NCL Research Newsletter February 2017


Main Topic(s):

          NCL gene therapy & conference summary 

Scientific and Medical Meetings

Recent Publications

Grants, Awards and Open Positions



Main topic(s)

NCL gene therapy & conference summary

NCL gene therapies on the move. For some of the NCLs, remarkable progress is being made in moving gene therapy to the clinic. Several speakers presented on this topic during the 15th International Conference on Neuronal Ceroid Lipofuscinosis that took place October 5-8, 2016 in Boston (for agenda and abstracts of oral (0) and poster (P) presentations see: For CLN6, which encodes a largely Endoplasmic Reticulum (ER)-resident transmembrane protein, a phase I/IIa gene transfer clinical trial delivering the CLN6 gene by self-complementary AAV9 is underway. The trial started in March 2016 and estimated study completion date is July 2018. It is the first human, open-label, single dose study using a self-complementary AAV9.CB.CLN6 vector that is delivered one-time intrathecally (lumbar puncture) into CLN6 disease subjects (050). Supporting preclinical efficacy studies in mice and non-human primate conducted prior to he trial were presented at the conference (09, P48).

  Gijsbert and Laura den Hertog (Batten Research Funds), Frank Stehr (NCL Foundation), Danielle Kerkovich (Beyond Batten Disease 

    Foundation), Ronald Jansen (Beat Batten Stichting), Anette Beetsma (Beat Batten Stichting)

On the forefront of recombinant enzyme delivery into the central nervous system, impressive efficacy data were presented by Angela Schulz for the CLN2 patients in Biomarin’s CLN2 Enzyme Replacement Trial (Cerliponase alpha/BMN190; 048). Mean CLN2 scores have remained stable after 81 weeks of treatment. Biomarin announced lately that the FDA and the European Medicines Agency (EMA) granted cerliponase alfa Orphan Drug Designation. The FDA granted cerliponase alfa Priority Review Status and Breakthrough Therapy designation. Also a new CLN2 gene therapy is making its way to the clinic. Preclinical studies in CLN2-deficient dogs have provided substantial support for going forward with CLN2 gene therapy in patients, although CSF delivery of the vector could not prevent loss of vision and retinal degeneration.


Abeona Therapeutics is targeting CLN3 disease with gene therapy. It aims to move to the clinic with ABO-201 (scAAV9 CLN3). Using a systemic (intravenous) delivery route this vector has shown promising preclinical efficacy in delivery and expression of a normal copy of the defective CLN3 gene in the central nervous system of CLN3 mice (031).


At the NCL meeting in Boston, also gene therapy data were presented to try and restore CLN5 and CLN6 expression in the respective sheep models (037). Lentiviral and AAV9-mediated delivery of CLN5 has shown promising results as it preserved neurological function and brain volume, and it also delayed the onset of visual defects in the vast majority of the treated sheep. CLN5, an intraluminal lysosomal protein of still unknown function, therefore also seems amenable to gene therapy. Unlike the promising studies conducted in CLN6-deficient mice and cited above, viral delivery of CLN6 in sheep has so far not been very successful. What remains an enigma is why an occasional animal has shown benefit from treatment.


Targeting the right cell type(s) is important. Several speakers touched on this topic. Preclinical work in the CLN6-deficient mouse was presented (020) showing that it is essential to transduce bipolar cells to successfully prolong photoreceptor survival in the retina. Perhaps somewhat surprising was also the outcome of a study using CLN3-deficient mice in which CLN3 expression was restored in a cell-type specific fashion (018). It suggests that, to achieve therapeutic benefit, CLN3 expression may need to be restored in multiple cell-types. Neither neuronal-only nor endothelial-cell-only restoration of CLN3 expression sufficed to correct lysosomal pathology in brain and retina and electroretinogram readings whereas restoring expression in all cells did. Furthermore, findings recently published by Bosch et al 2016 and presented also at the meeting (031) suggest that using the proper promoter to drive corrective transgene expression may be critical. These authors showed that disease improvement including motor deficits, attenuated glial activation and lysosomal pathology was seen in CLN3 mice following delivery to juveniles of scAAV9/MeCP2-hCLN3 but not when mice were treated with scAAV9/ß-actin-hCLN3. Expression of the former vector was most prominent in neurons whereas the latter vector drove CLN3 expression mainly in astrocytes. The study did not support earlier worries that AAV-mediated restoration of CLN3 expression may have undesirable toxic side effects. In their study, the authors treated juvenile mice to mimic studies planned in the clinic. Other studies have instead used newborns but a note of caution is that promoter behavior may also be influenced by the developmental stage of the brain and when a vector is administered.   


Delivery sites matter. Neuroinflammation and spinal cord pathology is known to occur in several NCLs but so far it has not been very clear how much spinal cord disease contributes to clinical deficits (013, 017, 034, P28, P33, P42). Experiments using AAV-based gene transfer of CLN1 in the CLN1-mutant mouse clearly showed that spinal cord pathology contributes significantly to CLN1 disease. This aspect of the disease was poorly rescued following intracranial administration of the vector, whereas intrathecal administration significantly reduced spinal pathology (029). Altogether, these findings seem to suggest that to achieve maximal benefit in CLN1 disease, gene therapy should target both brain and spinal cord.


