Dr. Herman van der Putten,
Two recent studies suggest that mutations in the Batten disease gene CLN3 are associated with a broad spectrum of clinical phenotypes. Mutations in CLN3 are known to cause the juvenile form of neuronal ceroid lipofuscinosis (JNCL) or Batten disease. In JNCL, first symptoms are usually loss of vision between age 5 and 10, followed by mental decline, motor coordination deficits, seizures and frequently cardiac problems. Some CLN3 mutations appear to cause a more protracted course of the disease. Now, one study reported that CLN3 mutations can cause Retinitis pigmentosa (RP) without any signs of Batten disease. The patients in this study were in their 40s, 50s and 60s. Yet another novel mutation was found in two brothers that presented with visual failure, seizures, and prominent cardiac involvement, but only mild cognitive impairment and no motor deterioration after 40 years of disease. The multiorgan syndrome in these two patients also included autophagic vacuolar myopathy (AVM). AVMs are a heterogeneous group of disorders characterized by vacuolation of skeletal muscle, cardiomyopathy, myopathy, mental retardation and variable retinopathy. Mutations in genes causing AVMs include VMA21 and LAMP2. VMA21 mutations prevent vacuolar ATPase (V-ATPase) assembly whereas LAMP2 plays roles in lysosome/autophagosome fusion and chaperone mediated autophagy. It remains poorly understood why dysfunction of CLN3 and other widely expressed lysosomal membrane proteins, which act at crucial steps of the lysosomal life cycle, affect specific cell-types. One possibility is that different CLN3 mutations affect cellular processes and compartments to different degrees. Regardless which CLN3 mutation, the retina is always affected which suggests, that one or more retinal cell types highly depend on wildtype CLN3 function. Right now, a molecular explanation for the different CLN3 genotype-phenotype associations remains enigmatic. The function of wildtype CLN3 is poorly understood. CLN3 deficiency can cause an accumulation of the cation-independent mannose 6-phosphate transporter in the trans-Golgi network, and this could lead to trafficking defects of newly synthesized digestive enzymes to the lysosome. Perhaps, different CLN3 mutations impact this process to variable degrees. A more in depth understanding of CLN3 function is needed to answer these questions.
To accelerate research we need to think outside the box. What is the link to other diseases? Which scientific expertise is missing? More research gaps will be addressed during the roundtable discussion on the last day of the 14th International NCL Conference (Sunday, 26th of October, 2014, 8:30-10:00).
Inés Noher de Halac, organizer of the 14th International NCL Conference in Argentina
We would like to introduce to you the organizer of the 14th International Conference on Neuronal Ceroid Lipofuscinoses, in Córdoba, Argentina, Inés Noher de Halac. Every two years scientists from all over the world working on Batten Disease get together, develop ideas and discuss latest findings.
Inés, why did you become a biologist and what were your goals at the beginning of your studies?
Inés Noher de Halac: I wanted to study medicine all my childhood, but as my father died when I was 16, I became afraid to have an activity so near to human suffering. So, I studied biological sciences. My goals at the beginning of my studies were to learn more about the secrets of life. Besides that, I was interested in science, but not too much in mathematics.
NCL is a very rare disease. Was there a special occasion why you have specialized in this particular research area?
Inés Noher de Halac: I admired very much the pioneer work of my teacher Dr. Raquel Dodelson de Kremer in Argentina who introduced me to the world of these “not so rare” diseases. In 1993 she needed a researcher in the field of electron microscopy. She asked me to join her team as I was specialized in that technology. So I began to recognize the peculiarities of the NCL bodies in human cells. I joined with enthusiasm the challenges of her research team. Later on we organized a research group specialized on NCL research that I was leading.
What are your experiences how Argentina deals with rare diseases?
Inés Noher de Halac: Only in recent times our health authorities became interested in rare diseases. Since July 2011 we have a national law of “less frequent diseases” approved by our parliament. Since then some progress has been achieved. Families with affected members now have more rights to get care from the state, but it is still a long way for obtaining what we need.
What can you tell us about the current medical care in Argentina?
Inés Noher de Halac: There are immense inequities to overcome. Needs are much bigger than achievements. In the few referential centers for that kind of diseases researchers and professionals are dedicated and have in general good knowledge and skills, but human resources are scarce, because the salaries are frequently too low and good positions not available. The money the government puts in medical care might be enough, but corruption is high.
What exactly was your motivation to organize the International Conference on Neuronal Ceroid Lipofuscinosis (Batten Disease) in South America?
