The Phase I trial
Phase I studies are performed on a relatively small number of volunteers—ten in this instance—for the primary purpose of establishing the safety of a treatment method before proceeding to larger trials designed to determine if the treatment is effective.
There is a lot of red tape to get through before this (or any) Phase I trial is allowed to begin. Multiple review boards check the proposal, informed consent must be obtained from the volunteers, and the design of the experiment is scrutinized to ensure that it will produce a clear answer to a single question: Is this treatment safe?
This particular Phase I study used CERE-110, a gene therapy construct owned by Sangamo Biosciences, and a stereotaxic delivery method unusual in human trials. Results were reported in, *A phase 1 study of stereotaxic gene delivery of AAV2-NGF for Alzheimer’s disease,* published in the September issue of the scientific journal *Alzheimer’s & Dementia.* (full reference at end of post)
Protecting at-risk neurons
What this treatment aims to do is use targeted genetic therapy to protect neurons that normally degenerate and die in Alzheimer’s disease.
Let’s back up a little and explain the idea behind this:
It’s been known for a long time that among the first neurons to die in Alzheimer’s disease are neurons in a particular part of the brain (the basal forebrain) that produce and use the neurotransmitter acetylcholine (abbreviated ACh). Neurons that make ACh (a.k.a. cholinergic neurons) send it from their cell bodies to the ends of a communicating process called an axon. When a message must be transmitted from one neuron to the next, the communicating axon releases ACh onto the receiving terminals (called dendrites) of the next cell in line. When that next cell is stimulated by ACh, the message has been passed.
Now imagine that you are a neuron, and that a message is passed to you when a friend pokes you in the arm. Would it be a good idea for your friend to continue poking you in the arm repeatedly, over and over again, after you had already received the message? Clearly not. You would want them to pass the message and then stop prodding you.
Similarly, the neuron needs a way to halt the ACh signal once a message has been received. To stop the signal from going on and on, the receiving neuron produces a molecule called acetylcholinesterase (abbreviated AChE). AChE’s job is to destroy ACh, thus stopping the signal.
In Alzheimer’s disease, cholinergic neurons are degenerating and dying. As this happens, the amount of ACh available to pass messages is decreased. And what little ACh there is, is getting chewed up by AChE. I’m sure you realize that it might be a good idea to stop AChE from destroying acetylcholine molecules.
That’s what biomedical researchers thought also, and today most of the drugs used to treat Alzheimer’s Disease are anticholinesterases—molecules that inhibit AChE, blocking it from destroying ACh.
Anticholinesterase drugs help many with Alzheimer’s, but their dosage must be carefully monitored because in excess these chemicals can cause severe negative side effects, and they are far from being a cure. Unable to rescue dying neurons; these drugs merely boost the signal a degenerating neuron can produce. Helpful? Yes. But merely as a way of getting messages through.
Nerve Growth Factor
Nerve Growth Factor (abbreviated NGF) is a protein that is continuously provided to cholinergic neurons in healthy brain. NGF keeps those neurons alive and functioning. It seems obvious that giving NGF to someone with Alzheimer’s might be a way to stop neurons—at least the cholinergic ones—from dying.
Of course, nothing is ever that simple. Factors like NGF are extremely potent—spreading them randomly throughout the body and brain would likely cause more problems than it would solve. And NGF, like all proteins, has a limited lifespan—it gets old, becomes ineffective, and is removed from the cell. So in order to rescue cholinergic neurons in a human brain, you would need a long-term input of NGF, targeted to the precise region where cholinergic cells were dying.
Long-term input of NGF
How to provide long-term input of NGF? Well, in the past you would have needed some kind of refillable pump that could provide fresh NGF to at-risk neurons over a period of years. The thought of any mechanical approach to providing a factor to the brain for years at a time probably makes you shiver—and well it should. Mini-pumps exist, but to put one in the brain would destroy more brain tissue than is acceptable. So perhaps a delivery device—a super-thin tube leading into the brain with the pump tucked away under the skin somewhere. Again, impractical. The risk of problems while maintaining such a set-up over a timeframe measured in years is much too high.
The solution turns out to be elegant and based on genetic engineering. We can take DNA for NGF—the instructions for making NGF protein—and insert these instructions into cells in the neighborhood of at-risk neurons. This should provide a long-term source of NGF following a single minimally-invasive surgical event.
The NGF instructions in the Phase I trial were attached to a viral vector.
All viruses have the ability to insert their own DNA into our cells. This is how viruses infect us. In genetic engineering, the viral ability to insert DNA into cells can be used to deliver non-viral DNA. To do this, the original virus is so altered that virtually nothing except the delivery mechanism remains. So a viral vector is simply a way to deliver specific DNA instructions to a cell—any cell—in the vicinity of the vector.
When humans are involved, however, extra care is taken. So, in the Phase I trial, extensive work and experimentation was carried out ahead of time to insure that the viral vector produced only human NGF, with no viral components. Then all that remained was to place the vectors into the precise brain regions where cholinergic cells were degenerating.
Targeted delivery of NGF
To be effective, NGF must be provided to the specific brain regions where cholinergic neurons are at-risk. This is done by a process called stereotaxic injection. Sophisticated imaging techniques are used to locate the precise regions of the brain normally inhabited by at-risk cholinergic cells. Small holes are drilled through the skull and precise injections of viral vector carrying NGF DNA are made. This technique is only minimally invasive, and requires very little recovery time.
Results of the trial
In the Phase I trial, injections were made using three different concentrations of vector. There were no ill-effects of the injections.
Two years later, the cells that had received the NGF DNA were still producing NGF protein. By the end of the six year study, five of the ten participants had died of causes unrelated to the experimental treatment. (You must remember, they were old when the study began.) These participants had agreed to donate their brains to science, and examination of those brains showed that the experimental treatment had not caused any unexpected damage to the brains. (There were, of course, the “normal” lesions found in Alzheimer’s disease brains.)
Did the treatment help?
We will have to wait for results from the Phase II trial to know that.
Tests designed to measure function were given to the Phase I trial participants, but it is impossible to say anything about improvement or a lack of improvement based upon the small number of persons receiving each dosage of DNA. While the number of participants was enough to establish a lack of severe negative side effects, subtle changes in brain function will require data from many more volunteers. Still, it is exciting and hopeful that this treatment option has been shown to be safe.
Raffia MS, Baumann TL, Bakay RAE, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, Chu Y, Kordower JH, Bishop K, Keator D, Potkin S, Bartus RT. A phase 1 study of stereotaxic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement 2014;10:571-581.
As usual, in this informal report, I have not referenced information that is common knowledge among those who study Alzheimer’s disease. However, the report itself has an extensive reference list for those who wish to track down further detail.