Info from Dr. Escueta

LAFORA PROGRESSIVE MYOCLONUS EPILEPSY

Antonio Delgado-Escueta, MD
UCLA Department of Neurology

Lafora Disease - From Basic Research to Developing a Treatment Arm

History

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).

Current

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.

Next Steps

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

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.

Funding

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.