Gene Therapy

And
Genetic Counseling

Much of the artwork in this presentation is taken

from Human Genetics: Concepts and Applications,
2008, by Ricki Lewis, Eighth Edition, McGraw Hill
Copyright © 2008 The McGraw-Hill Companies, Inc.
 Genetic Counseling

Genetic counselors

• Who are they?

• Who goes to a genetic counselor?

 Genetic counselors cont’d.
• What do genetic counselors do?

– Educate
– Evaluate risk
– Genetic testing
– Counsel patients
– Resource for referral or support group
Genetic counseling

How does the process work?

Goals
Uses of Genetic Testing
Newborn Screening
Started with Guthrie test for PKU

Tandem mass spectrometry

PCR to amplify specific mutations

2005: US mandated testing for 29 treatable and

recommended testing for 25 untreatable (to
help doctors in diagnosis)

Economically advantageous
 Newborn screening tests
Disease Incidence Treatment
Biotinidase deficiency 1/70,000 Oral biotin
Maple syrup urine 1/250,000-300,000 Diet low in overproduced
disease amino acids
Congenital adrenal 1/12,000 Hormone replacement,
hyperplasia 1/680 Yupik eskimo surgery
Congenital 1/3,600 -5,000 Hormone replacement
hypothyroidism
Galactosemia 1/60,000-80,000 Galactose-free diet

Homocystinuria 1/50,000-150,000 Low-methionine, high-

cysteine diet, drugs
Phenylketonuria 1/10,000-25,000 Low phenylalanine diet

Sickle cell anemia and 1/400 African Prophylactic antibiotics

hemoglobinopathies Americans
Direct-To-Consumer Genetic Testing

Company websites  $200  $2,000

DNA on a cheek swab

~~~~concerns
Genetic counseling issues

• Privacy
– Confidentiality within society
– Confidentiality within family
– “Duty to Warn”
– HIPAA

• Nondirective information / shared

deliberation and decision making

• Insurance

• Role within the health care

profession- shortage of counselors
Preimplantatin genetic screening and
diagnosis
allows detection of genetic abnormalities
prior to implantation.

• One cell of an 8-celled embryo

• The remaining cells continue development in lab

• Healthy embryos (80-120 cells) are implanted

• Implanted embryos complete normal

development
PGD

How?
Why?
• Avoid inherited disease
– 1989: first children born (screened for sex)

– 1992 first child born after screening for

cystic fibrosis

• Combined with IVF

• Stem cell donors

• Sex selection?
 Polar body biopsy

Pre-conception testing
for heterozygous moms

Test polar body Why?

Still considered experimental

Treating Genetic Disease

• Replacing missing proteins

• Obtaining pure proteins using

recombinant DNA

• Delivering replacement genes

– Treatments are still experimental
Enzyme Replacement Therapy
Enzyme Replacement Therapy

Hamster cells with

human gene
 Gene therapy

treatment of genetic disease by delivering

replacement genes to correct the genetic
deficiency

The first clinical trials ----1990s.

 MOST INVASIVE

Different
approaches

ALTERED OUTSIDE THE BODY

TO LOCALIZED AREA

Using stem cells is another (newer) approach

Challenges

• Delivery of gene
• Gene expression
• Duration of gene action
• Immune reactions
 Adenosine Deaminase Deficiency Story
• Disease:Severe combined immune deficiency
(SCID)

– adenosine deaminase (ADA) deficiency.

– toxins destroy T cells

– susceptible to infections and cancer.

• Replacement of ADA in individuals genetically

deficient was attempted.
Adenosine Deaminase Deficiency Story
 Adenosine Deaminase Deficiency Story

•1986:Injections of PEG-ADA

•1990:Ashanti DaSilva
–First gene therapy patient
–White blood cells receive a
functional copy of ADA and the
cells are returned
Adenosine Deaminase Deficiency Story

• 1993: Stem cells from umbilical cord blood

– Returned to newborn
– T cells with normal allele accumulate in
patient.

• 2003: three boys treated for X-linked SCID

develop leukemia
Ornithine Transcarbamylase (OTC) Deficiency

• X-linked recessive.

• OTC normally breaks down amino acids

• Lack of OTC
– build up of ammonia which damages brain
function.

• Treatment: low protein diet and ammonia-

binding drugs.
ornithine transcarbamylase deficiency
 Jesse’s story:
ornithine transcarbamylase (OTC) deficiency

• 1998:Clinical trials using adenovirus as a

vector for the normal OTC gene.

Jesse Gelsinger,18, volunteer

Sept.19,1999:Four days after

gene therapy Jesse died.
 Jesse’s story cont’d.

• Autopsy

• Public hearings

• Immediate halt of this trial and review of all

gene therapy trials

• Reform of gene therapy trials continues.

• Weekly reports of adverse effects have been

instituted.
Requirements for approval of a clinical trial

• Knowledge of defect and how it causes

symptoms

• An animal model

• Success in growing human cells in vitro

• No alternative therapies or group of

patients for whom therapies are not
possible

• Safe experiments
Bioethical concerns about gene therapy
• Does the participant of the trial truly understand
the risks?

• If the gene therapy is effective, how will recipients

be chosen assuming it is expensive?

• Should rare or common disorders be the focus of

gene therapy trials?

• What effect should deaths among volunteers have

on research efforts?

• Should clinical trials be halted if the delivered gene

enters the germline?
 Scientific concerns about gene therapy
• Which cells should be treated?

• What proportion of target cells must be corrected to

alleviate or halt disease progression?

• Is overexpression of the therapeutic gene dangerous?

• Is it harmful if the altered gene enters other types of

cells?

• How long will the treated cells function? (How long

lasting is the treatment?)

• Will the immune system attack the altered cells?

• Does the targeted DNA sequence occur in more than one

gene?
Germline versus somatic gene therapy

Germline gene therapy

• Involves alteration of the DNA of a gamete
or fertilized egg.
• Heritable
• Currently not done in humans.

Somatic gene therapy

• Involves alteration of the DNA of somatic
cells implicated in the disease.
• Not heritable.
Sites of somatic gene therapy
 So….

Great promise, but slower than

expected
More complex than anticipated
- gene interactions
- appropriate vectors
- adequately targeting and sustaining
therapeutic effects
- safety issues