Originally posted by MPS
In his last post, Andrew mentioned gene therapy as a topic of research in ophthalmology. Is anyone out there convinced of its possible merits?
Most of the research I've seen in the area has been in regard to retinal degenerations. It seems to be fundamentally flawed: a best case scenario is that we could achieve transfection of 50% of retinal cells (e.g. RPE). However Chimaeric mouse models show that dystrophic cells cause degeneration of normal cells. Taken together, these two pieces of information would suggest that it?s a waste of time.
MPS,
Medicine is still in it's early stages of genetic research. It's only been months that the sequencing of the human genome was completed.
You're correct that our transfection methods have fairly low gene delivery rates. But with discovery of new viral vectors and methods of transfection, these rates could easily increase within the next decade.
I also think the best targets for gene therapy are the retinal degenerations where genetic mutations have been identified. For example, in enhanced S-Cone syndrome, a.k.a. Goldmann-Favre disease, the genetic mutation is in the transcription factor NR2E3 which is a homolog of tailess. The NR2E3 transcription factor controls the development of photoreceptors in the retina. Mutations in NR2E3 causes accumulation of blue cones and the lack of rods and red & green cones. This occurs because blue cones are the default pathway for photoreceptors and NR2E3 regulates photoreceptor development. One can foresee that successful transfection of a functional gene may help the blue cones differentiate into the other types of photoreceptors. The problem is discovering when NR2E3 triggers photoreceptor differentiation and development.
A more hopeful example is retinitis pigmentosa (RP). One form of RP is due to a genetic defect in a rod cGMP phosphodiesterase, resulting in abnormal levels of cGMP resulting in cell death (
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nm/journal/v5/n10/full/nm1099_1183.html). Gene therapy would be helpful here by introducing normal rod cGMP phosphodiesterase to help regulate the levels of cGMP and preserve photoreceptor function. Even with 50% gene delivery, with today's technology, we may preserve up to 50% of photoreceptor function, which would be vision saving for a patient with retinitis pigmentosa. If the first treatment was inadequate, then we may increase gene delivery with a second or third treatment.
Some degenerative diseases are believed to be triggered by adjacent "dystrophic cells" as you mentioned, which subsequently cause the death of normal cells. If we can deliver the right gene to the dystrophic cells, then we can either slow down the vision loss or halt it completely. In a 40 year old patient, delaying the visual loss for 10, 20 or even 30 years would be tremendous. This patient could live a full life, work, and retire before visual impairment becomes disabling.
I anticipate the next wave of research will focus on "smart" gene delivery where we can target specific cell types via unique extracellular surface proteins, similar to how the HIV virus can find CD4 cells and bind to the gp120 surface protein.
There's huge potential for gene therapy in ophthalmology. The eye is an ideal organ too because:
1) there's a blood-ocular barrier that will reduce systemic side-effects.
2) delivery of genes can be injected directly into the eye with good concentration of the vector.
3) many retinal diseases are the result of a defect in a single gene product.
I am optimistic that, with increased knowledge in medicine and disease, we'll see amazing things in the next century.
