History of Batten disease
Four children with probable Juvenile Batten disease were first described by Otto Christian Stengel, MD, in 1826 (C 1826). He noted that four siblings developed normally until each began to lose their sight around six years old leading to blindness followed by progressive mental decline, loss of speech, seizures and death. The disease, however, is named after Frederick Batten, MA, MD, FRCP, when he reported almost 100 years later on two sisters with vision loss, neurocognitive decline and motor problems separating it from recently discovered Tay-Sachs disease and macular degeneration (FE 1903, FE 1914).
Juvenile Batten disease
Juvenile Batten disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). Over 400 different errors (mutations) in 13 segments of DNA (genes) have been attributed to various forms of Batten, which differ from one another primarily by when symptoms first appear (Mole , Mitchison, Lim et al. 2004, Chabrol, Caillaud et al. 2013, Mole SE 2013). These disorders all affect the nervous system with increasing seizures, movement disorders, altered thought processes, and cognitive decline. Childhood NCLs also include vision loss but adult onset Batten typically does not (Boehme, Cottrell et al. 1971, Burneo, Arnold et al. 2003, Sims, Cole et al. 2011). Although Batten disease was originally used to describe only the juvenile form, the term “Batten disease” is widely used to refer to all forms of NCL.
The CLN3 gene
Juvenile Batten disease results from mutations (mistakes) in the CLN3 gene (blueprint) responsible for making CLN3 protein. More than 60 different mutations in the CLN3 gene have been shown to cause juvenile Batten disease (Mole , 2011). However, most children with the disease are missing the same string of 966 DNA building blocks from the CLN3 gene; this mutation is known as the “1kb deletion.” Click here  for more information on the CLN3 gene and its protein.
Batten disease and other NCLs are linked to a buildup of substances called lipofuscins (lipopigments) in the body’s tissues. These lipopigments are made up of fats and proteins. Their name comes from the technical word “lipo,” which is short for lipid, or fat, and from the term “pigment,” used because they take on a greenish-yellow color when viewed under an ultraviolet light microscope. The lipopigments build up in brain cells as well as in skin, muscle, and many other tissues. Inside the cells, these pigments form deposits with distinctive shapes that can be seen under a more powerful electron microscope. All NCLs form deposits. JNCL deposits which look like fingerprints. Healthy lysosomes regularly dispose of these lipofuscins just as they recycle and get rid of other cellular wastes.
Many cells in the body contain CLN3 protein: skin cells (the cells that are biopsied for diagnosis), muscle cells, kidney cells, liver cells, etc. However, these cells don’t die from having malformed or absent CLN3 protein, and it’s unclear whether they’re affected by all of that material that builds up. So why are neurons so harshly – and uniquely – affected?
Neurons have advanced communication skills. They communicate information through both chemical and electrical signals via specialized structures called axons and dendrites. We aren’t sure why neurons are selectively affected, but we know that these cells are particularly susceptible to damage when their recycling centers fail to work properly, which occurs in many neurodegenerative diseases like JNCL, the other NCLs, and over two-thirds of the 50 lysosomal storage diseases. Although the genetic basis for many of these diseases is clear and some of the biochemistry of missing or affected proteins is well understood, the cellular mechanisms by which deficiencies in these proteins disrupt neuronal viability remain ambiguous. One analogy is to think of neurons as the Lamborghini of cells, capable of providing high performance but delicate.
For over 100 years, researchers have been investigating the cause and mechanism of Juvenile Batten disease. Until 1995 when the genetic culprit, the CLN3 gene, was located, progress was quite slow(1995). By the late 1990s, rapid technological advances in the development of small animal models and molecular biology techniques aided research efforts and helped to add significant knowledge to our understanding of the disease.
We need to capitalize upon new knowledge and advanced technologies being applied to other neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. We must recruit the best and brightest from our nation’s 173 medical schools and 261 doctoral programs as well as Pharmaceutical Industry experts and scientific thought leaders from around the world. We must provide them with salary support, specialized training, seed money and technological resources that open the door to even great opportunity. We need to build upon the following advances:
- The International Batten Disease Consortium comprised of 27 investigators across 9 academic institutions work together to locate the CLN3 gene responsible for JNCL and discover that CLN3 encodes a 438 amino acid transmembrane protein(1995).
- Investigators at the University College London Medical School determine the DNA alphabet of the CLN3 gene, critically important for determining its function(Mitchison, Munroe et al. 1997, Mitchison, Taschner et al. 1997).
- Researchers demonstrate that the CLN3 protein is located in lysosomes, or the recycling centers of the cell, which leads to the classification of Juvenile Batten disease as a Lysosomal disease(Jarvela, Sainio et al. 1998).
- Researchers demonstrate that the CLN3 protein is located in lysosomes, or the recycling centers of the cell, which leads to the classification of Juvenile Batten disease as a Lysosomal disease(Jarvela, Sainio et al. 1998).
- Investigators create a mouse that is missing the CLN3 gene, hoping its absence in the animal will provide important clues to its function in humans(Mitchison, Bernard et al. 1999).
- CLN3 protein is found in vesicles along neuronal processes and synaptic vesicles filled with neurotransmitters, the chemicals that neurons use to communicate(Luiro, Kopra et al. 2001).
- Researchers in Boston, MA, create a mouse with the same genetic defect in its CLN3 gene that most children diagnosed with JNCL have. They use this mouse to show, for the first time, that the disease begins its course even before birth(Cotman, Vrbanac et al. 2002).
- CLN3 protein is eventually found in multiple compartments of the cell beyond lysosomes and synaptic vesicles (endosomes, plasma membrane, and Golgi bodies), suggesting CLN3 protein plays a role in the processing, packaging, and possibly transporting of molecules through the cell for disposal or recycling(Kyttala, Ihrke et al. 2004, Persaud-Sawin, McNamara et al. 2004).
- Researchers find that in the early stages of the disease, certain groups of brain cells are affected much more than others, including those involved in motor activity and movement. This selectivity does not appear to be directly related to the amount of undigested material in the lysosome(Mitchison, Lim et al. 2004).
- Discoveries about the interactions between the CLN3 protein, microtubule-binding protein Hook1, and Rab GTPases suggest a link between CLN3’s function, the skeleton of the cell, and how cells absorb molecules from the outside (endocytosis)(Luiro, Yliannala et al. 2004).