Timing crucial. Given the progressive neurodegenerative nature of the NCLs most investigators would agree that therapeutic interventions should be targeted best early in the disease course (see e.g. 033). One question is how dogmatic should we be about this when translating treatments to the clinic. Evidence presented in the context of a chronic enzyme replacement (ERT) study in the CLN2 mouse model suggests that some pathology in CLN2 disease is reversible (030). ERT was definitely most efficacious when started in pre-symptomatic animals. Nonetheless, when ERT was started much later in severely affected animals, at least a subset of these did showed remarkable improvements in function. Altogether, these results seem to raise hope that symptomatic patients may benefit from treatment because the decline of certain neurological functions at a given stage of the disease may reflect impairment rather than a complete loss of neuronal function.        


CLN3 splicing therapeutics. A while ago it was proposed that recovering CLN3ex7/8 protein function, by correcting the reading frame, might translate in therapeutic benefit. The CLN3ex7/8 mutation deletes exons 7 and 8 and results in a shift in the open reading frame with a premature termination codon in exon 9. As a result, the mutant protein misses a large part of its C-terminal amino acids and is retained in the ER. Also, the C-terminal part of the CLN3 protein seems to provide an essential function for lysosomal Ca2+ homeostasis (06). Michelle Hastings and collaborators (011) showed that antisense oligonucleotides (ASO) that induce exon 6 skipping reframe the CLN3ex7/8 transcript and produce a CLN3 protein, which partially reduces phenotypic features in CLN3ex7/8 mice. Altogether, these findings raise hope for ASO-based therapeutics in CLN3 disease.


CLN3 large animal model. Mutations in canine orthologs of CLN1, CLN2, CLN5, CLN6, CLN7, CLN10 and CLN12 exist (P46) but until recently, no large animal model existed for CLN3. David Pearce and colleagues reported on the generation and first characterization of a CLN3ex7/8 minipig model (015).  It was reported that at age 12 months, the animals show first signs of CLN3-associated pathologies. A detailed characterization of this model is in progress to know how well it replicates human CLN3 disease phenotypes and pathology. Another remarkable and unexpected finding relevant to CLN7 disease was the identification of a non-human primate model in a Japanese macaque colony (038).  


Natural history of disease. Tremendous progress has been made in characterizing the natural history of CLN3 disease. The DEM-CHILD database contains clinical data from more than 500 NCL patients with all types of NCL (046). It continues to grow as more countries and centers join (currently 19 countries and 26 centers). Likewise, Jonathan Mink (044) presented  data from a large natural history study of CLN3 patients assessed using the Unified Batten Disease Rating Scale (UBDRS). Furthermore, lessons learned were presented from the first and thus far only clinical trial in CLN3 disease with CellCept (mycophenolate mofetil), (049). Data from the DEM-CHILD database are already being used for the evaluation of therapy in a current CLN2 ERT clinical trial. The hope is that these data collections will help to define tools to assess clinical outcome also in future CLN3 trials. A longitudinal 8-years brain volumetric analysis in 35 CLN3 patients was presented and showed that CLN3 patients lost on average 4.6% (±0.2%) of cortical grey matter per year (047). This seems to correlate nicely with the loss of a couple of points/year in the UBDRS. However, inter-patient variability in clinical parameters measured with the UBDRS is high and even when combining UBDRS and volumetric analysis, it will still take a considerable amount of time to know whether a therapeutic has

        Group picture of the DEM-CHILD consortium

efficacy in CLN3 disease. Therefore, the search for disease biomarkers has to continue.


Biomarkers. The search for biomarkers in CLN3 disease is part of the EU-sponsored BATcure program and efforts in other labs that for example use state-of-the-art proteomic and lipidomic technologies (010, 016, 028, P31). Such analyses have already revealed that CLN3 deficiency affects the biogenesis and enzyme composition of lysosomes. Another very interesting approach uses proteomics of differentially vulnerable synaptic populations in the thalamocortical system, early-on in CLN3 disease (027,028). The aim is to identify molecular fingerprints of synaptic alterations that occur early in the disease process and that

perhaps are common to different neurodegenerative conditions. At the same time the approach offers hope to identify novel targets for therapy.


Targeting TFEB and lysosomal Ca2+ to rescue CLN3 phenotypes. Marco Sardiello presented data showing that pharmacological activation of TFEB, a master regulator of autophagic-lysosomal pathways, reduces a number of CLN3 phenotypes in CLN3ex7/8 mice (010). Therefore, TFEB enhancers with proper pharmacokinetic and pharmacodynamics in humans may hold promise for ameliorating CLN3 disease. Emyr Lloyd-Evans showed that elevated lysosomal Ca2+ levels are present, not only in mouse CLN3ex7/8 mutant cerebellar cells as shown earlier, but also in patient fibroblasts harboring different pathogenic CLN3 mutations. Furthermore, data presented suggest that the C-terminus region of CLN3 can function in ion mobilization (06). Very exciting data, presented by Uma Chandrachud in Susan Cotman’s lab, suggest that overexpression as well as pharmacological activation of the late endolysosomal cation efflux channel TRPML1 can improve lysosomal morphology and neuronal health. These findings not only emphasize a likely role for CLN3 in lysosomal Ca2+ homeostasis. They also raise hope that modulation of some lysosomal channels might be able to compensate for the loss of CLN3 which could lead to novel therapies.


