Genetic Counselling and

Gene Therapy
Genetic Counselling
Introduction
• Genetic counselling is the process by which patients or relatives, at risk
of an inherited disorder, are advised of the consequences and nature
of the disorder, the probability of developing or transmitting it and the
options open to them in management and family planning in order to
prevent or avoid it.

• A person giving genetic advice is called Counselor.

• A person seeking genetic advice is called Consultand.
Purpose of Genetic Counselling
This involves an attempt by counsellor to help the consultand to:
• Understand the medical facts e.g. diagnosis, probable course of
disorder and available management

• Understand the mode of inheritance of the disorder and the risk of

developing and/or transmitting it.

• Understand the alternatives for dealing with the risk of recurrence.

• Choose the course of action which is appropriate for them.

 Indications for Genetic Counselling
• Advanced parental age:-
• Maternal age ≥35 yrs

• Previous child with or family H/O:-

• Congenital anomaly
• Dysmorphism
• Intellectual disability
• Isolated birth defect
• Chromosomal abnormality

• Adult onset genetic disorder (presymptomatic testing):-

• Cancer

• Consanguinity
Indications for Genetic Counselling
• Teratogen exposure
• Repeated pregnancy loss or infertility

• Pregnancy screening abnormality

• Maternal serum α-feto protein
• Ultrasonography
• Fetal karyotype

• Heterozygote screening based on ethnic risk

• Sickle cell anemia, Tay- sachs, Thalassemia

• Follow up to abnormal neonatal genetic testing

Types of Genetic Counselling
• Two types of genetic counselling: Prospective &
Retrospective

1. Prospective genetic counselling:

• Allows prevention of disease.

• Requires to identify heterozygous individuals for any particular

defect by screening.

• Explaining to them the risk of their having affected children if

they marry another heterozygote for the same gene.

• Ex: Sickle cell anaemia, Thalassemia

Types of Genetic Counselling
2. Retrospective genetic counselling:
• Most genetic counselling at present is retrospective
• i.e. the hereditary disorder has already occurred within the family

• Ex. Mental retardation, Psychiatric illness, Inborn errors of metabolism

• The methods which could be suggested under retrospective genetic

counselling are:
• Contraception
• Pregnancy termination.
• Sterilization
 Areas of Genetic Counselling

1. Prenatal Genetic Counselling

• There are several different reasons a person or couple may seek

prenatal genetic counselling
• E.g. If a woman is 35yrs or older & pregnant → increased risk of her fetus
having a change in chromosome number

• Changes in chromosome number may lead to mental retardation and

birth defects.
• Prenatal tests that are offered during genetic counselling
include:
• Maternal serum AFP
• Chorionic villus sampling
• Amniocentesis
2. Pediatric Genetic Counselling
• When a child has features of an inherited condition.

• Any child born with more than one defect, mental retardation or
dysmorphic features has an increased chance of having a genetic
syndrome.

• A common example of mental retardation for which genetic testing is

available is fragile X-syndrome.
3. Adult Genetic Counselling
• Adults may seek genetic counselling when:
• A person in the family decides to be tested for the presence of a
known genetic condition
• An adult begins exhibiting symptoms of an inherited condition
• There is a new diagnosis of someone with an adult onset disorder in
the family

• GC for adults my lead to the consideration of presymptomatic

genetic testing
4. Cancer Genetic Counselling
• A family history of early onset breast, ovarian or colon cancer in
multiple generations of family is a common reason.

• Example
Mary is a 48 year old woman who is referred to a genetic counselor
because her sister was recently diagnosed with ovarian cancer at age
52. Her father and paternal grandmother were also diagnosed with
breast cancer at ages 58 and 45 respectively. Mary tells you her sister
has a mutation in the BRCA2 gene.
Role of Cancer GC

• Obtain medical records and relative’s test results as appropriate

• Obtain family and medical history
• Pedigree analysis
• Discuss features and genetics of Hereditary Breast and Ovarian
Cancer
• Discuss risks and benefits of genetic testing
• Review cancer risks and options for risk reduction
• Arrange for testing if desired and follow-up counseling
Conclusion
• Genetic Counselling enables couples / affected individual to make
decision about a future pregnancy.

• It helps the affected individual to be educated and cope with the

disorders with minimal clinical problem.
• GC is done in an objective manner, so that any treatment selected remains
the personal choice of the individual involved.
• Thorough knowledge of the disease for giving information regarding the
cause and risk factors of the disease is necessary before counselling.
Gene Therapy
Introduction
• An experimental technique for correcting defective genes that are
responsible for diseases by replacing them.

• Several approaches to gene therapy:

1. Inserting a normal gene to replace an abnormal gene.
2. Inactivating or ‘’knocking out’’ a mutated gene that is functioning
improperly
3. Introducing a new gene into the body to help fight a disease.
Introduction..,
• Although gene therapy is a promising treatment option for a number
of diseases, the technique remains risky and is still under study to
make sure that it will be safe and effective.

• Gene therapy is currently only being tested for the treatment of

disease that have no cure.
Steps in Gene Therapy
• The faulty gene that causes a specific condition must be identified.
• The location of the affected cells in the body's tissues or organs must
be pinpointed.
• A working version of the gene must be available.
• The working version of the gene has to be delivered to the cell
Principal
Introduction of functional genes into appropriate cells
↓

Transferred gene (Transgene) encodes & produces proteins

↓

The Proteins encoded by Transgene corrects the disorder

Vectors in Gene Therapy
• To transfer the desired gene into a target cell, a carrier is needed.

