Bioengineering for Gene Therapy by David Schaffer #rejbio

Molecular engineering of gene therapies for the nervous system

DNA as medicine

Historical timeline in molecular medicine development
started with small molecules (1908 start)
Protein therapies (1920s start)
gene therapies (1980s had some therapies that were somewhat effective)
Stem cells (1960s start)

More chronic health conditions are now the problems.
Chronic age related disease
alzheimers, parkinsons, etc…

Three problems of gene therapy – delivery, delivery and delivery

Adeno associated virus (5 kilobases – AAV)
60 units of CAP protein assemble to form icosahedral capsid

numerous natural variants have been isolated
non-pathogenic.

Highly safe 90% of human population exposed to AAV

recent success curing gene based blindness
fixing Leber’s congenital amaurosis
success against hemophilia B

Taking care of rare monogenetic disease to gain momentum
Derisk the therapies
Lipoprotein lipase deficiency (AAV)
Choroideremia (AAV)

Need better delivery vehicles.
pre-existing immunity to AAV

Each of the viruses have issues
murine retrovirus

Nature did not evolve viruses to be used as human therapies

Continual viral evolution to get the right properties for biomedical applications
Using directed evolution to make designer viruses for medical applications.

Inner limiting membrane – barrier to delivering genes against blindness or other eye problems

evolve virus to penetrate the inner limiting membrane

Retinoschisis (another eye disease)

work on mouse model to delivery treatment and rescue the retina

5 kilobases is the max payload size, they are working to engineer larger version of the virus.
There are also approaches to try to cutdown the size of the payload while maintaining effectiveness

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