Note to Lafora Parents - From the Doctors
Info from Dr. Escueta
LAFORA PROGRESSIVE MYOCLONUS EPILEPSY
Antonio Delgado-Escueta, MD
Lafora Disease - From Basic Research to Developing a Treatment Arm
Dr. Antonio Delgado-Escueta is a world-renowned physician-scientist and authority on Lafora progressive myoclonus epilepsy and other types of epilepsy. His laboratories first mapped the chromosome 6q24 locus for Lafora progressive myoclonus epilepsy with Jose Maria Serratosa in 1995. Together with previous and present postdoctoral students, notably Jose Maria Serratosa and Berge Minassian, and collaborators S. Ganesh and Kazuhiro Yamakawa from RIKEN Brain Science Institute, they have been mainly responsible for refined mapping and isolation of Lafora Disease genes. Together with S. Ganesh and K. Yamakawa, they developed a mouse model of Lafora Disease, which is deficient in the laforin/DSP gene. This mouse model has aided in our understanding of the mechanisms of Lafora disease and developing treatment.
For over 20 years, Dr. Delgado-Escueta has been working diligently to solve the mystery that is Lafora disease epilepsy, but progress has been severely hampered due to limited resources. In 2003, Dr. Delgado-Escueta received a small grant to provide seed funding from Citizens United for Research in Epilepsy (CURE) to support gene therapy research in Lafora-deficient scientific models. This grant helped initiate the research of Dr. Eain M. Cornford and Shigeo Hyman and resulted in their NIH funding and even greater progress in developing experimental gene replacement therapy in Lafora disease mice.
Dr. Delgado-Escueta's former students and postdoctoral scholars and collaborator have started independent research groups that continue to study Lafora disease all over the world, including Spain (J. Serratosa), Canada (B. Minassian) and India (S. Ganesh).
Basic research continues at UCLA and the VA, as we gear up for clinical research and treatment. Dr. Delgado-Escueta's team continues to maintain the Lafora disease mouse colony at the VA Medical Center in West Los Angeles. This mouse model continues to be used to improve our understanding of the disease mechanisms of Lafora epilepsy and can also be used for drug trials and gene replacement therapy. Working together with neuroanatomists Jesus Machado-Salas (UCLA) and Maria Rosa Avila (Universidad Autonoma in Mexico City), and molecular biologists Dongsheng Bai and Miyabi Tanaka (UCLA and VA Medical Centers), the molecular mechanisms identified as disease pathways in cell cultures and neuropathology of mice with Lafora disease are related to epilepsy, seizures, cell death and Lafora inclusion bodies in human Lafora disease. With these basic research advances, Dr. Delgado-Escueta has now developed a multidisciplinary clinical trials team at UCLA to evaluate the safety and efficacy of IV gentamicin, a premature stopcodon readthrough drug, in treating nonsense mutations of Lafora progressive myoclonus epilepsy.
Dr. Delgado-Escueta is now building the infrastructure for an international clinical trials team that can test various treatments for patients with Lafora disease who live in various parts of the world. The developing infrastructure for this international clinical trials team will stand ready to assess safety and efficacy of new premature stopcodon readthrough drugs and gene replacement therapy as soon as they become available for humans with Lafora disease.
IV gentamicin is the first premature stopcodon readthrough drug that is ready for testing to assess safety and efficacy in patients who have nonsense mutations of Lafora disease epilepsy. With both UCLA IRB and FDA approvals in place, this research is ready to move forward at UCLA. [For more information about the Gentamicin treatment study, see UCLA IRB-approved study flyer.]
Funding is now needed to implement the IV gentamicin treatment.
Dr. Delgado-Escueta and the UCLA Department of Neurology are committed to continuing this important research and welcome private and corporate philanthropy to reach their goals. This kind of support provides unrestricted funds that are vital to the success of innovative research within an academic environment. While federal funding is important, it requires grant proposals that are based on massive amounts of preliminary data. The philanthropic support of private and corporate donors provides autonomy and freedom. This is the key ingredient necessary to make innovative discoveries. With this type of independence, researchers are able to acquire the initial data that are the "proofs of concept" which ultimately lead to ground-breaking discoveries.