• Such vehicles of gene delivery are known as vectors.

• Two main classes

• Viral vectors
• Non viral vectors
• E.g. DNA Molecular Conjugates, Human Artificial Chromosome
Viral Vectors
• Replicate by inserting their DNA into a host cell

• Gene therapy can use this to insert genes that encode for a desired
protein to create the desired trait

• Four different types

• Adenovirus
• Adeno-Associated Virus (AAV)
• Retrovirus
• Herpes Simplex Virus (HSV)
Gene Therapy Vectors
Types of Gene Therapy
Somatic Gene Therapy
• Therapeutic genes
transferred into the somatic
cells.
• E.g. introduction of genes
into bone marrow cells,
blood cells, skin cells etc.
• Will not be inherited later
generations.
Germline Gene Therapy
• Therapeutic genes
transferred into the germ
cells.
• E.g. genes introduced into
eggs and sperms.
• It is heritable and passed on
to later generations.
Somatic Gene Therapy
• Somatic gene therapy is effective in treating various kinds of
diseases
• E.g. cystic fibrosis, muscular dystrophy, cancer, and certain infectious
diseases.

• The effectiveness is usually short-lived

• Because the cells of most tissues ultimately die and are replaced by new
cells, repeated treatments over the course of the individual's life span are
required to maintain the therapeutic effect

• Broadly divided into two categories: ex vivo and in vivo

• Involves genetic
alteration of cells
outside the body

• By using viral vectors &

transplanting back to
the patient body in
order to correct the
disorder

• Used for treating

genetic diseases of
blood system
Ex vivo Gene Therapy
Advantages Disadvantages

Specificity of target cell infection Cells maintained and genetically modified in

Ability to target selectively specific cell types for vitro
production of the gene of interest before engrafting of Host cells must be capable of dividing, thus certain
cells into the host postmitotic cell populations such as neurons cannot
be targets of transduction for ex vivo gene therapy

Immunocompatibility Invasiveness of cell grafting

The cells are collected from patient to avoid rejection Grafting of cells is an intrinsically more invasive
process than injection of suspensions of in vivo gene
therapy vectors
In vivo Gene Therapy
• Direct introduction of
the genetic materials
into the human body.

• Target tissues of this

technique includes:
• skin, lung, colon,
muscle, pancreas, liver,
bone marrow, spleen
and brain.
In vivo Gene Therapy
Advantages Disadvantages

Simplicity Nonspecificity of target cell infection

Gene delivery is accomplished by the single step of Various different cell types can be infected when in
direct vector injection into the desired target organ vivo vectors are injected in the CNS, including
neurons, glia, and vascular cells.

Minimal evasiveness Might cause toxicity

Procedures involved in this technique are simple and Some in vivo vectors are toxic to host cells and elicit
safe immune responses.

It is repeatable
Same location can be injected more than once using in
vivo gene delivery approaches.
 Germline Gene Therapy
• Germ cells (sperms and
eggs) are modified by the
introduction of functional
genes into their genomes

• Offer the possibility of

permanent removing of an
inherited disorder from a
family line.
• However, this also raises controversy & it is unethical to conduct in human.
 Problems with Gene Therapy
Short Lived nature of gene therapy
Hard to rapidly integrate therapeutic DNA into genome and rapidly dividing
nature of cells prevent gene therapy from long time
Would have to have multiple rounds of therapy
Immune Response
new things introduced leads to immune response
increased response when a repeat offender enters
Viral Vectors
patient could have toxic, immune, inflammatory response
also may cause disease once inside

Multigene Disorders
Heart disease, high blood pressure, Alzheimer’s, arthritis and diabetes are hard
to treat because you need to introduce more than one gene
May induce a tumor
if integrated in a tumor suppressor gene because insertional mutagenesis
 Current Status
• The Food and Drug Administration (FDA) hasn’t approved any human
gene therapy product for sale

Reasons:
• In 1999:
18-year-old Jesse Gelsinger died from multiple organ failure 4 days
after treatment for ornithine transcarboxylase deficiency.
• Death was triggered by severe immune response to adenovirus
carrier
• January 2003:
• Halt to using retrovirus vectors in blood stem cells
• Children developed leukemia-like condition after successful
treatment for X-linked severe combined immunodeficiency disease
Successful Gene Therapy for Severe Combine
Immunodeficiency

• Severe combined immunodeficiency is inherited as an X-

linked recessive disease.

• Infants with severe combined immunodeficiency are unable

to mount an adaptive immune response, because they have
a profound deficiency of lymphocytes.
• Due to a deficiency of adenosine deaminase
• In these patients, peripheral T cells were transduced with a vector
bearing the gene for adenosine deaminase.

• The experiment was extremely labor intensive.

• Because mature peripheral-blood T cells were modified rather than stem
cells, and the procedure therefore had to be repeated many times to achieve
success.
Conclusion
• Theoretically, gene therapy is the permanent
solution for genetic diseases.

• But it has several complexities. At its current stage,

it is not accessible to most people due to its huge
cost.

• A breakthrough may come anytime and a day may

come when almost every disease will have a gene
therapy

• Gene therapy have the potential to revolutionize

the practice of medicine.