Alzheimer’s treatment completes Phase I trial

woman walking beneath ancient oaksA new potential treatment for Alzheimer’s disease recently completed a Phase I clinical trial—a study designed to determine if the treatment was safe for Alzheimer’s disease patients

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:
Cholinergic neurons
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.

New Drugs for Alzheimer’s: The Energy Connection

Last Friday, I discussed drugs that treat the synaptic dysfunction of Alzheimer’s Disease (AD). This week we will look at drugs that aim to safeguard brain neurons by protecting their energy supply. These drugs affect the function of organelles within the cell called mitochondria.

If you remember mitochondria from past Biology classes, the phrase “powerhouse of the cell” may come to mind. The function of mitochondria is to produce ATP molecules, which the cell uses as a form of stored energy.

ATP stands for adenosine-tri-phosphate—basically an adenine nucleotide with three phosphate groups attached. The phosphate groups are highly positively charged. To push three positive phosphate groups together takes a lot of energy, because objects of the same charge repel one another. So energy is used to form the bonds holding ATP together, and can be released by breaking, or cleaving, the bond holding the third phosphate in place.

When neuronal mitochondria become less effective producers of ATP, neurons don’t have the energy they need for metabolism, repair, and signaling. If mitochondrial function is badly impaired, neurons die.

Looking for drugs that protect organelle function is a new approach to treating Alzheimer’s Disease, but it makes sense. Mitochondria dysfunction occurs early in AD and promotes synaptic damage as well as neurodegeneration. Furthermore, amyloid proteins can interact with the mitochondria to cause even more impairment in the brain.

When researchers began to study mitochondria in AD, they found that some drugs already in use (Donepezil and Memantine) helped preserve mitochondial structure and enhanced mitochondrial function. How much of their effectiveness in AD is due to mitochondrial protection and how much to receptor blockade is not yet clear.

One new drug that enhances mitochondrial function is currently being tested on AD patients. Thus far it appears that this drug, Latrepirdine, is effective and improves overall well-being in people with AD.

Related articles: Alzheimer’s Disease: physical changes in AD brain. Alzheimer’s Disease: biochemical changes in AD brain. Finding new drugs for the AD brain.

Finding new drugs for the Alzheimer’s brain

Some great drugs have been found by accident. We’ve all heard the story of moldy bread leading to the discovery of pennicillin. But usually, drug discovery is an intentional process. So where does a scientist start?

Three Problem Areas In Alzhimer’s Disease

You have to begin by looking at the disorder you hope to treat and asking, “What are the major problems here?” In Alzheimer’s Disease, the three most obvious problems are:  1) Synapses stop working properly. 2) Cells lack energy. 3) Proteins are misfolded.

Today we’ll look at how scientists target synaptic performance.

Synapses Stop Working Properly

A synapse is the point of communication between two neurons. Here is a picture of two neurons grown in the lab. A synapse between them is circled.

It is at the synapse that messages pass from one neuron to the next. Although the messages that  make up our thoughts and perceptions travel through the neuron as electrical impulses, when they reach the point of passage from one neuron to the next (the synaptic cleft) they move across as chemicals, neurotransmitters. Neurotransmitters drift across the synaptic cleft by diffusion.

It’s as if you were to race across town in one speeding car, then stroll leisurely to another, only to get in and take off once again at breakneck speeds. The electrical impulses travel… well, like lightning. But at the synapse, neurotransmitters gently diffuse across. On the far side of the synaptic cleft, the neurotransmitters interact with receptor molecules and the electrical impulses produced by that interaction race off to the next synapse.

The problems with AD that are most approachable in terms of drug development are at the synapse itself, and are involved with the neurotransmitters and their receptor molecules. Here is a screen capture of a diagram of a normal synapse:

You see the vesicles containing neurotransmitter in the axon terminal (left) and the receptor molecules on the dendritic spine (right). What is not shown in this diagram is a mechanism for clearing neurotransmitter out of the cleft. All synapses have some way of doing this, because otherwise the neurotransmitter chemical would just hang around stimulating the receptors and overexciting the next neuron in line. It would be like you turned on the radio and the volume kept automatically increasing. Really annoying if you can hear well, but not such a bad idea if you’re a little deaf.

In AD, where many neurotransmitter levels are decreased, this is not a bad thing. Many drugs being developed for AD are designed to increase the signal sent through the cleft by intentionally blocking the clearance mechanisms in order to make the signals stronger. Blocking clearance has the same effect as increasing the amount of neurotransmitter available.  Rivastigmine (sold as Exelon) and Galantamine (numerous trade names) work this way, by blocking clearance of acetylcholine from the synapse.

Another drug, Memantine (Namenda), blocks NMDA receptors for the neurotransmitter glutamate.  NMDA receptors are one of six varieties of glutamate receptors, and though they are important in normal brain function, if they are overstimulated, they can actually kill neurons. Blocking the NMDA glutamate receptors, while leaving the other glutamate receptors alone, seems to improve function in many Alzheimer patients. The Alzheimer Reading Room recently ran a post on Memantine research.

Many other drugs in development act on synapses is ways similar to these three. Someday, researchers hope to give physicians a broader choice of remedies for synaptic problems than are available now.

Other posts related to this one:             Alzheimer’s disease: biochemical changes in AD brain             Neurons: you know you’ve got them, but what are they really?            Alzheimer’s disease: physical changes in AD brain            Brain Basics: a look at normal brain

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