http://www.cureangelman.org.au/content/2946
By Edwin J. Weeber, Ph.D. (From FAST Australia newsletter, June 2010)
What makes AS research different?
A good analogy for understanding how hundreds of laboratories around the world conduct their respective research is the tale of the three blind men examining different parts of an elephant and trying to describe to others what they think it is. In many ways this is what we do in science; each researcher looks at a different aspect of the condition and tries to see how their findings fit in the larger context. However, even if you fill the room with blind men, no consensus will ever be reached if there is a lack of open communication between the observers. This is why collaboration, synergy, and sometimes serendipity are paramount for quick advancement of a field of study. In 1998 Dr. Arthur Beaudet developed a mouse model for AS. This represented an expensive endeavor both in time and money. Can you imagine the stifling consequence to scientific discovery and the progression of AS research if Dr. Beaudet had kept this mouse model solely for his own research? Instead these animals were openly shared with whoever wanted to investigate them. I believe the collaborative spirit among the community of AS researchers today is a direct result of Dr Beaudet’s decision to share his valuable resources with other colleagues. This spirit is evident in the authorship of many AS-related scientific papers that list scientists from multiple academic institutions world-wide. Today, the community of AS researchers has remained in close communication and is continually growing.
Where is AS research now?
There have been a number of major advancements in the past year. Use of the mouse model has revealed structural changes in the cells of the brain. Changes have been identified in mitochondria, the energy suppliers of cell, and in the spines of neurons where synapses are formed and maintained (1,2). These studies suggest that morphological changes at the subcellular level play a role in the overall change in synaptic function. In two independent studies, changes in synaptic strength are seen in a specific area of the sensory cortex (3,4). These changes indicate that the dysfunction in how synaptic connections are maintained and strengthened during sensory inputs is more wide-spread throughout the brain than was previously believed. This is supported by the discovery that the AS gene product appears to be absent throughout the brain in the AS mouse model. Recent genetic research has shown that another gene mutation in the TC4 gene located on chromosome 18 were found in a small number of patients clinically diagnosed with AS, but with no identifiable genetic alteration in UBE3A (5). These identifications are important for two basic reasons. First, individuals with a clinical, but not genetic diagnosis represent approximately 12 % of all individuals diagnosed with AS. Identification of additional genetic mutations also associated with AS symptomology will reduce this percentage of unknowns. Second, identification of genetic disruption that results in AS symptoms may shed light on molecular mechanisms and down-stream biological consequences of UBE3A maternal deficiency. Finally, a recent study identified several new targets of the AS gene product, Ube3a (6). One of these targets is a protein called Arc. This protein regulates receptors at the synapse and is known to be involved in the processes that underlie the strengthening of synaptic connections and memory formation. The culmination of the studies listed above, and those not discussed due to brevity, will serve to help shape ongoing and future research.
What is the future of Angelman Syndrome research?
This may be an opportune time to talk briefly about the terms “cure” and “therapeutic”. A cure is defined as a method or course of medical treatment used to restore health completely. In essence to make a person healthy as if no malady had ever occurred. For example, a “cure” in the context of AS may represent a medical intervention after birth, or in utero, that would be given before the onset of symptoms. The “cure” in this definition for individuals with a current diagnosis of AS is extremely doubtful. With that said, the development of a therapeutic, defined as a treatment of a disease or disorder, is reasonable. However, the efficacy of therapeutics tends to be only as good as their targets. Thus, a “magic bullet” treatment for all of the symptoms associated with AS is easy to imagine given the one gene etiology, but may be more difficult to realize. This should not discount that the development of therapeutics to treat specific aspects of AS have the potential to profoundly impact individuals with a current diagnosis of AS. The development of novel drugs is an expensive and risky endeavor, but clearly not an impossible task.
Are there new drugs on the horizon?
Conclusions?
The past year has seen impressive progress of AS-related research across multiple disciplines. Increased awareness of AS in the scientific community and high profile scientific publications will continue to attract more basic and clinical scientists. The recipe for this is simple and often under-appreciated. For example, there were nearly 2000 scientific publications associated with Arc research in the past 2 years. The study mentioned above will introduce a multitude of new scientists to AS and will likely persuade some of those researchers to include Angelman Syndrome in their respective research programs. As I mentioned earlier, scientific research is a painstaking and slow progression, but a progression nonetheless. There is a deliberate and relentless march forward toward a better understanding, and one day a treatment for, Angelman syndrome.
What makes AS research different?
A good analogy for understanding how hundreds of laboratories around the world conduct their respective research is the tale of the three blind men examining different parts of an elephant and trying to describe to others what they think it is. In many ways this is what we do in science; each researcher looks at a different aspect of the condition and tries to see how their findings fit in the larger context. However, even if you fill the room with blind men, no consensus will ever be reached if there is a lack of open communication between the observers. This is why collaboration, synergy, and sometimes serendipity are paramount for quick advancement of a field of study. In 1998 Dr. Arthur Beaudet developed a mouse model for AS. This represented an expensive endeavor both in time and money. Can you imagine the stifling consequence to scientific discovery and the progression of AS research if Dr. Beaudet had kept this mouse model solely for his own research? Instead these animals were openly shared with whoever wanted to investigate them. I believe the collaborative spirit among the community of AS researchers today is a direct result of Dr Beaudet’s decision to share his valuable resources with other colleagues. This spirit is evident in the authorship of many AS-related scientific papers that list scientists from multiple academic institutions world-wide. Today, the community of AS researchers has remained in close communication and is continually growing.
