17 Questions
What is the main difference between somatic gene therapy and germinal gene therapy?
Somatic gene therapy alters cells of the hemopoietic lineages, while germinal gene therapy targets germ-line cells.
What kind of genetic chimera does somatic gene therapy create in the treated individual?
A genetic chimera with the transgene present in the target cells but not in other somatic cells or in germ cells
What is a key advantage of somatic gene therapy over germinal gene therapy?
The transgene is not transmitted to the offspring of the treated individual
Which type of gene therapy alters the germ-line cells which can pass on the therapeutic transgene to future generations?
Germinal gene therapy
What makes somatic gene therapy a potentially valuable treatment option for genetic diseases?
It can treat genetic diseases that show early symptoms in childhood
What is the primary advantage of non-viral delivery systems for gene therapy?
Longer lifespan in the body due to evasion of immune cells' digestion
What is a characteristic of X-linked SCID (SCID-X1)?
Characterized by the presence of the cytokine receptor common γ chain
Which type of gene therapy patient was Andrew Gobea identified as at birth?
Somatic gene therapy patient
How do molecular conjugates used for gene therapy differ from liposomes?
They involve attaching a DNA binding agent to protein or synthetic ligands
What is a key limitation of retrovirus-based gene therapy?
Temporary effectiveness with short-lived results
What is the primary cause of Severe Combined Immunodeficiency (SCID)-X1?
Deficiency in Adenosine Deaminase (ADA)
Which gene editing tool is adapted from bacterial 'immune systems'?
CRISPR/Cas9
What is the main purpose of Chimeric antigen receptor (CAR) T-cell therapy?
Target cell death in leukemia
What type of gene therapy was used to treat Emily Whitehead, the first child to receive CAR T-cell therapy?
Ex vivo gene therapy
What did two institutions do resulting in each institution paying fines of $500,000?
Under-reporting of adverse events related to a clinical trial
Which type of mRNA was mentioned as a potential treatment for cardiovascular diseases?
Naked but modified mRNA
What was the reason for the lead investigator's suspension from clinical research for 5 years?
Under-reporting of adverse events in clinical research
Study Notes
Gene Therapy
- Somatic gene therapy targets cells of various hemopoietic lineages, removing and treating them from bone marrow, and returning them to the same individual.
- This type of therapy turns the treated individual into a genetic chimera, with the transgene present in the target cells but not in other somatic cells or in germ cells.
- Somatic gene therapy can potentially treat genetic diseases whose phenotype becomes apparent early in childhood.
Germinal Gene Therapy
- Germinal gene therapy targets cells of the germ line, which give rise to gametes.
- This type of therapy alters germ-line cells, transmitting the therapeutic transgene to the progeny of the treated individual.
Non-Viral Delivery Systems
- "Naked" DNA plasmids have low efficiency and are most useful for ex vivo alterations.
- Modifications to stabilize DNA are necessary to evade digestion by immune cells.
- Passage into the nucleus is rate-limiting.
- Molecular conjugates, similar to liposomes, can target specific cells, but are usually short-lived due to degradation by the lysosome system.
Examples of Gene Therapy
- The first gene therapy was retrovirus-based and was used to treat Adenosine Deaminase Deficiency (ADA-SCID) in a four-year-old girl named Ashanti DeSilva in 1990.
- The second gene therapy patient in the USA was Andrew Gobea, who was tested and identified at birth with ADA-SCID in 1993.
Severe Combined Immunodeficiency (SCID)
- SCID is a severe defect in both T- and B-lymphocyte systems, which can be caused by several genetic defects.
- The most common type of SCID is X-linked SCID (SCID-X1), found only in males, characterized by the absence of the cytokine receptor common γ chain.
- Adenosine deaminase (ADA) deficiency is the next most common type of SCID.
Retroviruses in Gene Therapy
- Retroviruses have been used for gene therapy, but have raised concerns about under-reporting of adverse events.
FDA Approval of Gene Therapy
- In 2017, the FDA approved the first gene therapy for pediatric leukemia, which uses chimeric antigen receptor (CAR) T-cell therapy to target cancer cells.
- CAR T-cell therapy targets cell death in acute lymphoblastic leukemia (ALL), a type of pediatric leukemia that affects B-cells.
- Emily Whitehead, the first child to receive CAR T-cell therapy, has been cancer-free for 10 years.
Non-Viral Delivery (mRNA)
- Modified mRNA can be used to treat life-threatening cardiovascular diseases, such as heart failure, by promoting tissue regeneration.
Gene Editing
- There are two main ways to cut and replace specific regions of DNA proposed for gene therapy in humans: zinc finger nuclease and CRISPR/Cas9.
- Zinc finger nuclease is an engineered genomic scissor, while CRISPR/Cas9 is adapted from bacterial "immune systems".
Test your knowledge on clinical research ethics by answering questions related to the suspension of lead investigators, under-reporting of adverse events, and the FDA approval for gene therapy for pediatric leukemia.
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