised to do this, using several viral and
non-viral vectors.
In the future, this technique may allow doctors to treat a disorder
by inserting a gene into a patient's cells instead of using drugs or
surgery.
Gene Therapy
GENE TRANSFER
It is defined as a technique of insertion of unrelated, therapeutic
genetic information in the form of DNA into target cells.
Hurdles in Gene Therapy
The biggest hurdle faced by medical research in gene therapy is the
availability of effective gene-carrying vectors that meet all of the
following criteria:
Protection of transgene or genetic cargo from degradative action
of systemic and endonucleases,
Delivery of genetic material to the target site, i.e., either cell
cytoplasm or nucleus,
Low potential of triggering unwanted immune responses or
genotoxicity,
Economical and feasible availability for patients .
Gene Transfer Techniques- Based on Vectors
Viruses are naturally evolved vehicles that efficiently transfer their
genes into host cells.
Choice of viral vector is dependent on gene transfer efficiency,
capacity to carry foreign genes, toxicity, stability, immune
responses towards viral antigens and potential viral recombination.
There are a wide variety of vectors used to deliver DNA or oligo
nucleotides into mammalian cells, either in vitro or in vivo.
 The most common vector system based on retroviruses,
adenoviruses, herpes simplex viruses, adeno associated viruses.
Viral Gene Delivery System
Viral Gene Delivery System
Viral Gene Delivery System
 Provide greater gene transfer
efficiency in both in vivo and in
vitro environments
 Persist for longer periods of time in
most cases
 Can target a large number of cells
 A large variety of viruses are
available to choose from
 Innate ability of tropism toward
infection
 Capable of evading endosomes by
various mechanisms learned by
evolution of viruses
 Can trigger severe immune responses
and inflammatory reactions
 Their cloning capacity is very limited
 Produced by complex production
methods
 Low capability of tropism to some
specific target cells
 Can cause mutagenesis by inserting their
exogenous DNA into the host genome
 Research is needed to further understand
the mechanisms of molecular infection
by viruses
Advantages Disadvantages
Mechanism of Viral Gene Delivery
Viral Gene Delivery System
Mechanism  The mechanism of viral gene delivery starts with the
incorporation of the transgene into the viral DNA, and then
this modified DNA is injected into the viral vector.
 This vector, upon reaching the target site, attaches to the
receptors found on the cell membrane of the target cells.
 After cellular internalization, the vector is packed into
endosomes, followed by an acid breakdown of these
endosomes that release the capsid containing the modified
DNA.
 This capsid then travels to the nucleus and binds to nuclear
pores to enter the nucleus, where the modified gene is
integrated into the DNA of the target cell.
 After that, transcription and translation occur, which form
the protein of interest and bring about gene expression
Virus Size and Type
genome
Viral Proteins Physical Properties Disease in Animals
Retrovirus 7–10kb of single
stranded RNA
Gaga, Polb, Envc 100nm diameter;
enveloped
Rapid or slow
induction
of tumors; acquired
immunodeficiency
syndrome (AIDS
Adenovirus 36kb double
stranded linear
DNA
Over 25 proteins 70–100nm in
diameter;
nonenveloped
Cold;
conjunctivitis;
gastroenteritis
Adenovirus
associated virus
4-7 kb single
stranded linear
DNA
Repd and Cape 18–26nm in
diameter;
nonenveloped
No known disease
Herpes simplex
virus 1 (HSV1)
152kb of double
stranded linear
DNA
Over 81proteins 110nm in diameter Mouth ulcers;
genital
warts; encephalitis
Baculovirus 130kb of double
stranded circular
DNA
Over 60 proteins 270 by 45 nm
rectangles;
enveloped
None in mammals;
insect pathogen
Adenoviral Vectors
They contain a DNA genome that is double-stranded and has a size of 35 kb. They are non
enveloped viruses.
There are three generations of adenoviral vectors that are based on the level of attenuation
achieved by the deletion of genes.
In the first-generation adenoviral vectors, the E1A and E1B genes are deleted. In the second-
generation adenoviral vectors, a large number of the early genes are deleted. In third-generation
adenoviral vectors, the complete genome or genetic information of the virus is deleted, which is
why they are also called gutless vectors .
The adenoviral genome is quite large in size, and the prospect of complete genome deletion
greatly renders these viruses a high coding capacity. First-generation vectors can allow ~3.2 kb
of genome insertion, while third-generation vectors allow up to 30 kb.