May 2011: Exciting Possible Scientific Breakthrough from Dr. Berge Minassian
March 2, 2011 - Article: Glycogen Synthase: An Old Enzyme with a New Trick
Phosphorylation of glycogen has been known for decades; however, the basic metabolic pathways responsible for this modification are unknown. In this issue, Tagliabracci et al. (2011) report the enzyme responsible for incorporating phosphate and the chemical nature of the phosphate linkage, providing a framework for expanding our understanding of a devastating form of epilepsy. read more
March 2, 2011 - Article: Phosphate Incorporation during Glycogen Synthesis and Lafora Disease
Glycogen is a branched polymer of glucose that serves as an energy store. Phosphate, a trace constituent of glycogen, has profound effects on glycogen structure, and phosphate hyperaccumulation is linked to Lafora disease, a fatal progressive myoclonus epilepsy that can be caused by mutations of laforin, a glycogen phosphatase. read more
April 28, 2011 - Article: PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease
Lafora disease is the most common teenage-onset neurodegenerative disesase, the main teenage-onset form of progressive myclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. read more
Research Update from Dr. Escueta
We have two aims in our lab. 1) Understanding how Lafora bodies form. 2)
Finding a way to get rid of them.
So, our longer-term aim is to understand how these abnormal polyglucosans form and accumulate. You understand that had this kid of work been done in the decades prior to when Chelsea got sick (and it was not done simply because in those decades we were looking for the genes, an essential component of any research on a genetic disease), then we would have had knowledge that would certainly have allowed us to have a cure. Without knowing the cause and the process of a problem, it is very hard if not impossible to solve a problem. Therefore, we owe it to the children who are currently in the process of becoming Lafora teenagers, to work towards understanding this disease, so that when they are sick, we can cure them.
We are making great strides in the above aim, including most importantly, our recent discoveries in collaboration with Dr. Roach's group, that glycogen has phosphorus on it, and that the amount of this phosphate is what makes normal glycogen normal, or go awry and become polyglucosans. We are now following up this crucial insight and figuring out its details. We hope that when we know more precisely what is going on, we will know precisely where and how to intervene.
But what about the currently sick children with Lafora? What can we do for them? One idea is to replace normal laforin or malin into their brains, as the case may be, and see if that will reverse the problem. It is possible that this will work. But there are major problems with this. Firstly, remember that Lafora disease is only one of countless and much more common brain diseases. There is a world of scientists out there trying to get missing genes into human brains. It is a massive technical challenge, not only to get the gene in, but to make it so that it will not be gotten rid of by the host brain that sees it as foreign, and to make it express just the right amount of protein at just the right times, and in a continuous fashion over the life of the patient. No one has been able to achieve this yet. It will be achieved sometime in the future, but it is relatively unrealistic that we can do what huge groups working on huge diseases have not been able to do. Nonetheless, there is no harm in trying. The other problem with gene therapy is that in my own estimation, I do not see that replacing laforin can get rid of the ALREADY accumulated polyglucosans. My impression of the disease is that laforin's role is the prevention of their formation, not their degradation. To date, there is no publication that shows that replacing laforin in a mouse with Lafora, for example, gets rid of the Lafora bodies. Secondly, what about the malin patients? Replacing laforin cannot help them.
Then, there is the option of correcting stop codons in certain patients who have this particular type of mutation. This is akin to replacing laforin, and again, I have my doubts that this will get rid of the Lafora bodies, but I am obviously not sure, it may well work, though I don't see it that way. Again, this approach applies only to a fraction of the patients who have stop mutations. It does not work for the other patients.