- Trafficking and mitochondrial abnormalities precede ATP synthase subunit C accumulation in a cell model of JNCL suggesting JNCL is more than “cellular indigestion”(Getty, Benedict et al. 2011).
- Using the JNCL mouse model, which has a form of CLN3 that is genetically identical to the one found in affected humans, investigators show that these animals exhibit regional atrophy and glial reactions providing the first direct evidence that JNCL deficits are localized(Pontikis, Cotman et al. 2005).
- Investigators at the University of Rochester publish a clinical rating instrument to assess the motor, behavioral and functional capacity of children over the course of the disease (Marshall, de Blieck et al. 2005).
- Autophagy, a cell’s ability to recycle its own contents, is disrupted in the JNCL mouse model with the same genetic defect as most children with JNCL(Cao Y 2006).
- Following up on their work published in 2004, Luiro and colleagues carried out comparative analyses of cell cultures derived from CLN3 -/- mice missing the CLN3 gene and showed that in the absence of CLN3 protein, mouse neurons exhibit abnormalities in the microtubule cytoskeleton as well as microtubule-binding protein Hook1, mitochondrial dysfunction, and neuron-specific synaptic dysfunction suggesting a link between CLN3 protein and cytoskeleton-mediated neuron-specific function (presynaptic inhibition)(Luiro, Kopra et al. 2006).
- Samples obtained from patients with JNCL and mice that do not make CLN3 protein accumulate autoantibodies to GAD65 and other brain-directed antigens in their blood suggesting that autoimmune disease is a primary or secondary effect of JNCL and this effect is dissimilar to autoimmune disease found in Stiff Person Syndrome and Type I Diabetes in which GAD65 autoantibodies are also elevated(Lim, Beake et al. 2006).
- Investigators experimentally determine that Calsenilin/DREAM/KChIP3, a neuronal Ca2+ multifunctional binding protein may interact with CLN3 protein during one or more of its functions and the loss of Calsenilin /CLN3 interactions may mediate cell death(Chang, Choi et al. 2007).
- Deficiency of CLN3 protein results in altered lipid composition of cell membranes as evidenced by decreased bis(monoacylglycerol)phosphate (BMP) biosynthesis. Similar to other cellular dysfunctions found in JNCL, it is unknown whether reduced BMP biosynthesis is primary or secondary to disease. Regardless, each piece of evidence leads to clues as to establishing the true role(s) of CLN3 protein(Hobert and Dawson 2007).
- While CLN3 protein’s function is still a “black box” in many ways, much is known about cellular functions disrupted by the loss of normal CLN3 protein. Evidence for CLN3’s involvement in lipid metabolism includes its localization to Golgi/Rab4-/Rab11-positive endosomes and lipid rafts and its galactosylceramide (GalCer) lipid raft-binding domain(Rusyn, Mousallem et al. 2008).
- Investigators demonstrate that CLN3 protein interacts with plasma membrane-associated cytoskeletal and endocytic fodrin and the associated Na+, K+ ATPase complex suggesting that CLN3 protein is involved in the regulation of the cellular skeleton and non-pumping functions of Na+, K+ ATPase which may play a role in neuronal degeneration(Uusi-Rauva, Luiro et al. 2008).
- Altered arginine metabolism defects originally discovered using a yeast model are confirmed in CLN3-deficient mice(Chan, Ramirez-Montealegre et al. 2009).
- Applying computationally intensive techniques to existing data sets, investigators in Naples, Italy publish their discovery of Transcription Factor EB (TFEB) in Science, one of the top 1% of 28,000 scientific journals. TFEB increases the number of lysosomes in a cell and therefore could potentially rescue JNCL cells by making them more efficient(Sardiello, Palmieri et al. 2009).
- Due to the therapeutic potential of TFEB, Beyond Batten and Cherie and Jim Flores provided Texas Children’s with a $2.5 million gift to bring this group over to Texas Children’s and Baylor College of Medicine. This is the largest hospital and clinical research campus in the United States, home to some of the brightest minds in the world, with access to stellar resources. This was also the largest single research award in JNCL research history. 
- Proteomics or the large scale study of proteins, the main components of cellular processes, together with computerized technology was used to identify the interaction network in human cells necessary for autophagy or intracellular recycling revealing a network of 751 interactions among 409 protein candidates including CLN3 protein. Upon closer examination it was revealed that CLN3 protein may interact with as many as 30 other proteins(Behrends, Sowa et al. 2010).
- Investigators show that CLN3 mutations result in different courses of disease as determined by the Unified Batten Disease Rating Scale, a clinical tool that examines motor, behavioral and psychological symptoms over time(Adams HR 2010).
- Immunosuppression alters disease severity in mice missing the CLN3 gene, suggesting immunomodulation may represent a possible treatment strategy(Seehafer, Ramirez-Montealegre et al. 2011).
- Using an in vitro (cell culture) model of JNCL, investigators show that Lithium, which exerts therapeutic effects in a variety of neuronal disease models for stroke and Huntington’s disease and clinical disease such as bipolar disease, rescues the impaired cellular recycling program in JNCL mouse model cells and reduces disease-specific neuronal cell death(Chang, Choi et al. 2011).
- Investigators examined cell lines derived from animal models of variant late-infantile NCL caused by CLN6 mutations and JNCL caused by CLN3 mutations to learn that CLN6 and CLN3 mutations trigger distinct processes that converge on a shared pathway(Cao, Staropoli et al. 2011).
- Investigators find six calcium channel modulators capable of lowering calcium levels inside JNCL cell models. Calcium dysregulation, occurring in JNCL, has been linked to synaptic dysfunction and cell death(An Haack, Narayan et al. 2011).
- Scientists continue their initial work examining cardiac involvement in JNCL to learn that children as young as 14 years old may develop heart function irregularities that progress with age. The authors therefore recommend surveillance of heart function, which should be intensified at 18 years of age, if not sooner(Ostergaard, Rasmussen et al. 2011).
- Scientists in London use a fruit fly model to show that a lack of functional CLN3 protein leads to a failure to manage oxidative stress which may be a key deficit in JNCL that leads to neuronal degeneration(Tuxworth, Chen et al. 2011).
- Altered excitotoxic glutamate receptor activity suggests that AMPA and NMDA glutamate receptors are potential therapeutic targets in JNCL(Finn, Kovacs et al. 2011).