 An advantage of adenoviral vectors is that there is a very negligible possibility of integration of
their genome into the genome of the host cell, which makes them rather safe and nontoxic for
use. However, long or sustainable gene expression is difficult to achieve with adenoviruses
because their life cycle is not adapted to it.
Applications of Adenoviral Vectors
 In vivo gene therapy
differentiated cells. transduce
non dividing and terminally
 Transfect cells in vivo in the
intact organ.
 Gene therapy for cystic therapy.
 Gene therapy of muscle in liver
and therapy of disease of CNS.
Retrovirus Vector
 Commonly employed vectors
derived from Murine Leukemia
Virus(MuLV).
 Virus genome has two single copy
RNA molecules, complexed with
viral core proteins, surrounded by
lipid envelope.
 The main benefit that retroviral
vectors offer is their capacity to
change their ssRNA genome into a
dsDNA particle that steadily
incorporates into the genome of its
host cells. T
Applications
 Ex-vivo gene therapy.
 In-vivo gene transfer using retro
viral vectors for suicide genes
used in brain tumour.
 Treatment of T-lymphocyte
deficiency (ADA), Tumour
Infiltrating Lymphocytes (TIL),
Bone marrow cells(ADA
deficiency, Gauchers disease),
hepatocytes (LDL receptor
deficiency) and melanoma
Adeno Associated Virus Vector
 Members of Parvo virus family.
Heat stable and resistant to
various chemicals.
 Depend on virus - cannot
replicate its own, another virus is
necessary for replicate,.
 Major disadvantages of these
vectors are complicated process
of vector production and the
limited transgene capacity of the
particles.
 Applications
 Used in haematopoietic stem
cells for treatment of ß-
thalassemia and sickle cell
anaemia.
 ẞ-thalassemia erythrocyte
contains insufficient ẞ- globin
chain whereas, mutant ẞ- globin
chains are produced in sickle
cell.
Belonging to the Poxviridae family of viruses, they are the most complicated and
largest of all viruses that infect humans and cause diseases.
Their genome is double-stranded and has a size of approximately 180–220 kb.
The smallpox virus is the most popular virus belonging to this family and
represents its group very well.
The vaccinia virus belonging to the poxvirus family is the virus which was used for
the development of smallpox vaccine.
There are two features unique to this virus: its capability to carry out its life cycle
in the cell cytoplasm due to which it does not insert its genome into the host cell
genome, and its occurrence in two different infectious variants i.e., an intracellular
mature virus (IMV) and an extracellular enveloped virus (EEV)
Pox viruse vector
A class of double-stranded DNA viruses that infect a particular cell
type, neurons.
Herpes simplex virus type 1 is a common human pathogen that
causes cold sores.
It is a human neurotropic virus, which is mostly used for gene
transfer in nervous system.
It has a large genome compared to other viruses, which enable
scientist to insert more than one therapeutic gene into a single virus,
paving the way for treatment of disorders caused by more than one
gene defect. HSV makes an ideal vector as it can infect a wide
range of tissues including muscle, liver, pancreas, nerve and lung
cells.
Herpes simplex viruses (HSV)
Baculoviruses that belong to the Baculoviridae family are also being
explored for their potential to be used as vectors in gene delivery.
These viruses possess a reasonable cloning capacity of about 38 kb,
and they allow insertion of about 100 kb of genomic material in their
capsid.
These viruses also do not replicate in mammalian cells, which
reduces their risk of causing toxicity. Several studies are exploring the
use of these viruses for gene delivery in treatment of certain
lymphomas
Other Viruses
References
Butt MH, Zaman M, Ahmad A, Khan R, Mallhi TH, Hasan MM,
Khan YH, Hafeez S, Massoud EES, Rahman MH, et al. Appraisal
for the Potential of Viral and Nonviral Vectors in Gene Therapy: A
Review. Genes. 2022; 13(8):1370.
Seow Y, Wood MJ. Biological gene delivery vehicles: beyond viral
vectors. Molecular therapy. 2009 May 1;17(5):767-77.
Pan X, Veroniaina H, Su N, Sha K, Jiang F, Wu Z, Qi X.
Applications and developments of gene therapy drug delivery
systems for genetic diseases. Asian journal of pharmaceutical
sciences. 2021 Nov 1;16(6):687-703.
