DRUG COCKTAILS In order to find new treatments and get them to patients in the shortest time, the May ALS Center is utilizing an innovative strategy to test/identify therapeutic combinations - so-called drug "cocktails" - comprised of as many as four different agents. We are testing drugs which are either already approved by the FDA for other diseases and conditions, and nutraceuticals (e.g., compounds derived from foods, spices, and herbs). Generally Regarded As Safe (GRAS) by the FDA based on years of human use. We are also testing a third class of agents known as metabolic precursors (which are also GRAS). Approved drugs, nutraceuticals, and precursors are collectively referred to as agents.
The concept of drug combinations - or "cocktails" isn't new. The idea of using several drugs, each working via a different mechanism, has been a mainstay in cancer and HIV-AIDS chemotherapy for years. However, combinational therapy of drug cocktails is relatively new to ALS. In cancer and HIV, the goal is to kill the abnormal cells, be they tumor cells or viruses. In ALS, the goal is to prevent the death of motor nerves in the spinal cord, but the principle is the same: identify agents that work by different mechanisms, so that they can produce additive, or synergistic therapeutic effects.
ADDITIVE VS. SYNERGISTIC
When the final therapeutic effect equals the sum of the parts, we refer to it as additive, i.e. 1 + 1 = 2. In rare instances, the final result is greater than the sum of its parts: such effects are referred to as Synergistic, 1 + 1 = 3, or 4, or even 5. Synergies are difficult to predict, often unexpected and the results of lucky coincidences. An example of a synergistic effect is a car with disc brakes on all four wheels, as opposed to just two: you can stop 4X faster with only 2X more brakes.
It is also possible for an agent to contribute to the total therapeutic effect even though it may not have any effect on its own. We have seen evidence of such a combination in our laboratory (i.e., total effect of 4 combined agents was better than 3 agents) even though the 4th had no beneficial effect when tested alone. These effects are relatively rare, but knowledge of how different agents work can help predict them in advance.
"FINGERPRINTING" OF THERAPEUTIC AGENTS
We are employing a new, state-of-the-art technique to help us determine which agents are more likely to have additive therapeutic effects: our technical name for this is "proteomic fingerprinting". Each therapeutic agent will produce specific changes in the molecular make-up of the spinal cord - its own specific fingerprint. If two agents produce very similar fingerprints, the odds are that they are working by similar mechanisms and, therefore, not likely to have additive effects. However, if they produce different fingerprints, then they will be more likely to act in an additive manner. The results of our proteomic fingerprinting work will not only help us formulate therapeutic cocktails, but also has the potential of providing new ways to monitor the effects of therapeutic agents, and even to predict who is at risk for ALS long before symptoms appear.
STOPPING THE PROGRESSION
Years of research by many laboratories worldwide have yielded several important clues as to how and why spinal motor neurons die. It is now clear that death signals (in the form of specific chemical messengers) flow from dying motor neurons to healthy ones. These signals may also come from other spinal cord cells known as glial cells. The flow of death signals can be likened to a river which is fed by many smaller streams and tributaries. The "magic bullet" cure for ALS would be a drug (or drug combination) which dams the river, and shuts off all death signals to the neurons. However, that has proven to be very challenging, because we don't yet know where these chemical signals converge into a common river. Also, it may well be that sources of these signals differ slightly from one individual to another. That is, one stream may contribute more to total river flow in one person and a different stream may be more important in someone else.
The alternate strategy we are aggressively pursuing uses several agents simultaneously (drug cocktails), where each agent shuts down one of known streams, and thereby, slows the flow of the entire river. Thus, we are seeking to slow the flow that produces the relentless loss of spinal motor neurons until such time that we can stop it entirely, and end this terrible disease. Not only are we looking to slow the flow, but to preserve the best possible quality of life in the process. We are learning more about how to do this every day and with your continued support, we will ultimately succeed.