Counseling Slides

8/14/2019 Counseling Slides

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Gene Therapy

And

Genetic Counseling

Much of the artwork in this presentation is takenfrom Human Genetics: Concepts and Applications,2008, by Ricki Lewis, Eighth Edition, McGraw HillCopyright 2008 The McGraw-Hill Companies, Inc.


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Genetic Counseling

Genetic counselors

Who are they?

Who goes to a genetic counselor?


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Genetic counselors contd.

What do genetic counselors do?

Educate

Evaluate riskGenetic testing

Counsel patients

Resource for referral or support group


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Genetic counseling

How does the process work?

Goals


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Uses of Genetic Testing


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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 (tohelp doctors in diagnosis)

Economically advantageous


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Newborn screening tests

Oral biotin1/70,000Biotinidase deficiency

TreatmentIncidenceDisease

Prophylactic antibiotics1/400 AfricanAmericans

Sickle cell anemia andhemoglobinopathies

Low phenylalanine diet1/10,000-25,000Phenylketonuria

Low-methionine, high-

cysteine diet, drugs

1/50,000-150,000Homocystinuria

Galactose-free diet1/60,000-80,000Galactosemia

Hormone replacement1/3,600 -5,000Congenitalhypothyroidism

Hormone replacement,surgery

1/12,000

1/680 Yupik eskimo

Congenital adrenalhyperplasia

Diet low in overproducedamino acids

1/250,000-300,000Maple syrup urinedisease


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Direct-To-Consumer Genetic Testing

Company websites $200 $2,000

DNA on a cheek swab

~~~~concerns


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Genetic counseling issues

Privacy

Confidentiality within society

Confidentiality within family

Duty to Warn

HIPAA

Nondirective information / shareddeliberation and decision making

Insurance

Role within the health careprofession- shortage of counselors


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Preimplantatin genetic screening anddiagnosis

allows detection of genetic abnormalitiesprior 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 normaldevelopment


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PGD

How?


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Why? Avoid inherited disease

1989: first children born (screened for sex)

1992 first child born after screening forcystic fibrosis

Combined with IVF

Stem cell donors

Sex selection?


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Polar body biopsy

Test polar body Why?

Still considered experimental

Pre-conception testingfor heterozygous moms


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Treating Genetic Disease

Replacing missing proteins

Obtaining pure proteins usingrecombinant DNA

Delivering replacement genes

Treatments are still experimental


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Enzyme Replacement Therapy


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Enzyme Replacement Therapy

Hamster cells withhuman gene


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Gene therapy

treatment of genetic disease by deliveringreplacement genes to correct the geneticdeficiency

The first clinical trials ----1990s.


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TO LOCALIZED AREA

ALTERED OUTSIDE THE BODY

MOST INVASIVE

Differentapproaches

Using stem cells is another (newer) approach


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Challenges

Delivery of gene

Gene expression

Duration of gene action

Immune reactions


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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 geneticallydeficient was attempted.


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1986:Injections of PEG-ADA

1990:Ashanti DaSilva

First gene therapy patient

White blood cells receive afunctional copy of ADA and thecells are returned


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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


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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.


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ornithine transcarbamylase deficiency


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Jesses story:ornithine transcarbamylase (OTC) deficiency

1998:Clinical trials using adenovirus as avector for the normal OTC gene.

Jesse Gelsinger,18, volunteer

Sept.19,1999:Four days aftergene therapy Jesse died.


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Jesses story contd.

Autopsy

Public hearings

Immediate halt of this trial and review of allgene therapy trials

Reform of gene therapy trials continues.

Weekly reports of adverse effects have beeninstituted.


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Requirements for approval of a clinical trial

Knowledge of defect and how it causessymptoms

An animal model

Success in growing human cells in vitro

No alternative therapies or group ofpatients for whom therapies are notpossible

Safe experiments


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Bioethical concerns about gene therapy

Does the participant of the trial truly understandthe risks?

If the gene therapy is effective, how will recipientsbe chosen assuming it is expensive?

Should rare or common disorders be the focus ofgene therapy trials?

What effect should deaths among volunteers have

on research efforts?

Should clinical trials be halted if the delivered geneenters the germline?


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Scientific concerns about gene therapy

Which cells should be treated?

What proportion of target cells must be corrected toalleviate or halt disease progression?

Is overexpression of the therapeutic gene dangerous?

Is it harmful if the altered gene enters other types ofcells?

How long will the treated cells function? (How longlasting is the treatment?)

Will the immune system attack the altered cells?

Does the targeted DNA sequence occur in more than onegene?


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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 somaticcells implicated in the disease.

Not heritable.


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Sites of somatic gene therapy


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So.

Great promise, but slower thanexpected

More complex than anticipated

- gene interactions

- appropriate vectors

- adequately targeting and sustainingtherapeutic effects

- safety issues

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