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Gene Therapy and Exudative Age Related Macular Degeneration
Tracy Doll, OD
Portland Veterans Administration Medical Center
Contents
- The Current Impact of Age Related Macular Degeneration
- Genetic Disease: The Human Genome Project and Mutations
- Gene Therapy
- Gene Therapy in Pre-Clinical Trials
- Gene Therapy in Clinical Trials
- Future Applications: TrpRS, Nanoparticles, Other Therapy Categories
- Conclusions
- Sources
- Exam
The Current Impact of Age Related Macular Degeneration
Age Related Macular Degeneration (ARMD) is the leading cause of blindness in Industrialized Nations[1]. Currently 1.8 million Americans over the age of 40 are affected with advanced age related macular degeneration. This number is projected to grow to 2.9 million by the year 2020[2].
Prevent Blindness America released a report this April estimating the cost of adult related vision related disorders (including age-related macular degeneration, cataract, diabetic retinopathy, primary open-angle glaucoma, refractive error, visual impairment and blindness) at $51.4 billion. An estimated $575 million is spent solely on ARMD costs[3].
New potential methods of ARMD treatment and management are currently being researched in hopes to lessen the impact ARMD has on our society. |
 Exudative ARMD Portland VAMC |
Genetic Disease: The Human Genome Project and Mutations
The Human Genome Project was completed in 2003 and it was revealed that there are somewhere between 30,000 and 40,000 human genes [4]. Maps were then produced showing the locations of the important parts of our chromosomes that are responsible for our inherited traits, including the traits that cause disease. These working portions of our chromosomes could potentially identify new technologies of disease prevention and treatment.
Diseases can be caused by a defect (mutation) in only one gene, multiple genes, or in combination with environmental factors. It is becoming more evident since the advent of the Human Genome Project that many diseases have some genetic component.
A mutation is a change to a base pair that could be caused by copying errors, radiation, viruses, or ordered by the cell itself. The following types of mutations apply specifically to genes [5-7]:
- A point mutation is when one nucleotide (base) is replaced by another nucleotide.
There are three types of point mutations:
1. Silence: the same amino acid is still made
2. Missense: a completely different amino acid is made
3. Nonsense: code for a stop codon and stop protein synthesis
- An insertion mutation is when a nucleotide is added
- A deletion is a nucleotide is left out
Genetic Links to ARMD
Past studies have alluded to the possibility that specific genes could be responsible for the susceptibility of developing ARMD. Twin concordance and linkage studies have shown varying genetic linkage for different ARMD subtypes[1]. First-degree relatives of those with ARMD are also three times more likely than controls to develop ARMD [1].
Current research is now showing that in fact there are specific genes linked to age related macular degeneration.
A mutation in the complement factor H (CFH) gene could allow damage from inflammation in the retina to occur. This damage has been theorized to lead to ARMD. Three separate studies showed this link to ARMD with CFH [8].
The CST3 gene aids in the inhibition of enzymes that allow RPE to effectively process rod outer segments. A variant in the CST3 was also linked to exudative ARMD [1].
Two additional studies have confirmed a connection to ARMD with a mutation in Chromosome 1q31[1].
Apolipoprotein E ε allele deficient mice exhibit accumulations in the retina similar to human drusenoid changes at an earlier age than control mice. The E ε2 allele is associated with a 50% increased risk [1] of ARMD development.
Finally, the ABCR gene at chromosome 1q21 has been linked to genetic dystrophies similar to ARMD, such as Stargardts. Conflicting studies suggest that missense mutations in the ABCR gene may be more common in non-exudative ARMD patients vs. controls [1].
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