Information for the Lay Person
The following articles were written by Dr. Pearce and/or colleagues on Batten Research for families.
Summary of 2005 International Conference
NCL2005 Conference Report. The 10th International Congress on Neuronal Ceroid Lipofuscinosis (Batten Disease). Helsinki, Finland, June 5- June 8 2005.
Every two years there is an international NCL (Batten disease, BD) conference which brings together scientists, medical doctors and some families from all over the world, with the US and Europe taking turns to host the conference. NCL2005 was hosted by scientists in Helsinki, Finland and took place early in June. This conference is the ideal venue for scientists and clinicians to establish new links, plan future work together and to present the latest research findings. This year's conference was spread over three days with sessions devoted to learning what happens inside cells in BD, how models are helping us to learn more about BD, progress that is being made towards therapies and the clinical management of BD.Molecules and DNA: We have known for some time which genes are mutated in most forms of BD. These genes would each normally make a different protein, but it's still not clear what these proteins usually do inside cells or what happens when these genes are mutated in BD. We don't fully know the answer to questions like: what do these proteins look like? where are they inside cells? and how does this go wrong in disease? Several advances have been made in answering these questions. There may be a role for infantile and juvenile BD proteins at the synapses that nerve cells use to communicate with one another. How each of the BD proteins move around inside cells also appears to be important, especially in the brain. We are also learning for the first time the identity of the partners that these BD proteins may interact with. Yeast, worms, flies and fish: The idea of trying to study something as complex as BD in something as simple as brewers yeast, nematode worms, fruit flies or zebrafish seems to make no sense.
However, these species are ideally suited to discovering what the BD proteins normally do. Breeding these models is relatively quick and easy, letting us perform basic genetic tricks to learn what happens in each form of BD. Because of their small size and relatively simple organization these models will also be very useful for the large scale testing of drugs that might be useful in BD.Mouse and large animal models: Moving up the scale of complexity there are several mouse models of different forms of BD. There are also larger animal models ranging from dogs and sheep to cows. With the discovery of which BD genes are mutated in these large animal models we can now begin using these species in much the same way as mouse models to understand the effect of BD upon the brain.
Studies are underway in mice to learn the effects of each form of BD upon a range of biological processes. These have pointed towards immune and inflammatory responses, the cytoskeleton (or scaffolding) inside each cell and nerve synapses as possible targets for the disease. Studying the brains of these models has also told us of early effects upon the brain's immune system an important event in both mice and sheep. We are now learning just how early the brain is affected and that the effects of disease move through the brain via interconnected groups of brain cells. What do we know now that we didn't know before? Our understanding of the genes and proteins involved in BD is rapidly increasing and mouse models are clearly proving useful for learning about the effects of disease upon the brain. Armed with this information we are now trying to compensate for the effects of disease in mice by using a variety of approaches. However, it's clear that we still need to learn much more if we are to optimize these strategies. A new approach to BD? The “storage material” or “autofluorescence” (or “stuff”) that builds up in BD is considered a hallmark of the disease. However, there is a growing consensus that this material may well be a secondary event, rather that being an important part of the disease process. Because of this we are now likely to focus on what causes the material to build up, rather than trying to eliminate it from cells. Moving towards therapy? Each of the models of BD gives us the chance to test whether any given therapy might be effective or not. A range of potential therapies are now being tested in mouse models of different forms of BD and a small number of very limited clinical trials are beginning in affected children.
Gene therapy is theoretically a way to deliver a corrected copy of the faulty gene and make the enzyme that is missing in infantile or late infantile BD. However, important questions of where and when these treatments must be given must be answered first. Also there are many sorts of viruses that can be used to deliver these genes and discovering which type works best is crucial. We heard that these studies to begin answering these questions are now underway in both infantile and late infantile BD mice and have showed promising effects upon disease related changes in their brains. But these effects are only partial at best and different strategies will be needed to make this approach more effective. A clinical trial of gene therapy for late infantile BD is also underway, but is only in its early stages.
Stem cell therapy may be another way to deliver the enzymes that are missing in infantile or late infantile BD. This could also possibly be a way to replace brain cells that have been lost in juvenile or other forms of BD. Although we heard that stem cell transplants are being tried in infantile BD mice, it is not yet clear what happens to the stem cells after grafting or whether this has any clinical benefit for these mice.
Immune approaches: The immune system appears to play a part in some forms of BD, especially in juvenile BD. Because of this a small trial is underway in Finland to see whether suppressing the immune system with steroids will be helpful in juvenile BD. However, steroids are not without side effects and it is too early to know what the effects will be.