The only way known, and proven, to get rid of starch/polyglucosans, is to digest them with amylase, an enzyme humans, including Lafora patients, make everyday in their saliva. If we could make brain cells make amylase even for a few minutes or hours, it would get rid of the 20-year worth of polyglucosans accumulated. So, our second research aim is find ways to introduce amylase into the brain for a very short time. If we can do this, we could get rid of the Lafora bodies and restore the patient to health. We face the same problem of getting a protein into the brain, but in our case, we need to get it in extremely transiently. Also, this method would work for any Lafora patient, laforin, malin, and all the many types of mutations.
In summary: 1) we want to KNOW Lafora disease, in order to conquer it. 2) meanwhile, we are trying to use a Trojan horse approach to see if we can sneak an army in there through the back door to get rid of the Lafra bodies.
January 4, 2009
Dr. Antonio V. Delgado-Escueta and his team are developing two treatment approaches, including 1) gene therapy for all Lafora disease patients, and 2) gentamicin treatment for those patients with nonsense mutations.
Another Research Perspective
The problem facing a Lafora patient is the conversion in brain cells of normal glycogen, a soluble sugar, into a starch-like insoluble sugar. This insoluble compound accumulates in the brain cells and devastates their function. How and why this happened was a great mystery until recently. We have now discovered that the problem is that normal glycogen in the Lafora patients acquires excessive phosphate, and that it is this phosphate that distorts normal glycogen and makes it become starch-like and insoluble. We now are trying very hard to uncover where this excess phosphate comes from, and then we will try to prevent this, or find ways to remove it so as to re-normalize the glycogen and keep it from precipitating and accumulating. If we can do this, we can treat or cure our patients. How long the way is from this point towards a treatment we do not know, but we now know we are on the right track”.
Words From One of Our Researchers
We essentially breathe, sleep, dream and ceaselessly work on this disease. Our hope is to understand it so fully that we can come up with a treatment. My personal dream is this: Next time a Matt or a Jessica or an Amanda is brought to a neurologist, and the diagnosis of Lafora is made, the doctor would simply write a prescription and say: you have Lafora, take this, all will be alright.
Based on the genes, we have found the proteins disturbed in this disease and we are now painstakingly finding all the interacting proteins and step by step reconstructing the biochemical pathway that is disturbed. We are certain that with understanding will come insights into the cure.
Lafora patients form Lafora bodies in their brain cells, which cause the horrible epilepsy these patients suffer from. In parallel to unraveling the disease processes that lead to Lafora body formation, we are designing a method to remove them from the brain, and return the patient to normalcy. We know that amylase, the starch-digesting enzyme in saliva, can digest Lafora bodies. We are working on a method to introduce amylase into neurons to melt the Lafora bodies away and cure our patients.
The hurdles are many and the work is large, but so is our commitment. The disease is rare, and hard to find government funding for. We therefore count on you.
- Berge Minassian, MD.
We seek to raise money through contributions to help fund research about these specific treatment protocols and monitoring assays. Please visit the subpages of the research section to learn more about what is going on in Lafora Disease research and to learn more about what we need to do to help combat this disease.
RESEARCH DEVELOPMENTS -- The Lafora Disease Story So Far
MYSTERIES OF BRAIN METABOLISM AND LAFORA DISEASE
Finding the Disease Causing Gene of Lafora Disease
Setting the Stage for Laforin Gene Replacement Treatment
Blood Brain Barrier Experts in the Epilepsy Center of Excellence at Los Angeles
Monitoring Results of Laforin Gene Therapy
Where is the Story of Lafora Disease Leading us
Thus, funds are urgently needed to develop a treatment team for Lafora Disease. This treatment team should address the following:
(1) A treatment team dedicated to
(2) An assay team that monitors gene replacement treatment results
(3) A PET scan team that assays turnover and purging of Lafora bodies during gene replacement treatment
December 28, 2007 - Progressive Myoclonus Epilepsy, Lafora Type
Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between 12 and 17 years. read more
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