THANKYOU

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Gene Expression System-viral gene delivery Mpharm(Pharamaceutics)

  • 1.  Submitted To-  Dr- Priyanka Kriplani  Professor GENE EXPRESSION SYSTEM (VIRAL GENE THERAPY) Submitted To- Dr. Priyanka Kriplani Professor Submitted By- Muskan (M-506) M.Pharm (2nd sem) GURU GOBIND SINGH COLEGE OF PHARMACY
  • 2. Gene therapy Gene Transfer Gene Transfer Techniques Viral delivery systems Reference Contents
  • 3. Gene therapy can be broadly defined as the transfer of genetic material to cure a disease or at least to improve the clinical status of a patient. One of the basic concepts of gene therapy is to transform viruses into genetic shuttles, which will deliver the gene of interest into the target cells.  Safe methods have been devised to do this, using several viral and non-viral vectors. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient's cells instead of using drugs or surgery. Gene Therapy
  • 4. GENE TRANSFER It is defined as a technique of insertion of unrelated, therapeutic genetic information in the form of DNA into target cells.
  • 5. Hurdles in Gene Therapy The biggest hurdle faced by medical research in gene therapy is the availability of effective gene-carrying vectors that meet all of the following criteria: Protection of transgene or genetic cargo from degradative action of systemic and endonucleases, Delivery of genetic material to the target site, i.e., either cell cytoplasm or nucleus, Low potential of triggering unwanted immune responses or genotoxicity, Economical and feasible availability for patients .
  • 6. Gene Transfer Techniques- Based on Vectors
  • 7. Viruses are naturally evolved vehicles that efficiently transfer their genes into host cells. Choice of viral vector is dependent on gene transfer efficiency, capacity to carry foreign genes, toxicity, stability, immune responses towards viral antigens and potential viral recombination. There are a wide variety of vectors used to deliver DNA or oligo nucleotides into mammalian cells, either in vitro or in vivo.  The most common vector system based on retroviruses, adenoviruses, herpes simplex viruses, adeno associated viruses. Viral Gene Delivery System
  • 9. Viral Gene Delivery System  Provide greater gene transfer efficiency in both in vivo and in vitro environments  Persist for longer periods of time in most cases  Can target a large number of cells  A large variety of viruses are available to choose from  Innate ability of tropism toward infection  Capable of evading endosomes by various mechanisms learned by evolution of viruses  Can trigger severe immune responses and inflammatory reactions  Their cloning capacity is very limited  Produced by complex production methods  Low capability of tropism to some specific target cells  Can cause mutagenesis by inserting their exogenous DNA into the host genome  Research is needed to further understand the mechanisms of molecular infection by viruses Advantages Disadvantages
  • 10. Mechanism of Viral Gene Delivery
  • 11. Viral Gene Delivery System Mechanism  The mechanism of viral gene delivery starts with the incorporation of the transgene into the viral DNA, and then this modified DNA is injected into the viral vector.  This vector, upon reaching the target site, attaches to the receptors found on the cell membrane of the target cells.  After cellular internalization, the vector is packed into endosomes, followed by an acid breakdown of these endosomes that release the capsid containing the modified DNA.  This capsid then travels to the nucleus and binds to nuclear pores to enter the nucleus, where the modified gene is integrated into the DNA of the target cell.  After that, transcription and translation occur, which form the protein of interest and bring about gene expression
  • 12. Virus Size and Type genome Viral Proteins Physical Properties Disease in Animals Retrovirus 7–10kb of single stranded RNA Gaga, Polb, Envc 100nm diameter; enveloped Rapid or slow induction of tumors; acquired immunodeficiency syndrome (AIDS Adenovirus 36kb double stranded linear DNA Over 25 proteins 70–100nm in diameter; nonenveloped Cold; conjunctivitis; gastroenteritis Adenovirus associated virus 4-7 kb single stranded linear DNA Repd and Cape 18–26nm in diameter; nonenveloped No known disease Herpes simplex virus 1 (HSV1) 152kb of double stranded linear DNA Over 81proteins 110nm in diameter Mouth ulcers; genital warts; encephalitis Baculovirus 130kb of double stranded circular DNA Over 60 proteins 270 by 45 nm rectangles; enveloped None in mammals; insect pathogen
  • 13. Adenoviral Vectors They contain a DNA genome that is double-stranded and has a size of 35 kb. They are non enveloped viruses. There are three generations of adenoviral vectors that are based on the level of attenuation achieved by the deletion of genes. In the first-generation adenoviral vectors, the E1A and E1B genes are deleted. In the second- generation adenoviral vectors, a large number of the early genes are deleted. In third-generation adenoviral vectors, the complete genome or genetic information of the virus is deleted, which is why they are also called gutless vectors . The adenoviral genome is quite large in size, and the prospect of complete genome deletion greatly renders these viruses a high coding capacity. First-generation vectors can allow ~3.2 kb of genome insertion, while third-generation vectors allow up to 30 kb.  An advantage of adenoviral vectors is that there is a very negligible possibility of integration of their genome into the genome of the host cell, which makes them rather safe and nontoxic for use. However, long or sustainable gene expression is difficult to achieve with adenoviruses because their life cycle is not adapted to it.