- A second Science paper from Naples Italy and Texas Children’s Hospital begins to look at pharmacological approaches to modulating the amount and location of TFEB. We know that adding lots of TFEB to JNCL and Huntington mouse models induces their cells to make more lysosomes. Now we also know that putting drugs called kinase inhibitors into dishes of cells stimulates normal existing TFEB sitting outside the cell to move into the nucleus and turn on all of those genes that make lots of lysosomese(Settembre and Ballabio 2011).
- Based upon data obtained in the CLN3 protein-deficient mouse, the University of Rochester initiates a clinical trial to test the safety and potential efficacy of short-term treatment with Mycophenolate mofetil (MMF), a potent immunosuppressive agent(Rochester 2011).
- In addition to trafficking inside the cell, programmed cell death, recycling and waste disposal, the loss of CLN3 protein results in motility defects in endothelial (skin and vessel) cells suggesting that CLN3 protein may play a role in wound healing outside and possibly, inside the central nervous system(Getty, Benedict et al. 2011).
- Investigators in Korea demonstrate that N-acetylcysteine (NAC), a well-known antioxidant, improves the health of cells from patients with Batten disease suggesting that NAC could benefit children with juvenile Batten disease(Kim, Lim et al. 2012).
- Investigators in the US demonstrate that mouse models of juvenile Batten disease benefit from AMPA-antagonists at various stages of development suggesting the presence of optimal treatment windows resulting from changes in disease pathology over time(Kovacs, Hof et al. 2015). US-based investigators provide preliminary evidence that suggests that boys with juvenile Batten disease develop symptoms earlier but girls experience a more aggressive disease including a shorter lifespan(Cialone, Adams et al. 2012).
- Researchers in Korea demonstrate that white blood cells from juvenile Batten disease patients are different from white blood cells of children without Batten disease. Understanding what happens to different cells when they’re missing CLN3 protein will help us understand CLN3’s role in nerve cells (neurons) and how to fix it(Kang, Kim et al. 2013, Kang, Seo et al. 2013).
- Investigators working in Italy and the US test their hypothesis, that TFEB activation and clearance of accumulated waste material in a mouse model of lysosomal storage disease, improves cellular processing. Investigators are currently working on determining whether the same is true for juvenile Batten disease mouse models and patient cells(Spampanato, Feeney et al. 2013).
- Building upon previous studies in the US, investigators in Denmark confirm that girls develop symptoms later than boys yet experience more aggressive disease. These studies are the first step to determining which hormones or other gender-specific factors accelerate disease and why. This information may be used to modify seizure or disease-modifying medications under development(Nielsen and Ostergaard 2013).
- Researchers in Great Britain explore the experiences of siblings of children with Batten disease to identify interventions that support their emotional health and family unit(Malcolm, Gibson et al. 2014).
- Investigators in the US show that CLN3 protein, normally found in multiple locations in the cell but deficient or missing entirely in JNCL, changes its location in response to cellular stress. Understanding where proteins are found under various conditions helps investigators determine their functions(Getty, Kovacs et al. 2013).
- Evidence suggests that abnormal levels of calcium contribute to the death of nerve cells (neurons) in juvenile Batten disease. Researchers demonstrate that manipulation of calcium levels in cell culture models of Batten, prevents those cells from dying suggesting calcium regulation as a potential drug target in Batten(Warnock, Tan et al. 2013).
- Researchers in the US confirm that microglia, immune cells of the brain, are activated prior to signs of nerve cell (neuron) degeneration and provide further evidence that factors involved in microglial activation, Caspase-1 and hemichannel inhibition, may act as novel drug targets(Xiong and Kielian 2013).
- Mouse models of juvenile Batten disease represent a powerful resource for investigating underlying disease mechanisms. Investigators in London provide new perspectives on how regional brain atrophy (loss) occurs during the course of disease(Kuhl, Dihanich et al. 2013).
- Researchers in Spain compare protein degradation mechanisms in CLN2 versus CLN3 disease patient skin cells (fibroblasts). Whereas TPP1 activity is completely abrogated in CLN2 disease, TPP1 is only partially diminished in CLN3 disease. Overlapping deficiencies in TPP1 activity support the conclusion CLN2 and CLN3 are both part of the same lysosome-endosome pathway(Vidal-Donet, Carcel-Trullols et al. 2013).
- Researchers in Finland employed Tandem Affinity Purification coupled with Mass Spectrometry with Significance Analysis of Interactome to identify potential interaction partners for CLN3 protein. Bioinformatic analysis revealed 58 potential binding partners, 16 of which were high confidence previously identified through other means(Behrends, Sowa et al. 2010).The identity of CLN3 binding partners supports the conclusion that CLN3 protein plays a role in transmembranre transport, lipid homeostasis, neuron excitability, G-protein signaling, and protein folding/sorting in the endoplasmic reticulum(Scifo, Szwajda et al. 2013).
- It has long been a matter of debate whether children with the common deletion in their CLN3 gene, produce biologically active mutant protein. Researchers at Sanford Children’s Health Research Center in South Dakota show a substantial decrease in the transcript level of truncated CLN3 protein in patient fibroblasts and an analysis of expressed Cln3Dex1-6 mouse transcripts supports the conclusion that nonsense-mediated decay ensures that no protein is made(Chan, Mitchison et al. 2008, Miller, Chan et al. 2013). This contradicts earlier findings from Massachusetts General Hospital of Cln3Dex7/8 knock-in mice to reveal decreased yet stable mutant RNA levels consistent with CLN3 mRNA expression from patient tissue (Cotman, Vrbanac et al. 2002). In line with Massachusetts investigators, in contradiction to those in South Dakota, investigators at University College London support the presence of mutant CLN3 transcripts and postulate the presence of CLN3 protein activity comparing healthy, and affected patient fibroblasts in the presence of RNA interference(Kitzmuller, Haines et al. 2008).
- The hippocampus, a small region located inside the brain responsible for balance, emotions, short-term and long term memory, has been shown to undergo accelerated cell death in Alzheimer’s diseases as well as other forms of neurodegeneration. To assess whether the same is true in JNCL, researchers in Finland conducted a 5-year study on hippocampal volumes using magnetic resonance imaging. The mean total hippocampal volume decreased by 3.3% annually, which is higher than previously published reports and slightly higher than whole brain volume decrease of 2.9% per year. These results suggest that the absence of CLN3 protein may have region-specific effects on the brain which may be important for identifying biomarkers, treating symptoms and the function of CLN3 protein itself(Tokola, Salli et al. 2014).