Cystagon is a drug that might possible break down the storage material that builds up in the brain in infantile BD. This could only work in infantile BD and would not be useful in other forms of BD. Because cystagon appears to work in infantile BD cells in a dish, there is a small trial of this drug in the US. Some children with infantile BD have also been given cystagon in Finland. The children in the US have a later onset and slowly progressing form of infantile BD and it will take some years to know if cystagon has had an effect. However, cystagon has had no positive impact upon the more aggressive course of infantile BD in Finland.Medical update: In moving towards therapies for BD, one of the most important steps will be to have a good understanding of how the disease usually progresses. Collecting this sort of clinical information will give us landmarks to judge whether any test therapy has been successful. The Unified Batten Disease Rating Scale for juvenile BD has been developed in the US and is available for use generally. We also now have a more detailed picture of the behavioural and psychiatric symptoms in this form of BD.
Until new therapies become available, the support that is provided to families and effective clinical management of BD children become even more important. The Finnish foundations have particularly well established systems for educating and supporting parents. Efforts are now underway in the UK to bring medical doctors, occupational therapists, physiotherapists, and teachers together to provide much more effective care for affected children.
In conclusion, as scientists involved in BD research we recognize that progress is never fast enough. But with a growing number of scientists working on BD, we are now moving towards a much better understanding of these devastating disorders.
Summary of 2003 International Conference
Since the 2002 BDSRA conference, much scientific research on the NCLs has been published, some of which received funding from the BDSRA. In addition there was an international conference held in Chicago in April 2003 where researchers presented their most recent findings.
Infantile NCL- A mouse that lacks the PPT1-protein defective in INCL, and a mouse lacking a similar but an apparently different protein, PPT2 were described by Dr. Sandy Hofmann's group. Further characterization of the PPT1-defective mouse was presented by Dr. Jon Cooper's group with regard to the neuroanatomical effect lacking PPT1 has on the brain. Dr. Sands is also researching this model with a focus on gene therapeutic strategies (see below). Dr. Hofmann's group introduced a yeast model for studying PPT1. Drs. Glaser and Korey described a Drosophilia (fruit fly) model for studying the function of CLN1. These studies will aid in understanding the biological pathways that are affected by PPT1 dysfunction
Late Infantile NCL- Dr. David Sleat reported that they are at the early stages of characterizing a mouse model for LINCL which has a mutated version of the TPP1 protease. Dr. Warburton presented a study on the role of TPP1 on degradation of certain peptides, which may be important in the brain. This may help us understand the natural substrates for the TPP1 protease. Dr. Golabek presented data indicating that TPP1 activity is highly regulated post-transcriptionally.
Juvenile NCL- Dr. MacDonald's group reported the initial characterization of a mouse that has the genetic mutation most common in JNCL; namely, a 1.02Kb deletion of the CLN3 gene. Dr. Mitchison presented evidence of necrotic cell death in the cln3-knockout mouse. Dr. Pearce's group presented data from a yeast model for Batten Disease, which suggested that CLn3 may be a transport protein. Drs. Cooper and Guerin presented data suggesting an inflammatory response and a possible blood brain barrier breach in the cln3-knockout mouse. Dr. Jalenko's group showed that the CLN3-protein is targeted to the synapse in neurons, suggesting a role for CLN3 in neurotransmission. Dr. Bennett has been working on identifying proteins that interact with CLN3 and presented findings suggesting that CLN3 interacts with proteins at the synapse. Dr. Mole's and Dr. Taschner's group have independently established nematode (worm) models for studying the function of CLN3. Dr. Mole's group introduced a yeast model for studying CLN3. Dr Pearce presented further evidence suggesting that there may be an autoimmune component to JNCL. Dr. Boustany's group presented a study that indicates a role for CLN3 in regulating cell growth and having anti-apoptotic activity.
CLN5- Dr. Peltonen's group reported preliminary characterization of a mouse that lacks the CLN5 gene. This will help identify whether there is a common theme amongst the NCLs.
CLN6- The gene defective in a variant late-infantile NCL, CLN6, was recently identified. Representatives from the groups of Dr. MacDonald and Dr. Mole presented different sub-cellular localizations for the CLN6-protein--to the mitochondria and ER, respectively. These studies are preliminary and further work will no doubt reveal the exact localization of the CLN6-protein. Dr. Palmer presented data characterizing the degeneration of sheep that have mutation of CLN6.
Update on research on Batten disease presented at BDSRA meeting 2002
Since last years BDSRA conference, much scientific research on the NCL's has been published, some of which received funding from the BDSRA. The following by disease type will be summarized in an overview and by some of the researchers themselves.
Infantile NCL- A mouse that lacks the CLN1 and bears a genetic defect that mimics this disease was generated by Dr. Sandy Hofmann, and has been further characterized by Dr. Hofmann and Dr. Jon Cooper. This is important for understanding exactly what happens the brain during the course of the disease. Dr. Sands is also researching this model with a eye on gene therapeutic strategies. Dr. Chu-LaGraff has established a drosophilia (fly) model for studying the function of CLN1.
