Gene Therapy: Gene Therapy: Molecular Bandage?Molecular Bandage?

An Overview of the curriculum module available on

Learn.Genetics

What is gene therapy?

• A way to treat diseases caused by mutated genes

• Adding a normally functioning copy of the gene(s) to enough affected cells to restore normal function.

Which disorders are candidates for gene therapy treatment?

• Disorders due to mutations in one or more genes– Single-gene disorders are more easily treated

• The responsible gene is known– Copies have been made in the laboratory– The role of the protein encoded by the gene is known– Adding a normal gene will fix the problem

• The affected tissues are known and accessible

Hallmarks of Successful Gene Therapy• Targeting the right cells

– Ensuring that the gene gets to the affected cells

• Activating the gene– The gene must get into the cells’ nuclei– The gene must be “turned on”; i.e., transcription

and translation must take place at the correct time

• Integrating the gene into the cells– DNA is integrated into the cells’ chromosomes or

otherwise survives in the nucleus

• Avoiding harmful side effects– The gene delivery vehicle must not trigger an

immune response

How do you do gene therapy?

• Identify the gene responsible for the disorder• Make copies of the normal gene• Insert the copies into vectors (such as viruses)

– Remove the viral DNA– Insert the gene of interest

• “Infect” the affected cells with the vector– The normal gene is carried into the nucleus– The DNA may integrate into the genome

• Activate the gene– Transcription and translation takes place

Critical factors in choosing a vector• Gene size

– Most vectors have an upper limit on the number of base pairs they can hold

• Target tissue– Some vectors only infect a particular type of cell– Other vectors can be engineered to infect a particular

type of cell

• Integration into the genome– Vectors that do not lead to genome integration have a

short-lived effect– Vectors that integrate into the genome or are copied

along with the genome have a long-lasting effect– Vectors that lead to random integration may disrupt

other genes leading to negative side-effects

Ways to Deliver Genes

• In Vivo– Inject the vector directly into the desired cells in the

body

• Ex Vivo– Isolate the desired cells from the body– Culture the cells in a Petri dish in the laboratory– Deliver the genes to the cells using a vector– Activate the genes and make sure they have

integrated properly– Return the modified cells to the body

Challenges in Gene Therapy• Gene delivery and activation

– Genes must be delivered to a large number of cells (several million) of the affected tissue

– The genes must be activated for transcription and translation to take place

• Introducing changes into the germline– Not causing changes in sperm or eggs, if this is not

desired

• Triggering an immune response– Can be fatal

• Disrupting genes in the target cells– Can cause other diseases or problems

Gene Therapy Successes & Failures

Ethical and Social Issues

• Patient safety while participating in clinical trials

• Which applications are therapies and which are enhancements?– “Designer” babies

• Effects on future generations if germline cells are allowed to be altered

• Access to gene therapies

Gene Therapy Module on Learn.Genetics:

Tools of the Trade

Space Doctor

Cystic Fibrosis Case Study

Vector Selector

• You are a researcher at Advanced Bio Delivery Systems

– Supplies gene therapy vectors

• Marketing department requests your assistance– Want to sell ABDS vectors to biotech companies

pursuing specific gene therapies

• Your job:– Research disorders these companies are targeting– Decide on the vector that you think will work the best

Vector SelectorKey issues in deciding which vector to select:• Size of the gene

– Will the replacement gene fit into the vector?

• Tissue type– Does the vector naturally target, or can it be

engineered to target, the appropriate type of cells?

• Cell cycle stage (dividing vs. non-dividing)– Are the cells at the right stage of the cell cycle for

the vector to “infect” them?

Vector Selector• Read the situation assigned to your group• Decide on the best vector to use for that

disease– Use the Vector Types Table as a reference to

assist in making your decision

• Select a reporter who will report:– The disease– The vector you selected– The reasons why you thought this was the best

vector for the job