- Researchers in France contribute to our understanding that different mutations in the juvenile Batten disease (CLN3) gene can result in profound differences in disease progression(Pebrel-Richard, Debost-Legrand et al. 2014).
- Investigators at Weill Cornell Medical Center developed an adeno-associated virus vector expressing the human CLN3 protein to reverse the CLN3 disease lysosomal storage defect, gliosis, and neuron loss. After 18 months, CLN3 transgene expression was detected throughout the brain, particularly in the hippocampus and deep anterior cortical regions. AAVrh.10hCLN3 administration resulted in significant reductions in storage material burden, a significant decrease in gliosis and a trend toward improved neuron counts. These data suggest CLN3 gene therapy will result in partial correction of CLN3 disease(Sondhi, Scott et al. 2014).
- Abnormal biometal metabolism is a feature of many neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Researchers in Australia show that biometal metabolism is dysfunctional in juvenile Batten (CLN3) mice and that biometal accumulation precedes significant neurodegeneration and parallels disease severity(Kanninen, Grubman et al. 2013, Grubman, Pollari et al. 2014).
- CLN3 protein has long been proposed as an anti-apoptotic or agent responsible for preventing regulated cell death in healthy cells and some cancers(Puranam, Guo et al. 1999, Rylova, Amalfitano et al. 2002, Narayan, Rakheja et al. 2006). In a report from Biomedicine and Pharmacotherapy, researchers show CLN3 protein is highly expressed in colorectal cancer and that inhibition of CLN3 protein expression in these cells inhibits their expansion and promotes cell death. Understanding how CLN3 protein functions in multiple situations, both artificial and out of the ordinary, provides important clues as to its function in Batten disease(Zhu, Huang et al. 2014).
- When discussing Batten disease, researchers and others often focus on neurons, the most vulnerable cell type in Batten. However, CLN3 protein is deficient in astroglia as well and considering the intimate interplay between astroglia and neurons, maintaining a healthy balance of neurotransmitters, researchers in Omaha and Japan examined the role of CLN3 in glia. Their findings show that CLN3-specific alterations in astroglia communication may impact the progression of Batten disease(Burkovetskaya, Karpuk et al. 2014).
- By harnessing the power of technology for which the 2012 Nobel Prize in Physiology or Medicine was awarded, researchers at Massachusetts General Hospital and Harvard University, successfully reprogrammed skin cells (fibroblasts) from patients with juvenile Batten disease into induced pluripotent stem cells (iPSCs). IPSCs are produced by artificially “turning back the clock” of skin cells to a time when they were stem cell-like and capable of becoming any cell in the body. With a pharmaceutical nudge, these cells can then be pushed to become, not the skin cells they once were, but brain cells. In other words, successful reprogramming gives researchers their first opportunity to watch Batten disease develop directly in brain cells. Prior to this, efforts to study Batten disease were restricted to rodent models or human skin cells; neither of which accurately represents disease in the brain leaving without the proper tools to study the disease or a solid platform for testing drugs that will prevent, halt, or reverse its progression(Lojewski, Staropoli et al. 2014).
- The normal function of CLN3 protein remains unclear. CLN3 may be responsible for one function across many cell types, serve different functions inside a cell or both. To examine the function of CLN3 protein in endoplasmic reticulum (ER), researchers measured proliferation and cell death in cells treated with tunicamycin. Tunicamycin has been shown to promote cell death by causing the accumulation of misfolded or unfolded proteins in the ER. Their results demonstrating that normal CLN3 protein protects cells from ER stress-inducing tunicamycin, overexpression of CLN3 protein has an additive effect, and silencing of CLN3 leads to cell death supports the conclusion that CLN3 protein has a functional role in folding and processing proteins through the ER(Wu, Liu et al. 2014).
- Cdc42 protein is a small GTPase  which regulates signaling pathways that control diverse cellular functions including scaffolding, intracellular trafficking, and endocytosis through actin polymerization/depolymerization. Because cell lines derived from patients and mice with CLN3 deficiency have impairments in these and other processes, investigators in Iowa hypothesized that CLN3 protein functions as a regulator of Cdc42 protein. While they were not able to demonstrate a direct connection or functional role for CLN3, researchers demonstrate that active Cdc42 (Cdc42-GTP) is elevated in endothelial cells from CLN3 deficient mouse brain, and correlates with enhanced PAK-1 phosphorylation, LIMK membrane recruitment, and altered actin-driven events. They also demonstrate dramatically reduced plasma membrane recruitment of the Cdc42 GTPase activating protein, ARHGAP21. In line with this, GTP-loaded ARF1, an effector of ARHGAP21 recruitment, is depressed. Together these data implicate misregulated ARF1-Cdc42 signaling as a central defect in JNCL cells, which in-turn impairs various cell functions(Schultz, Tecedor et al. 2014).
- Biomarkers, measurable characteristics of one’s health, disease severity or response to treatment, are critically important for the successful completion of a clinical trial. Without tools to measure its effect, there is no way of knowing whether a drug is beneficial, how beneficial ,or even whether it is harmful to patients. Researchers in Germany used spectral domain optical coherence tomography (OCT) to reveal increased accumulation of autoflourescent storage material and reduced thickness of the inner retina in 16-month old CLN3-/- mice. These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in an animal model of the disease which may have an important role in establishing efficacy or lack thereof in emerging clinical trials(Groh, Stadler et al. 2014).
- Atomic structures of membrane proteins are playing a major role in understanding their individual functions and roles within cell systems. While several inferences have been made as to the 3-dimensional structure of CLN3 protein and many of these structures overlap or complement one another, the structure of CLN3 protein has not been experimentally proven. Researchers in Germany applied a combination of advanced molecular cloning, spectroscopy, and in silico computation to create a six-transmembrane domain and cytosolic N- and C-terminal model. This model largely agrees with often cited prediction models but differs with respect to the positions of the transmembrane domains and size of the luminal loops(Ratajczak, Petcherski et al. 2014).
- Although gene defects most of the 13 forms of Batten disease are well-known, very little is known about how defects in these genes affect development and contribute to pathogenesis of disease. Investigators in California examined the timing of the expression of CLN2, CLN3 and CLN5 to determine that these three genes are co-expressed spatially and temporally during brain development suggesting that these three genes may play important roles during embryonal development alone or in concert with one another(Fabritius, Vesa et al. 2014).