Late Infantile NCL- Dr. Peter Lobel's group has been able to purify CLN2 (TPP1) protein from cultured cells. This is important for understanding the nature of the protein for potential protein replacement studies. Dr. Warburton has published a study on the role of TPP1 on degradation of certain peptides, which may be important in the brain. This may help us understand the natural substrates for the TPP1 protease.
Juvenile NCL- Dr. Jalenko has shown that the CLN3-protein is targeted to the synapse in neurons, suggesting a role for CLN3 in neurotransmission. Dr. Bennett has been working on identifying the specific type of cells that harbor the CLN3 protein. Dr. Mole has established a nematode (worm) model for studying the function of CLN3. Dr. Pearce published a study suggesting that there may be an autoimmune component to JNCL. Dr. Boustany published a study on the fact that CLN3 has increased expression in cancer, which may help us understand the function of CLN3.
Dr. Jalenko, Dr. Bennett, Dr. Mole and Dr. Boustany have received BDSRA funding.
CLN5- Dr. Peltonen published a study showing that CLN5 resides in the lysosome of cells. This will help identify whether there is a common theme amongst the NCL's.
CLN6- The gene defective in a variant late-infantile NCL, CLN6, was identified by the groups of Dr. Wheeler and Dr. MacDonald.
CLN8- Dr. Messer has further characterized a mouse model for CLN8. Dr. Katz is exploring stem cell replacement in this same mouse model.
General- Dr. Boustany published a study on the anti-apoptotic properties of Flupirtine.
Yeast model for Batten's Disease
We have been using baker's yeast as a model to study JNCL. The yeast cell contains a gene designated BTN1 that is essentially the same as the human CLN3, which when defective causes Batten disease. Using yeast has many advantages, as it is simple to grow and easy to manipulate. We are studying BTN1 on the assumption that any information we gain as to what role BTN1 has in the yeast cell will be directly applicable to studying what the function of CLN3 will be.
Microarray-Lay persons description
When the human genome is completed it is expected to reveal that humans are made up of 30,000-50,000 genes. What are genes ? A gene is a portion of DNA that translates into a protein. What is a protein ? A protein is one of the specific components that make us humans work…Yes, it takes 30,000-50,000 components !
Mouse Models for NCL's
We often hear of the importance of animal models for the study of devastating diseases such as the NCL's. It is of great importance to those studying the cause of such disorders, that they have an animal that in some way resembles the disorder that they are studying. The best characterized laboratory animal of choice for such studies is the mouse. Mice are well studied, easy to maintain and can be manipulated genetically.
Dr. Sandy Hoffman's PPT1 knock-out mouse
Dr Sandy Hofmann's group recently reported the construction and initial characterization of mice that lack PPT1 (CLN1) which is defective in Infantile-NCL, and also PPT2 an enzyme similar to PPT1, in the Proceedings of the National Academy of Sciences (PNAS, 98, 13566-71, 2001). This publication is significant as there is now an animal model that lacks the same protein activity associated to Infantile-NCL that can be utilized to gain a better understanding of the effects of lacking PPT1, and therefore further our understanding of Infantile-NCL. Dr. Hofmann also presented some of her finding to the BDSRA conference in Chicago, 2001.
Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhood. by Z Zhang, J Butler, S Levin, K Wisnieski, S Brooks and A Muhkerjee. April 2000, Nature Medicine.
Cutting a long story short the authors have identified drugs, one called phosphocysteamine in particular, with the ability to hydrolyze or break thioester bonds in compounds made to mimic those that accumulate in Infantile NCL in the test tube.
Will this help break the thioester bonds of proteins accumulating in Infantile NCL?
Will these alleviate Infantile NCL?
Lysosomal Storage Diseases
Lysosomal Storage diseases are inherited genetic defects which result in protein deficiency. The absence of the protein prevents the lysosome in the cells of the body from performing its natural recycling function, and various materials are inappropriately stored in the cell. This leads to a variety of progressive physical and/or mental deterioration over time. Some patients survive into adulthood, but others with more severe symptoms die in their teens or earlier.
The neuronal ceroid lipofuscinoses, or Batten disease, are a group of pediatric diseases that result in degeneration of the brain. These devastating disorders are characterized clinically by vision loss, seizures, mental retardation and premature death. Pathologically these disorders are characterized by accumulation of storage material in the lysosome of cells. These disorders result from inheritance of defects in the code of life, DNA, that make proteins called CLN-proteins. Different types of Batten disease are associated to defects in different CLN-proteins. Several researchers worldwide are working on trying to understand the function of these CLN-proteins. This will enable researchers to better understand what goes wrong when there is a defect in one of these CLN-proteins, with the ultimate aim of trying to correct this defect.