Inés Noher de Halac: Our colleagues around the world encouraged us to take this responsibility. We were so happy that they believed in us, and we were convinced that the NCL community could have a good experience in Argentina. The Congress is organized alternatively in one and the other side of the Atlantic Ocean, but America is not only North America, South America is an important part of the continent. We wanted to disseminate the discussion on this kind of diseases from a scientific perspective in South America. To host the congress in Argentina opens the door for more research and for the first time calls attention to these pathologies on an international level in South America.
Can you give us a brief insight into the priorities of this year´s International NCL Conference?
Inés Noher de Halac: The strongest fields will be genetics, cell biology, new experimental systems and other basic science approaches oriented towards new therapeutic perspectives. Another question that emerged is the translational medicine “from bed to bench” with a perspective on “rare disease” for the NCL research. A valuation of the phenotypes is visible, and not only the genetic variants of disease. The approaches are no more sorted by NCL types, but centered in genomics, proteomics, cell biology and basic pathogenic phenomena. The discussion “What is NCL?” is intended to re-elaborate old conceptions in the genomics era. Links to other diseases are gradually emerging. Some bioethical definitions are discussed for the first time in an international NCL conference, as well as the priority of international cooperation in the field of orphan drugs and disease. An outstanding issue in the conference is the translation of research progress into information to the international patient’s organization meeting. This will be achieved by means of the “Marketplace” and the final round table.
To conclude, it would be great if you could give us a few suggestions how to prepare for Argentina, for those who have never been there.
Inés Noher de Halac: I would suggest a website that has recommendations for people travelling to Argentina: argentina.embassyhomepage.com. It will be a unique possibility for you to explore Argentina´s culture. Food is very good and people are usually friendly. Take care of yourself just as you usually do when travelling to other countries. Be careful with your big cameras and sophisticated equipment in the streets. I am sure your experience will be unforgettable and you will have a lot to tell your families.
We look forward to welcoming all the international visitors in Cordoba City!
Human skin fibroblast-derived pluripotent stem cells (iPSC) are becoming mainstay to model cell-autonomous as well as cell non-autonomous disease phenotypes in a dish. These human cellular systems are starting to impact drug discovery, in the hope they will facilitate translation to the clinic. A wide variety of disease-relevant human cell types including motor and dopaminergic neurons, cardiomyocytes and retinal pigment epithelial cells have successfully been generated from iPSCs. In a number of cases, disease phenotypes have been obtained and shown to be reversed using pharmacological treatments. In a proof-of-concept study, Susan Cotman (Boston, USA) together with colleagues in Dresden and Münster (Germany) have shown, that CLN3 iPSCs have abnormal endosomal/lysosomal structures and that CLN3 iPSC-derived neural precursors and mature neurons display abnormalities in organelle structure and the accumulation of lysosomal storage material. These extremely encouraging results suggest that CLN3 disease-related cellular phenotypes are partially mimicked in the culture dish. Rapid progress is also being made in generating human iPSC-derived “organs in a dish”. These 3-dimensional tissues offer the possibility to study cell-type specific effects of mutations in a complex tissue environment. Rescuing the degenerating retina in Batten disease is a major challenge and recent success in generating iPSC-derived neuroretinal cell types and retina-like structures (publications 1, 2 and 3) holds great promise to model human CLN3-associated retinal phenotypes and test treatments. Findings in such retinal models may also translate to central neurons since the retina is an extension of the brain. Altogether, CLN3 iPSC-derived cellular models might open the door to identify treatments that can alleviate CLN3-dysfunction and help design readouts for proof-of-concept trials in the clinic.
Experts working on the differentiation of iPSCs to retinal cells, neuronal cells and cardiomyocytes will be presenting their findings and ideas during the 12th National NCL Congress in Hamburg, Germany (Dec 15, 2014).
A combination of 2 drugs is being tested in patients suffering from infantile NCL. Pubmed abstract
Currently CLN2-patients are being treated with a TPP1-enzyme replacement therapy in a clinical study. Study centers are in Hamburg (Germany), London (UK) and Rome (Italy). Recently first results obtained in a canine model have been published. Pubmed abstract 1, Pubmed abstract 2
A JNCL patient was treated with immunosuppressive therapy. Visual function has been characterized. Pubmed abstract
The ARF1-Cdc42 pathway might be a target for JNCL therapy developmen. Pubmed abstract
Altered biometal homeostasis is a key feature of CLN1, CLN3, CLN5 and CLN. Pubmed abstract
Cysteine String Protein alpha oligomerizes in adult NCL mutants Pubmed abstract
A new mouse model is available recapulating most of the neuropathological features of human CLN7 disease. Pubmed abstract
22-26 October: 14th International Congress on Neuronal Ceroid Lipofuscinoses (Batten Disease), Córdoba, Argentina. Every two years scientists working on Batten Disease meet and discuss new findings. This conference is usually aligned with an international family meeting.
