Ex vivo genetic intervention to treat Alzheimer's

In a number of my posts describing the potential hazards posed by gene therapy techniques I explained that discoveries made by the ENCODE project research teams disclosed that much more than just specifically targeted genes were involved in the transcription process -- that the complete RNA template was comprised of a combination of gene segments and non-genetic DNA components constructed around the primary gene for the purpose of synthesizing proteins. I reported that at least one death and the development of a number of leukemia's had directly been attributed to the gene therapy process whereby a viral vector was used to deliver the "fixed" gene into the cell and where it was left to the cell machinery to incorporate the gene into its DNA. I concluded that we had much to learn before incorporating this otherwise elegant method of correcting "broken" DNA into an effective gene therapy for healing genetically inherited diseases and other disorders involving mutant alleles. Now experiments conducted on mice which had been treated to develop rapid onset of Alzheimer's demonstrate that ex vivo manipulation of the genetic information to generate amyloid plaque-ridding enzymes in the brain cells of the mice may prove that method to be a safe and workable therapy.

The procedure involves making genetic changes to cells taken from the patient and then putting back the cells. Introducing modified cells into the brains of the mice showed "..robust clearance of plaques in the brains of the mice" in the experiments carried out by Dennis Selkoe, Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School. In the Harvard study a gene for the enzyme neprilysin was introduced into skin cells taken from the mice which were subsequently planted in the brain.

The technique has not as yet been tried on humans. Apparently logistical problems involving the blood-brain barrier can be overcome but humans have a much larger brain than mice, making effective treatment using this method somewhat problematic since this requires more precise delivery of the modified cells to the affected areas where the amyloid plaques have gathered.

The body's own immune response to the buildup of amyloid plaques in the AD brain has been studied. Microglia are the phagocytes of the brain -- that is, these are the cells that engulf and absorb waste material, harmful microorganisms, or other foreign bodies including plaque material in the brain. Their efficacy is notable only in the early stages of AD and it is assumed that their inflammatory responses are ultimately detrimental because their action can't keep up with plaque production. They do have the unique property of being able to target the plaques directly in a process in which the amyloid beta release a chemotactic protein which serves as a homing beacon for migrating microglia.

It is tempting to think of a scenario whereby an AD patient's microglia might be harvested and then the gene for the enzyme neprilysin introduced into them thereby leaving the issue of targeting the plaques to the body's own defenses. This may or may not be possible as the microglia may not have those benign properties which make the skin cell such a suitable candidate. On the other hand, the homing properties of the microglia might be incorporated into the patient's modified skin cells. Either way, I admit that I am being purely speculative and can offer only ideas.

"Reality leaves a lot to the imagination"
- John Lennon