Where is AS research now?
There have been a number of major advancements in the past year. Use of the mouse model has revealed structural changes in the cells of the brain. Changes have been identified in mitochondria, the energy suppliers of cell, and in the spines of neurons where synapses are formed and maintained (1,2). These studies suggest that morphological changes at the subcellular level play a role in the overall change in synaptic function. In two independent studies, changes in synaptic strength are seen in a specific area of the sensory cortex (3,4). These changes indicate that the dysfunction in how synaptic connections are maintained and strengthened during sensory inputs is more wide-spread throughout the brain than was previously believed. This is supported by the discovery that the AS gene product appears to be absent throughout the brain in the AS mouse model. Recent genetic research has shown that another gene mutation in the TC4 gene located on chromosome 18 were found in a small number of patients clinically diagnosed with AS, but with no identifiable genetic alteration in UBE3A (5). These identifications are important for two basic reasons. First, individuals with a clinical, but not genetic diagnosis represent approximately 12 % of all individuals diagnosed with AS. Identification of additional genetic mutations also associated with AS symptomology will reduce this percentage of unknowns. Second, identification of genetic disruption that results in AS symptoms may shed light on molecular mechanisms and down-stream biological consequences of UBE3A maternal deficiency. Finally, a recent study identified several new targets of the AS gene product, Ube3a (6). One of these targets is a protein called Arc. This protein regulates receptors at the synapse and is known to be involved in the processes that underlie the strengthening of synaptic connections and memory formation. The culmination of the studies listed above, and those not discussed due to brevity, will serve to help shape ongoing and future research.
What is the future of Angelman Syndrome research?
This may be an opportune time to talk briefly about the terms “cure” and “therapeutic”. A cure is defined as a method or course of medical treatment used to restore health completely. In essence to make a person healthy as if no malady had ever occurred. For example, a “cure” in the context of AS may represent a medical intervention after birth, or in utero, that would be given before the onset of symptoms. The “cure” in this definition for individuals with a current diagnosis of AS is extremely doubtful. With that said, the development of a therapeutic, defined as a treatment of a disease or disorder, is reasonable. However, the efficacy of therapeutics tends to be only as good as their targets. Thus, a “magic bullet” treatment for all of the symptoms associated with AS is easy to imagine given the one gene etiology, but may be more difficult to realize. This should not discount that the development of therapeutics to treat specific aspects of AS have the potential to profoundly impact individuals with a current diagnosis of AS. The development of novel drugs is an expensive and risky endeavor, but clearly not an impossible task.
Are there new drugs on the horizon?
An interesting development in new drugs for AS is the investigation of a novel compound developed by Ardane Therapeutics (www.ardanetherapeutics.com). Their new drug called CN 2097 is currently in a Phase I feasibility study for the potential use as a therapeutic to treat the cognitive impairment in AS. This novel drug targets a sub-type of neuronal receptor that is well known to be involved in learning and memory. In fact, a mouse genetically designed to produce more of these receptors was found to be ‘smarter’ then genetically unaltered mice. This ‘smart’ mouse was termed “the Doogie Mouse” with deference to the 80’s TV child prodigy, Doogie Howser M.D. CN 2097 is shown to reduce the threshold for synaptic plasticity; a measurable defect found to exist in the AS mouse model. While these studies are in the first stages of drug development, it indicates that these types of drugs are becoming of interest to the business-minded pharmaceutical development companies.
The past year has seen impressive progress of AS-related research across multiple disciplines. Increased awareness of AS in the scientific community and high profile scientific publications will continue to attract more basic and clinical scientists. The recipe for this is simple and often under-appreciated. For example, there were nearly 2000 scientific publications associated with Arc research in the past 2 years. The study mentioned above will introduce a multitude of new scientists to AS and will likely persuade some of those researchers to include Angelman Syndrome in their respective research programs. As I mentioned earlier, scientific research is a painstaking and slow progression, but a progression nonetheless. There is a deliberate and relentless march forward toward a better understanding, and one day a treatment for, Angelman syndrome.
- Mardirossian, S., Rampon, C., Salvert, D., Fort, P., and Sarda, N. (2009) Exp Neurol 220, 341-348
- Su, H., Fan, W., Coskun, P. E., Vesa, J., Gold, J. A., Jiang, Y. H., Potluri, P., Procaccio, V., Acab, A., Weiss, J. H., Wallace, D. C., and Kimonis, V. E. (2009) Neurosci Lett
- Sato, M., and Stryker, M. P. Proc Natl Acad Sci U S A 107, 5611-5616
- Yashiro, K., Riday, T. T., Condon, K. H., Roberts, A. C., Bernardo, D. R., Prakash, R., Weinberg, R. J., Ehlers, M. D., and Philpot, B. D. (2009) Nat Neurosci 12, 777-783
- Takano, K., Lyons, M., Moyes, C., Jones, J., and Schwartz, C. Clin Genet
- Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T. K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., and Greenberg, M. E. Cell 140, 704-716
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