19-21 November: The workshop “Drug Targeting the Lysosome” will take place in the New York Academy of Sciences’ conference center in New York City. For more information, please get in touch with the Beyond Batten Disease Foundation.
15 December: 12th National NCL congress (Hamburg, Germany) will cover the topic “iPSC-derived cellular systems as translational models for NCL”.
5-7 February: Scientists working on the blood-brain-barrier will meet researchers of the lysosomal storage disease field. 9th Brains4brain Workshop in Frankfurt, Germany. If you want to participate, please get in touch with Prof. Mauricio Scarpa and/or Prof. David Begley.
9-13 February: The 11th Annual WORLDSymposium™ will take place in Orlando, USA focusing on lysosomal storage disorders.
27-28 February: During the 2nd Heidelberg Symposium of the pediatric center Dr. Angela Schulz will give insights into the current CLN2 ERT tria.
15-20 March: Lysosomal disease will be covered in depth during the Gordon Conference in Galveston, USA.
23-26 April: 41st annual meeting of the Society of Neuropediatrics in Basel, Switzerland.
14-19 June: A new Gordon Conference will cover “Organellar Channels & Transporters” in Waltham, USA.
1-3 July: 3rd Rare Diseases Summer School in Wädenswil, Switzerland.
Dr. Marco Sardiello
The NCL Foundation is delighted to announce that the 5th NCL Research Award goes to Dr. Marco Sardiello and his team at Baylor College of Medicine, in Houston, Texas. The official hand-over of the award will be later this year. The award, which amounts to € 100,000, is to finance a postdoctoral fellow who’s work will be dedicated to unraveling the primary role of the wildtype CLN3 protein and the lysosomal defects that result in Batten disease where both copies of the CLN3 gene are mutated. Dr. Marco Sardiello and his team hope to gain insight into roles of CLN3 that can be translated to the clinic and that can pave the road to therapy. The funds for the NCL Research Award came from the proceeds of charity dinners and an art auction organised by the NCL Foundation.
Dr. Marco Sardiello and his team are dedicated to the research and development of innovative therapies to treat lysosomal storage diseases (LSDs). LSDs are the most common neurodegenerative diseases of childhood. The majority of LSDs are caused by defects in one of over 60 known soluble lysosomal enzymes. Lysosomes are cellular organelles that play a key role in the degradation and recycling of cellular organelles, proteins, lipids and other substances. Therefore, defects in genes that encode lysosomal enzymes or proteins whose function is essential to maintain lysosomal homeostasis, have devastating effects in cells and organisms. The latter, because of an excessive accumulation of waste and toxic substances inside cells, often resulting in cell death. Transport mechanisms exist that allow soluble enzymes to travel from one cell to another. Hence, candidate therapies for enzyme deficiencies include enzyme replacement therapy, bone marrow transplantation, or gene therapy. The wildtype CLN3 gene, however, encodes a transmembrane protein which in Batten disease/JNCL is defective and many neurons die. For this reason candidate therapies targeting soluble enzyme deficiencies are generally not considered for treating JNCL. However, Marco Sardiello’s laboratory leverages the idea that therapeutic approaches for JNCL perhaps can benefit from strategies that are currently exploited to treat “classical” LSDs.
BDSRA has issued an open call for Letters of Intent (LOI) for grant projects related to Batten disease. The LOI should describe proposals of innovative research that have the potential to advance therapeutic strategies for all of the Neuronal Ceroid Lipofuscinoses. Each award, depending on funding availability, will be no more than $60,000 over a one-year period. Letters of intent must be submitted by November 15, 2014. The LOIs will be reviewed by members of the BDSRA board and invited scientific reviewers. Requests for full proposals that will be peer reviewed will be made in February, 2015. Awards will be announced midyear. For more information visit the BDSRA webpage.
Please inform us if you are looking for students (Bachelor, Master or PhD) as well as PostDocs in the field of NCL research. We can try to advertise it in our NCL Research Newsletter.