- Researchers in the UK found that lack of functional CLN3 protein results in accumulation of waste material in the Retinal Pigment Epithelium (RPE) cells, cells that are vital for maintaining good retinal function. Targeting the RPE cells with therapeutic approaches could help slow vision problems in patients or even help restore vision(Wavre-Shapton, Calvi et al. 2015).
- US researchers further studied the part of the brain that is responsible for motor coordination in a mouse model of juvenile Batten disease and find that AMPA receptor activity is enhanced, likely contributing to motor coordination problems. Their studies show that decreasing the receptor activity with an inhibitor results in immediate improvement of motor skill in young mice. These finds show that the CLN3 protein somehow interacts with the AMPA receptor and helps maintain normal AMPA receptor activity(Kovacs, Hof et al. 2015).
- US researchers do a comparative study of two mouse models of juvenile Batten disease in order to help researchers better select the most suitable mouse model for their studies and therapeutic testing(Kovacs and Pearce 2015).
- Researchers in China show that the CLN3 protein plays a role in ovarian cancer and may contribute to keeping cancer cells alive, growing and resistant to chemotherapy. This makes CLN3 an interesting target for cancer therapies but also helps Batten Disease researchers understand the different roles that the CLN3 protein plays in a cell(Mao, Che et al. 2015).
- Researchers from Lebanon together with US and UK researchers, show that the CLN3 protein has increased expression in certain types of breast cancer and can contribute to cancer growth via interactions with other proteins, including ceramide. Not only does this make the CLN3 protein a potential biomarker as well as therapeutic target for cancer cells, this also helps Batten Disease researchers better understand CLN3 protein function in a cell(Makoukji, Raad et al. 2015).
- Researchers from Boston together with experts in the UK, create a new genetically accurate mouse cerebral cell line with fluorescent properties to better screen and identify new therapeutic targets for juvenile Batten Disease. Furthermore, through an initial screen done with molecules known to modify autophagy, researchers identified that the CLN3 protein is likely to play a role maintaining the cell’s calcium homeostasis, making the calcium pathway of the cell a new potential drug target for therapies(Chandrachud, Walker et al. 2015).
- It has long been assumed that CLN3 protein, whose absence is responsible for juvenile Batten (CLN3) disease, is functionally related to the other 12 forms of Neuronal Ceroid Lipofuscinosis. The reasoning behind this theory is the close correlation of symptoms between these diseases suggesting they are all part of the same or similar pathway. In line with this theory, investigators at the University of California in Los Angeles, show relationships between the expression patterns (where each protein lives and works inside a cell) of NCL genes 1, 2, 3, and 5(Minye, Fabritius et al. 2016).
- One of the first and most frustrating symptoms for those affected by juvenile Batten (CLN3) disease is its early and rapid visual decline. To understand more completely why this occurs, researchers in Germany followed affected children to learn that children lose their first and second neuron retinal layers from the macula outward, which contradicts a preferential reduction of photoreceptor layers seen in other eye diseases affecting the macula (i.e. center vision)(Preising, Abura et al. 2016). Investigators in Germany contributed to our understanding of the unique features of vision loss in CLN3 disease by demonstrating patients have a specific macular striation pattern(Dulz, Wagenfeld et al. 2016). While researchers in Denmark show that the Ocular Coherence Tomography technology used in both of these studies could detect macular changes before children report problems with their eyesight(Hansen, Hove et al. 2016). While, there are presently no treatments known to preserve sight in children with juvenile Batten disease, early and accurate diagnoses along with an understanding of which cells are selectively lost early-on, provides researchers with therapeutic targets to preserve sight(Preising, Abura et al. 2016).
- Investigators at the University of Nebraska in Omaha and Ohio State University in Ohio published their findings using adeno-associated virus 9 (scAAV9)-mediated gene therapy to treat animal models of juvenile Batten (CLN3) disease. Initially, investigators did not consider gene therapy to be an option for transmembrane protein defects, like those in CLN3 disease. However, this investigation showed that intravenous injection of scAAV9-containing CLN3 genes is possible and may inhibit disease progression. After a single injection of the construct containing the gene, animal models showed fewer motor deficits and reduced signs of inflammation in the brain.(Bosch, Aldrich et al. 2016)
- CLN3, the protein missing in children and young adults affected by juvenile Batten (CLN3) disease, is poorly understood. Reasons for this include an incomplete understanding of which cellular structures contain CLN3 during which periods of development and normal function. To fill these gaps in our understanding, researchers in Germany analyzed tissue and cellular localizations of CLN3 protein during development. Their findings confirm previous studies showing CLN3 protein expression in and outside of the central nervous system, predominant localization in lysosomal (and late endosomal) compartments. Interestingly, researchers show that the dysfunctional form of CLN3 protein potentially made by children with Batten disease, is “stuck in traffic” and does not efficiently move to its final destination(Oetjen, Kuhl et al. 2016).
- Investigators at the University of Nebraska in Omaha publish the results of their 2-year study funded by the National Institutes of Health to explore whether modifying the function(s) of non-neuronal cells in the brain inhibits disease progression in an animal model of juvenile Batten (CLN3) disease. By inhibiting overactive hemichannels, reducing glutamate accumulation and lessening the production of pro-inflammatory cytokines (harmful substances produced by cells), researchers show that PDE4 inhibitors can reduce inflammation and prevent the death of neurons. This work may represent the first step towards applying PDE4 inhibitors to the treatment of Batten disease(Aldrich, Bosch et al. 2016).
- Investigators in the United States use clinical grade adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of human CLN3 to explore proof-of-principle for the initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of CLN3 associated retinal degeneration. Following injection into the subretinal space of wild-type mice, the animals showed little to no signs of rejection(Wiley, Burnight et al. 2016).
- Investigators in Great Britain created a zebrafish model of CLN3 disease using antisense morpholino injection to characterize the pathological and functional consequences of CLN3 deficiency and use as a tool for drug discovery(Wager, Zdebik et al. 2016).
- Following up on early work identifying immune system involvement in the pathology of juvenile Batten (CLN3) disease, investigators in South Dakota characterized bone marrow-derived antigen presenting cells, peritoneal macrophages and leukocytes from the blood and spleens of CLN3-deficient mouse models of juvenile Batten disease. Their results show that CLN3 deficiency alters Antigen Presenting Cells which may be a major contributor to immune-mediated acceleration of juvenile Batten (CLN3) disease(Hersrud, Kovacs et al. 2016).