  • 14. Applications of Adenoviral Vectors  In vivo gene therapy differentiated cells. transduce non dividing and terminally  Transfect cells in vivo in the intact organ.  Gene therapy for cystic therapy.  Gene therapy of muscle in liver and therapy of disease of CNS.
  • 15. Retrovirus Vector  Commonly employed vectors derived from Murine Leukemia Virus(MuLV).  Virus genome has two single copy RNA molecules, complexed with viral core proteins, surrounded by lipid envelope.  The main benefit that retroviral vectors offer is their capacity to change their ssRNA genome into a dsDNA particle that steadily incorporates into the genome of its host cells. T Applications  Ex-vivo gene therapy.  In-vivo gene transfer using retro viral vectors for suicide genes used in brain tumour.  Treatment of T-lymphocyte deficiency (ADA), Tumour Infiltrating Lymphocytes (TIL), Bone marrow cells(ADA deficiency, Gauchers disease), hepatocytes (LDL receptor deficiency) and melanoma
  • 16. Adeno Associated Virus Vector  Members of Parvo virus family. Heat stable and resistant to various chemicals.  Depend on virus - cannot replicate its own, another virus is necessary for replicate,.  Major disadvantages of these vectors are complicated process of vector production and the limited transgene capacity of the particles.  Applications  Used in haematopoietic stem cells for treatment of ß- thalassemia and sickle cell anaemia.  ẞ-thalassemia erythrocyte contains insufficient ẞ- globin chain whereas, mutant ẞ- globin chains are produced in sickle cell.
  • 17. Belonging to the Poxviridae family of viruses, they are the most complicated and largest of all viruses that infect humans and cause diseases. Their genome is double-stranded and has a size of approximately 180–220 kb. The smallpox virus is the most popular virus belonging to this family and represents its group very well. The vaccinia virus belonging to the poxvirus family is the virus which was used for the development of smallpox vaccine. There are two features unique to this virus: its capability to carry out its life cycle in the cell cytoplasm due to which it does not insert its genome into the host cell genome, and its occurrence in two different infectious variants i.e., an intracellular mature virus (IMV) and an extracellular enveloped virus (EEV) Pox viruse vector
  • 18. A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores. It is a human neurotropic virus, which is mostly used for gene transfer in nervous system. It has a large genome compared to other viruses, which enable scientist to insert more than one therapeutic gene into a single virus, paving the way for treatment of disorders caused by more than one gene defect. HSV makes an ideal vector as it can infect a wide range of tissues including muscle, liver, pancreas, nerve and lung cells. Herpes simplex viruses (HSV)
  • 19. Baculoviruses that belong to the Baculoviridae family are also being explored for their potential to be used as vectors in gene delivery. These viruses possess a reasonable cloning capacity of about 38 kb, and they allow insertion of about 100 kb of genomic material in their capsid. These viruses also do not replicate in mammalian cells, which reduces their risk of causing toxicity. Several studies are exploring the use of these viruses for gene delivery in treatment of certain lymphomas Other Viruses
  • 20. References Butt MH, Zaman M, Ahmad A, Khan R, Mallhi TH, Hasan MM, Khan YH, Hafeez S, Massoud EES, Rahman MH, et al. Appraisal for the Potential of Viral and Nonviral Vectors in Gene Therapy: A Review. Genes. 2022; 13(8):1370. Seow Y, Wood MJ. Biological gene delivery vehicles: beyond viral vectors. Molecular therapy. 2009 May 1;17(5):767-77. Pan X, Veroniaina H, Su N, Sha K, Jiang F, Wu Z, Qi X. Applications and developments of gene therapy drug delivery systems for genetic diseases. Asian journal of pharmaceutical sciences. 2021 Nov 1;16(6):687-703.