Cystic Fibrosis

Korben Bergmann

Cystic Fibrosis (CF) is a disease that causes a thick buildup of mucus in the lungs,
pancreas, and other organs (Pamela B. Davis). This causes bacteria to be built up in airways
that are blocked up by mucus, and can also hinder the release of digestive enzymes from the
pancreas. These effects can be devastating, especially in the airways, where it can lead to lung
damage and even death (About Cystic Fibrosis). This is why patients with CF are only expected
to live for another six months after diagnosis (Pamela B. Davis). Thankfully, in 1989 the
scientists Lap-Chee Tsui, Jack Riordan, and Francis Collins discovered the CF gene, which
resides on chromosome 7 and is 250 BP long (Pamela B. Davis). Since the discovery, scientists
have been studying different paths for treatment. Some have taken a more conservative route to
look into different treatments for the symptoms, while others have gone for a more aggressive
approach to curing the disorder with gene therapy methods like Adeno-associated virus (AAV)
(U Griesenbach et al).

In order to use AAV for gene therapy, one must edit the genes expressed. The method
that is widely used, is known as viral packing (Wei Zhang, Michael J. Imperiale), where the virus
encapsulates outside DNA (Wei Zhang, Michael J. Imperiale). Knowing this, the scientist takes
previously extracted AVV DNA from other virus and use enzymes to cut the DNA. From there
they allow the original DNA to be repaired with a functional CF gene in vitro. After the process
is done and with any luck, an AAV would be successfully formed.

Adeno-associated virus is an incredibly small virus (25-nm) with single-stranded DNA

encased inside of it (Shyam Daya, Kenneth I. Berns). Interestingly, AAV-2 (Adeno-associated
virus stereotype 2) can perform site-specific chromosome insertion, where it will insert itself onto
chromosome 19q13.4. (Shyam Daya, Kenneth I. Berns). This is has made AAV-2 very attractive
for gene therapy, because it would allow scientists to be certain that the gene ends up in the
correct spot to avoid unwanted consequences. In CF studies, the use of AAV-2 had increased in
the past, but therapeutic challenges remain. One of these challenges comes from the hosts
immune system after repeated administrations of AAV-2 (U Griesenbach et al). Repeated
administrations are needed for AAV-2, because not all the affected cells will be altered the first
time around, and as Shyam Daya, Kenneth I. Berns points out that after the first infection of
AAV-2, 96% of patients had antibodies developed, with 32% of those patients having the ability
to neutralize AAV-2 (Shyam Daya, Kenneth I. Berns). Because of this problem, the use of
AAV-2 has decreased in the last three years, but some studies have continued to use them. In
these studies, it has been shown that AAV-2 has been able to decrease bacterial load in the
airways, but is still limited by the body's immune response (Shyam Daya, Kenneth I. Berns).

Unfortunately, due to AAV inefficiency, it will not be a good choice for gene therapy.
While AAV theoretically could be a good choice for gene therapy, it lacks the efficiency to
perform gene repair. Because of this bottleneck, the only way to get around it would be to cause
the body to identify the virus as self or repress the body's immune response, which could be
detrimental to the health of the patient. While research should continue to be done on AAV,
more energy should be directed at other areas of gene therapy for CF (U Griesenbach et al).

Citations
"Cystic Fibrosis Foundation." About Cystic Fibrosis | CF Foundation. N.p., n.d. Web. 07 Mar.
2017. <https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/>.

Davis, Pamela B. "Cystic Fibrosis Since 1938." American Journal of Respiratory and Critical
Care Medicine. N.p., 1 Mar. 2006. Web. 07 Mar. 2017.
<http://www.atsjournals.org/doi/full/10.1164/rccm.200505-840OE>.

Daya, Shyam, and Kenneth I. Berns. "Gene Therapy Using Adeno-Associated Virus Vectors."
Clinical Microbiology Reviews. American Society for Microbiology (ASM), Oct. 2008. Web. 07
Mar. 2017. <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570152/>.

Pozsgai, Eric R. "Systemic AAV-Mediated Beta-Sarcoglycan Delivery Targeting Cardiac and

Skeletal Muscle Ameliorates Histological and Functional Muscle Deficits in LGMD2E mice."
Molecular Therapy. N.p., 28 Feb. 2017. Web. 7 Mar. 2017.
<http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(17)30090-
4>.

U, Griesenbach, DGeddes M. D, and Alton W F W E. "Gene therapy progress and prospects:

cystic fibrosis." Nature News. Nature Publishing Group, 01 July 2006. Web. 7 Mar. 2017.
<http://www.nature.com/gt/journal/v13/n14/full/3302809a.html>.

Zhang, Wei, and Michael J. Imperiale. "Interaction of the Adenovirus IVa2 Protein with Viral
Packaging Sequences." Journal of Virology. N.p., 01 Mar. 2000. Web. 09 Mar. 2017.
<http://jvi.asm.org/content/74/6/2687.full>.