- Investigators in Germany investigate the role of inflammation-related cell adhesion molecule sialoadhesin (Sn) in CLN3-deficient mice to learn that increased Sn expression on microglia contributes to neural perturbation. These studies support the conclusion the immune-mediated responses to CLN3 disease exacerbate the disease and immunoregulation treatment may slow disease progression(Groh, Ribechini et al. 2016).
- Investigators explored the possibility that fibrates have a neuroprotective effect on CLN3-deficient cells by exposing the to fibrates, fenofibrate, bezafibrate and gemfibrozil. Interestingly, fibrates increased cell viability and therefore, may be a treatment option following thorough examination of their use and safety for children with juvenile Batten (CLN3) disease(Hong, Song et al. 2016).
- In 2009, a $2.5 million gift from Beyond Batten Disease Foundation and Cherie and Jim Flores enabled the Jan and Dan Duncan Neurological Research Institute (NRI) to invite Drs Ballabio, Sardiello and their colleagues to the NRI at Texas Children’s Hospital. In February 2017, Drs Palmieri, Sardiello and their colleagues published their methods for activating TFEB to treat animal models with Batten disease in Nature Communications. Nature Communications is ranked in the top .04% of 28,000 subject journals. The team discovered that “TFEB is under the control of another molecule called Akt, which is a kinase, a protein that can modify other proteins. Akt has been studied in detail. There are drugs available that can modulate the activity of Akt. We wanted to inhibit Akt to keep TFEB more active,” said Palmieri. “We discovered that the sugar trehalose is able to do this job.”(Palmieri, Pal et al. 2017)
- To examine changes in brain cell (neuronal) activity during disease progression, electrical (electrophysiological) activity was measured in various brain regions over time. Researchers in Nebraska found previously unreported age- and region-dependent changes in the excitability of neurons and postulate that this information may inform our understanding of how this disease progresses in children and young adults with juvenile Batten (CLN3) disease (Burkovetskaya et al 2017).
- Building upon the work of others in vitro (cell culture), researchers at the University of Nebraska in Omaha conducted the first evaluation of neuronal function in vivo (live animals). Researchers show that some, but not all, electrical properties of nerve cells in animal models of juvenile Batten (CLN3) disease are altered. These changes in electrical activity away from normal are region-specific and change over the course of disease.(Burkovetskaya, Karpuk et al. 2017)
- Neurons, glia, and other cells in and outside of the central and peripheral nervous system of affected children contain ceroid autoflourescent lipofuscin inclusions enriched in ATP synthase subunit c, a mitochondrial inner membrane protein. This includes cell types primarily affected in CLN3 disease. In addition, it has been reported that Batten-affected cells are deficient in galactosyl ceramide, which has been implicated in a wide range of biological activities. Using brain cell cultures obtained from newborn CLN3 knock-out mice, researchers in Pennsylvania and South Dakota showed that an analogue of beta-galactosyl ceramide (SNB-4050) decreased the accumulation of ceroid lipofuscin. The treatment also had a beneficial effect on affected neurons. These early results suggest that beta-galactosyl ceramide relieves certain disease-mediated cellular changes. Whether such disease-in-a-dish results can translate into beneficial changes for affected children and young adults with Batten disease remains to be shown. (Brenneman, Pearce, and Kovacs et al 2017)
- BBDF-funded investigators and King’s College in London discovered that glial cells, responsible for structural, homeostatic, and housekeeping functions, may play a role in the pathological progression of juvenile Batten (CLN3) disease. When placed into culture, nerve cells from mice genetically engineered to have CLN3 disease, display difficulty extending their branches and communicating with other nerve cells. Whereas CLN3-/- glia exhibit fewer protein secretions, impaired signaling and attenuated homeostatic functioning. When Batten nerve cells are surrounded by Batten glial cells, their nerve defects are much more pronounced. When healthy nerve cells are surrounded by Batten glia, the nerve cells show signs of compromised health and die at higher rates than normal. However, when Batten nerve cells are surrounded by healthy glia, Batten nerve cells exhibit higher survival rates suggesting that drug targeting glial cells could result in an effective treatment for Batten disease (Parviainen L, Dihanich S, Anderson GW, et al. 2017).
- The juvenile Batten (CLN3) gene is evolutionarily conserved. In other words, CLN3 has remained unchanged throughout evolution appearing nearly identical between species which gives researchers the unique opportunity to introduce minimal changes to the gene in a lower organisms to learn more about it’s function. Researchers at the University of Birmingham and King’s College London in the UK worked together to create drosophila (fruit fly) models of CLN7 and CLN3 disease. Unexpectedly, both models show that, unlike humans, CLN7 and CLN3 proteins are restricted to the brain and spinal cord, are limited to specific cell types and are limited to specific regions within each cell. Researchers do not yet know the significance of these results (Mohammed A, O’Hare MB, Warley, et al. 2017)
- Several investigators have shown that animal models of Batten disease exhibit signs of chronic inflammation and that inflammation may accelerate disease progression. Here, researchers at the University Hospital Würzburg in Würzburg Germany added fingolimodand teriflunomide, immunomodulatory drugs approved for the treatment of multiple sclerosis, to the drinking water of CLN1 and CLN3 animal models. Results show that treatment with either compound reduces the number of cytotoxic T cells and microglia. Importantly, overt signs of neurodegeneration, neuron loss, retinal thinning, and brain atrophy, were substantially reduced (Groh J, Berve K, and Martini R 2017).
- Evidence suggests that the loss of CLN3 protein, deficient or missing altogether in children and young adults with juvenile Batten (CLN3) disease impacts cellular transport of galactosylceramide and its subsequent loss is damaging to brain cells. Investigators from Sanford Health in South Dakota and Yale University in Connecticut worked together to show that brain cell cultures established from Batten mouse models developed fewer autoflourescent deposits and exhibited more and longer neuron branches when treated with galactosyl- ceramide replacement with GC analog SNB-4050. Much work remains to determine the safety, bioavailability and efficacy of such compounds in affected children but this initial indication that SNB-4050 or similar GC analogues can help maintain healthy brain cells is an exciting development (Brenneman DE, Pearce DA, Kovacs A, et al. 2017).
