The mechanism of autophagy is a normal cellular process by which the cell degrades proteins selected for elimination or entire organelles. This process has been described for many years, and it was thought to be needed to survive in conditions of lack of nutrients. When cells are starved of nutrients, in order to survive, they induce this process to try to generate energy from its own internal organelles. The process allows cells to survive through rough periods. After nutrients (amino acids) are available for growth, the autophagy pathway is inhibited. The autophagy mechanism is tighly regulated as one can imagine, and it is intimately connected with a variety of signals which allow a cell to divide or to grow. The autophagy mechanism was initially found in single-celled organisms, where it allowed those organisms to survive during difficult periods where environmental conditions were such that energy sources were scarce. Similar mechanisms, as it is often the case in biology, are conserved throughout evolution, and is also present in human cells. When a cell is exposed to nutrient rich environments, and to growth factors, the cell can divide and grow, since there is plenty of energy around. Without certain growth factors, the cells stop growing and can induce the process of autophagy. I am attaching a schematic below from an antibody product company (abcam) that I found on the web, so you can see the exact details of the process.
Autophagy is a mechanism utilized normally in cells to degrade certain proteins (and not just organelles, which is termed macroautophagy as a way to distinguish it from regular autophagy), which are misfolded or that dont belong to the organism (such as after a bacterial or viral infection, typical intracllular parasites). This mechanism allows the cells to degrade these proteins, and turn them into its constituents parts, the amino acids. These can then be reutilized for building up good proteins in the cell. It has been known for several years that the process of autophagy is needed for several organs to function normally, including the brain. If some of the genes which form necessary components of autophagy are deleted through genetic techniques in mice (through the technique called homologous recombination), these mice develop neurodegeneration because the process of autophagy is necessary during development of the brain. There are similar roles for autophagy in other tissues, such as the immune system. So autophagy is necessary for life.
As with many normal process which are tightly regulated, too much or too little is not good. Induction of autophagy in ways that are not subject to its normal regulation also can lead to disease. The secret of autophagy beneficial roles is its tight regulation by a variety of signals (such as nutrients or growth factors). For instance, in several cancers, the cancer cells evade death by inhibiting the autophagy pathway (which would normally be induced when cancer cells grow continuously in the absence of the normal growth factors which regulate the number of cells in a tissue). So many companies have been developing ways of inducing autophagy modulating small molecules to selectively kill the cancer cells.
Since autophagy mechanisms also degrade certain kinds of proteins in the cell, scientists studied whether the process of autophagy could be effective in degrading proteins known to cause neurodegeneration (such as in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease). In all of these diseases, some proteins are toxic to the cell. Therefore, eliminating those proteins should delay the progression of the disease. When scientists stimulated autophagy (for example, using small molecule inhibitors of the protein called mTOR), they observed that these toxic proteins could be cleared from the cell, and therefore mouse models of these diseases (engineered genetically to express mutant versions of these proteins which cause the human disease) were less sick. One such molecules is called rapamycin which is a marketed drug used for transplant rejection. In the case of HD, several groups reported that rapamycin adminstration delays the disease. These studies showed that inducing autophagy might be a novel way to treat degenerative conditions such as HD.
However, one problem with the clinical use of rapamycin for chronic conditions such as PD or HD is that there is significant toxicity observed in patients treated with this drug. Therefore, it seems that this drug cannot be used for long term usage (such as for HD). The mechanism of toxicity is dependent on the ability of rapamycin to inhibit signaling by mTOR, and therefore all treatments which eliminate mTOR signaling will display similar problems. Until recently, it was not known whether autophagy could be induced by other mechanisms which did not inhibit mTOR. Recently, scientists have demonstrated that indeed, there is a way to induce autophagy and degradation of brain toxic proteins (such as in HD) without touching mTOR signaling. This was a great finding since it opened the way to new ways to inducing autophagy and which might have more success as chronic treatments for neurodegenerative conditions.
At the CHDI Palm Springs conference, the company Link Medicine showed evidence from Alzheimer’s and Parkinson’s mouse models which showed that their lead molecule (LNK-754), currently in Phase II in the clinic, could induce autophagy and eliminate the toxic proteins. This molecule completed two Phase I studies in human subjects safely, opening the way for Phase II studies in people suffering from neurodegenerative conditions. CHDI and Link Medicine are currently testing this molecule for Huntington’s disease, and it is possible that a clinical study will be conducted to assess whether LNK-754 can be beneficial for HD as well. It is likely that there will be findings from AD or PD earlier than for HD, so we will know in the next couple of years whether this mechanism and molecule are better tolerated that rapamycin or other molecules for the treatment of slowly progressive mental disorders.
LNK-754 inhibits the activity of a protein called farnesyl-transferase (FT). This class of molecules are called FTIs (or farnesyl-transferase inhibitors). As with mTOR inhibitors, many companies developed them to treat cancers, where they were unsuccesful. The mechanism by which FTIs work is through inhibition of this enzyme, which adds a fatty acid molecule to proteins (such as the oncogene, or cancer-generating, ras). Many proteins can exist in a cell in various locations, and the addition of a farnesyl group targets proteins to the plasma membrane. When ras gets to the plasma membrane, it becomes activated, and leads to tumour formation if this process is not stopped. It was thought that by inhibiting FT, ras will not be activated, therefore preventing cancer growth. The problem was that ras can also be modified by other mechanisms, and thus FTIs were not sufficient to inhibit malignant growth induced by ras signaling.
Most FTIs also have side effects (since they also indirectly affect mTOR), and their development for HD would likely not be successful. However, the remarkable finding is that Link Medicine has developed an FTI which does NOT affect mTOR signaling. This is a novel and important molecule, and might have higher probability to be of use for long term chronic diseases such as HD.
However, as with any new approach, it is too early yet to see if it will be safe in longer trials, and effective in people. But there is much room for hope, as this represents a completely novel mechanism to evaluate in people. If autophagy mechanisms in humans are similar as those of mice, then there is much reason for optimism. Lets hope for continued success for Link Medicine, so that it will be safe and the lead molecule progresses to the stage of being tested in HD subjects.
Will keep you updated of any new developments!
Have a nice weekend – back soon!
If you have any special topics you would like me to write about, please ask!