Exam 2 Study Guide Flashcards
Definition and Description of Gene Therapy
Gene therapy is defined as a set of strategies that modify the expression of an individual’s genes or that correct abnormal genes.
Each strategy involves the administration of a specific DNA (or RNA).
When is Gene Therapy effective?
Single gene, simple problems
Like Hemophilia
Rhetts syndrome
Spinal Muscular Atrophy
Leber’s Congenital Amausorsisi
When is Gene Therapy not effective?
Multiple gene disorders, complex disorders
Like diabetes
Obstacles to CNS gene therapy:
Bone
Bones (skull, vertebral column)
Only certain patient populations can tolerate a procedure that drills through bone.
Obstacles to CNS gene therapy:
BBB
The BBB is formed primarily of Epithelial Cells that form tight junctions that keep things out, including disease and medications. Due to factors of size and charge, many molecules cannot get past the BBC.
Obstacles to CNS gene therapy:
Anatomy
Spinal Motor Neurons
Once you have gotten beyond bone and the BBB, astrocytes present another defense.
Astrocytes can also modulate the rate at which the brain’s vasculature lets things in and out.
Obstacles to CNS gene therapy:
Widespread pathology
Example of a disease with widespread pathology: Alzheimer’s
Can one possibly design a treatment that would go after literally everything in the brain and fix it?
Obstacles to CNS gene therapy:
Multiple targets
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Ways to deliver gene therapies:
Direct Injection
Cerebrospinal Fluid (CSF)
Retrograde Transport
Systemic Injection
NON-Viral Vectors
Scaleable, ease of manufacture:
“You can make a bucket of this stuff.” Viral vectors are more complicated.
Transient Expression: It’s active for a short time and then it goes away. This can be good (when someone has an adverse reaction or low tolerance) or bad (need to keep injecting for chronic conditions).
High payload capacity
Customizable
Liposomes
Polymers
Molecular Trojan Horses
Nuclear Entry –> RNAi
Advantages of Non-viral over viral vectors
Nonviral less likely to stimulate immune responce.
Nonviral is easier to produce large-scale.
Very transient.
Viral Vectors
Types
Adenovirus
Lentivirus
Adeno-Associated Virus
Prosavin
Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease
Improves motor symptoms in
lesioned NHP
No dyskinesias
In Phase I/II in Britain
Advantages over “naked” RNA/DNA transfer
Free Floating Nucleic acids stimulate immune responce = bad (unless in the case of Adenivirus and cancer)
Phosphates carry a negative charge. Both DNA and cell membranes have of these negative components. Negative and negative don’t go together, so they repel each other.
Thus a vector is needed to get DNA in the cell.
Basic biology of SMA
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