- The development of clinical trials for the treatment of Batten disease are hampered by the inability to accurately measure disease progression and response to treatment over a short period of time anytime during disease. Therefore, to enable the design of informative studies, researchers at Rutgers University analyzed brain and cerebrospinal fluid (CSF) from patients with CLN1, CLN2 and CLN3 disease. Out of 2553 significantly altered protein profiles found in autopsy material from brains, 392 (∼15%) were altered in all three. In CSF, out of a total of 469 significantly altered proteins in any of the three diseases, 18 (∼4%) were altered in all three NCLs. Furthermore, researchers discovered that the magnitude and direction of those changes was similar in 17 of the 18 proteins. Similar responses to neurodegeneration suggest that the same or similar biomarkers could be used to measure response to treatment of all 3 diseases. Of special interest is calbindin 1 (CALB1). CALB1, a calcium-binding protein that is relatively highly expressed in the cerebellum, CALB1 is highly elevated in CSF in CLN1, CLN3 and Niemann-Pick type C1 disease and shown to be lowered in NPC1-treated patients (Sleat DE, Tannous A, Sohar I et al. 2017).
- Using gene therapy techniques to introduce light-sensitive genes into Batten mice, investigators in Germany created a Batten model of vision loss in the hope of more closely mimicking the disease in humans and using the model to develop treatments that prevent blindness.
- Investigators show that subunit C waste accumulation, dysregulation of lysosomal enzyme, cathepsin D, light-dependent dysregulation of genes, and the immune responses in the new model resemble the disease in children more closely than untreated Batten mice. Furthermore, researchers show that minocycline, an approved drug that has been shown to dampen microglial reactivity and to prevent photoreceptor loss in several mouse models of neuronal degeneration, exhibited a protective effect on light-triggered microglial activation and retinal thinning in this model. These findings suggest that exposure to specific light conditions accelerates CLN3-dependent retinal degeneration and that immunomodulation could be a possible treatment option to delay vision loss in juvenile Batten (CLN3) disease (Dannhausent, Möhle, and Langmann et al 2018).
- Researchers in the Netherlands demonstrate that cognitive dysfunction including learning, memory perception and problem solving are often present at the time of diagnosis in CLN3 disease. Furthermore, these problems are independent of co-occuring vision loss. (Kuper, W.F.E, Van Alfen, C, Rigterink, et al 2018).
- Researchers in Australia report that they have generated a human induced pluripotent stem cell line and co-isogenic control from a patient with mutations in her CLN3 genes resulting in retinal degeneration with no effects on the brain. (Zhang, Zhang, and Chen et al 2018).
- Previous studies demonstrate that microglia exhibit exaggerated caspase 1 inflammatory reactions to CLN3 disease. To tease apart the contribution of caspase 1 to disease, researchers at the University of Nebraska have created a new animal model by crossing the Cln3Δex7/8knock-in model with caspase 1-deficient mice. Results from these studies demonstrate that the Caspase 1 deletion positively influences both astrocyte activation and motor deficits. However, microglial activation and waste material buildup were unaffected. Further studies are needed to determine whether astrocyte activation and motor deficits in this animal recapitulates the human condition and whether mitigation of these phenotypes alters the trajectory of disease (Burkovetskaya M, Bosch ME, Karpuk et al 2018).
- Researchers at the University of Rochester conducted a Phase I safety and tolerability study of Mycophenolate, an immunosuppressant, in children with CLN3 disease (https://clinicaltrials.gov/ct2/show/NCT01399047 ). While preclinical studies suggest that inhibition of chronic inflammation could have a profound effect on disease progression in animal models of disease (Immunosuppression alters disease severity in juvenile Batten disease mice). The results of this study did not support the same conclusion. The investigators conclude that Mycophenolate is safe for short-term use in children with CLN3 disease and that the determination of whether Mycophenolate can inhibit disease progression long-term will require longer studies (Augustine EF, Beck CA, Adams HR, et al 2018).
- It has been a long-held belief that neurons are selectively vulnerable to juvenile Batten (CLN3) disease. However, recent reports out of the Los Angeles UCLA Medical Center and King’s College London show that CLN3-deficient astrocytes fail to clear harmful levels of glutamate and exhibit impaired calcium signaling (Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons). A deeper dive into these issues at the University of Nebraska indicates that neither glutamate transporter expression nor glutamate update deficiencies are responsible. Cln3Δex7/8neurons are, in fact, hyper‐responsive to glutamate reflected by heightened and prolonged Ca2+ These findings revisit the question of whether intrinsic defects, extrinsic defects, or both are responsible for neuronal cell death in Batten Disease (Bosch ME and T Kielian 2018).
- BCL2, downregulated in CLN3 disease, prevents cytochrome C induced cell death. Therefore, researchers in Beirut Lebanon in collaboration with researchers in Amarillo Texas used immortalized PC12 neuronal cell lines to investigate whether Flupirtine, which upregulates BCL2, is able to rescue CLN3-deficient, immortalized PC12 cells. Their results show that Flupirtine and its derivatives are able to upregulate BCL2 in PC12 cells. However, more work is needed to determine whether these results can be repeated in patient cells, animal models of disease and real-world patient situations (Makouki J, Saadeh F, Mansour KA, et al 2018). Previous results from the University of Rochester, suggest that Flupirtine is not effective for the treatment of CLN3 disease. (Parent-reported benefits of flupirtinein juvenile neuronal ceroid lipofuscinosis (Batten disease; CLN3) are not supported by quantitative data). 
- The function of CLN3 protein is unknown. To investigate potential functions for the protein, researchers in Russia compared lymphocyte protein profiles of slow and fast progressors of the disease. Five genes were dysregulated by a similar way in all three groups while 13 other genes were either upregulated in patients with rapid disease progression or downregulated in patients with slow disease progression. Interestingly, the dysregulated genes coded for membrane receptors, co-receptors or the regulation of signaling cascades. These results led to the hypothesis that CLN3 protein functions as a molecular chaperone for other transmembrane proteins and its absence leads to pathological changes in MAPK signaling (Shematorova EK, Shpakovski DG, Chernysheva AD, et al 2018).
- The function of the CLN3 protein, whose deficiency results in juvenile Batten (CLN3) disease, is unknown despite intense study following its discovery 20+ years ago. Recently, investigators in the UK have examined AMPA-type glutamate receptors (AMPAR) in the CLN3 deficient mouse brains. Their results suggest that normal quantities of glutamate proteins are present. Pre-synaptic differences are seen in CLN3 deficient versus normal animals and post-synaptic activities are normal. The significance of these findings is unknown. However, disruptions in communication between brain cells could explain why affected children exhibit so many symptoms (Studniarczyk D, Needham EL, Mitchison HM, et al. 2018).
- LEIi004-A and an associated co-isogenic control line with one of the 2 heterozygous mutations corrected. Mutations in CLN3 are classically associated with CLN3 disease where retinal degeneration is followed by mental and physical deterioration, the lines created result in a nonsyndromic retinal degeneration. CLN3 disease joins a growing number of genes such as TTC8, BBS2, and USH2A, whose mutations are commonly associated with syndromic diseases that include a subset of patients with isolated vision loss. CLN3 deficient iPS cells from patients with classical CLN3 disease were initially generated in the laboratory of Susan Cotman at Massachusetts General Hospital and Harvard University. Additional lines were created by investigators at the University of Iowa. CLN3 deficient carrier, homozygous mutant and heterozygous mutant stem cell lines are also available through the New York Stem Cell Foundation in partnership with Beyond Batten Disease Foundation https://nyscf.org/wp-content/uploads/2018/04/Available_BBDF_APRIL2018.pdf  (Rivolta C, Sweklo EA, Berson EL, et al 2000, Lojewski X, Staropoli JF, Biswas-Legrand S, et al 2014, Shevach E, Ali M, Mizrahi-Meissonnier L, et al 2015, Wiley LA, Burnight ER, Drack AV, et al 2016, Goyal S, Jäger M, Robinson PN, et al 2016, Zhang X, Zhang D, Chen SC, et al 2018).
- CLN3 protein has long been proposed as an anti-apoptotic or agent responsible for preventing regulated cell death in healthy cells and some cancers (Puranam, Guo et al. 1999, Rylova, Amalfitano et al. 2002, Narayan, Rakheja et al. 2006, Zhu, Huang et al. 2014). In a report from the Journal of Surgical Oncology, investigators in China correlate hepatocellular carcinoma progression and metastasis with CLN3 expression (Xu Y, Wang H, Zeng Y, et al. 2019).
- Investigators in Moscow Russia applied math, computer science and statistical analyses to existing data to identify potential interactors of CLN3 protein. Interestingly, their analyses suggest that CLN3 interacts with a subunit of Na/K ATPase ATP1A1, a protein responsible for maintaining electrochemical gradients across cell membranes critical for sending messages from one nerve cell to another. Experiments will need to be conducted to prove these findings and if true, how this contributes to disease in the absence of CLN3 (Shematorova EK, Shpakavski DG, Chernysheva AD, 2019).
- Following preclinical animal model studies demonstrating that a reduction in neuroinflammation in animal models of CLN3 disease inhibits disease progression, investigators at the University of Rochester conducted a Phase I/II trial using immunosuppressant mycophenolate to treat children with CLN3 disease. Investigators used a placebo-controlled, crossover study design. Group 1 was treated for 8 weeks, underwent a 4-week washout period and then given a placebo for 8 weeks. Group 2 was given a placebo first. Participants and investigators were blinded as to which Group patients belonged. The results show that immunosuppressant mycophenolate was well-tolerated. Long-term exposure to the drug is needed to determine whether mycophenolate inhibits CLN3 disease progression in affected children (Seehafer SS, Ramirez-Montealegre D, Wong AM et al. 2011, NCT01399047, Augustine EF, Beck CA, Adams HR et al. 2019).
- Recent studies from the laboratory of Anil Mukherjee at the National Institute of Child Health and Human Development reveal that CLN3 deficient cells lack palmitoyl-protein hydrolase 1 (PPT1), whose absence is responsible for the CLN1 form of Batten disease. CLN3-deficient cells have intact CLN1 genes. Therefore, CLN3 disease may be partially due to a PPT1 cellular transportation problem. (Appu AP, Bagh MB, Sadhukhan T, et al. 2019).
- In June 2019, following the publication of Appu et al. 2019, Schmidtke et al in Hamburg Germany published their comparison of CLN3-deficient and healthy cellular waste centers (lysosomes). Their results show that lysosomes from CLN3 deficient knock-in mouse models have reduced levels of 17 hydrolases (including PPT1) responsible for breaking down proteins, 11 lipid-degrading lysosomal enzymes, and 3 lysosomal cargo receptors. These findings further suggest that CLN3protein plays a crucial role in regulating lysosome composition and maintaining cellular homeostasis (Schmidtke et al. 2019).
- The loss of neurons in CLN3 disease is believed to occur, at least in part, due to overexcitement (glutamate toxicity). To understand how non-neuronal astrocytes contribute to glutamate toxicity and pathological events, researchers at the University of Nebraska examine CLN3-/-astrocyte and mitochondrial function. Their results show that glutamate transporter expression and uptake were mildly impaired while mitochondrial respiration and ATP production were significantly affected. More studies are needed to determine if or how these findings result in neurons which are hyper-responsive and adversely affected by glutamate (Bosch and Kielian 2019).
As you can see, even though Juvenile Batten disease has been known to exist for over 100 years, most of the research progress has been made in the last few years. For many families across America and around the world, this is quite literally a race against time. Science provides hope for a cure, but in order to turn this hope into reality, we need to raise enough capital to fund multi-year research programs, drug discovery projects, and clinical trials.
Because Juvenile Batten disease is so rare, affecting several hundred children in the United States, research aimed at finding a cure is also extremely underfunded. Of the $31.3 billion awarded by the U.S. Department of Health and Human Services for medical research in 2016, 1.67 million went to financing research for Juvenile Batten disease. Other rare diseases such as childhood leukemia, which is 8 times more prevalent than juvenile Batten disease, received 100 times more funding than juvenile Batten disease.
While these various avenues of clinical research reflect the progress in our search for a treatment for NCLs, increasingly vulnerable funding sources threaten the ability of these scientists to continue their pursuit for a cure. The best hope we have for a treatment is in empowering investigators to continue their research into the mechanisms of NCLs to identify targets for therapies, work with the pharmaceutical industry to create drugs that match those targets and together, move potential treatments through clinical trials delivering them to children and families suffering from these devastating diseases.[/vc_column_text][vc_column_text]References
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