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Scientific and Medical Meetings


Summary 14th National NCL Congress, Hamburg, Dec 12, 2016

The mission of the NCL Foundation is to help find and advance therapies that enhance quality of life, increase life expectancy, and ultimately provide a cure for childhood dementia caused by CLN3-deficiency in patients that suffer from juvenile Neuronal Ceroid Lipofuscinosis. To this end we provide educational activities, research support through grants and an award and we organize and host annual research workshops devoted to specific topics relevant for CLN3 disease.


The title and aim of last year’s meeting was to discuss “clinical and translational aspects of the retina in CLN3 disease”. Together with a relatively small group of experts from academia and industry it was discussed how we might effectively use retina-based models and retina-based clinical readouts to facilitate and perhaps more rapidly translate therapies to the clinic.


Why the retina and retinotectal system are of great importance in CLN3 disease. Visual defects are the first manifestation and first highly debilitating symptoms of CLN3 disease. Although the age of onset may vary, loss of vision typically starts at school age (5-6 years) and it progresses rapidly. Other CLN3 clinical symptoms typically emerge years later. Early and correct ophthalmic diagnosis of CLN3 disease has remained a challenge. Mainly, because very similar retinal manifestations are found in other diseases for which juvenile onset forms exist such as retinitis pigmentosa, cone-rod dystrophies, and Stargardt disease. Today, no disease modifying therapies exist for CLN3 disease. Nonetheless, early and correct diagnosis is critical. First, to provide patients and their families with the best possible support regarding genetic counseling, family planning, access to insurance coverage, social and educational support, palliative treatment options, best clinical practices, and patient care throughout the course of the disease. This was underlined by Ronald Jansen, chairman of Beat Batten in the Netherlands,

who described his odyssee as father of an affected child, and his current and future plans to beat the disease. As potential therapies emerge, the general consensus is that chances for successful treatment increase when intervention starts early in the course of the disease. Thanks to recent results and work presented by Dr. Simon Dulz (Hamburg, Germany) and Prof. Birgit Lorenz (Giessen, Germany) it is now feasible, using non-invasive spectral domain optical coherence tomography (SD-OCT), to

  Prof. Dr. Bart Leroy on the 14th National NCL Congress                                                                       discriminate CLN3 disease from

                                                                                                                                                                             other   juvenile    retinopathies.

Also, it seems feasible to measure certain progressive changes even in patients who are already legally blind. Time to diagnosis will hopefully continue to decrease by ensuring that CLN3 is included in large scale genetic screens for retinal diseases. Altogether, these findings raise hope that besides using the Unified Batten Disease Rating Scale (UBDRS) and brain Magnetic Resonance Imaging (MRI), ophthalmic retinal imaging might facilitate clinical assessment in future therapeutic trials. Both speakers and Prof. Bart Leroy (Gent, B and Philadelphia, USA) also addressed the question what parts of the retina and which cell types might be affected first and/or most dramatically. Techniques including SD-OCT, fundus auto fluorescence (specifically discussed by Prof. Thomas Ach, Würzburg, Germany) and various types of ERG measurements have and are being used. More recently developed techniques such as retinal oximetry, discussed by Dr. Wouter Vehmeijer (Leiden, Netherlands) have not been used in CLN3 patients yet. Earliest changes appear to occur in the macular/foveal area and inner layer of the retina seem affected most dramatically.


Therapeutic effects seen with anti-inflammatory principles in the mouse retinotectal system.

Recently, important new insights into CLN3 protein function have emerged thanks to experiments using a variety of cell and animal models that were high-lighted by Dr. Susan Cotman (Boston, USA). Important knowledge gaps remain and hamper the design of targeted therapies. Nonetheless, experiments in a novel CLN3 mouse retina model, presented by Prof. Thomas Langmann (Cologne, Germany), and the retinotectal system of the well known CLN3ex7/8 mouse model presented by Dr. Janos Groh (Würzburg, Germany), suggest that therapeutic interventions targeting secondary or innate inflammation in the mouse can have therapeutic benefit. The open question remains whether these therapeutic effects are translational to the brain and to the disease in humans where similar inflammatory processes have been noted.


CLN3 human induced pluripotent stem cell-derived models. Dr. Luke Wiley (Iowa, USA) discussed the generation of CLN3 human induced pluripotent stem cells (iPSCs) and their utility in assessing therapeutic effects of adeno-associated virus (AAV)-mediated CLN3 gene delivery to correct CLN3 deficits in stem cells and stem cell-derived retinal tissue. Dr. Mike Karl (Dresden, Germany) presented the generation and utility of CLN3 human iPSC-derived retinal organoid models to model CLN3 retinal disease in human tissue and study therapeutics.


Moving towards gene therapy. The CLN3 gene encodes a transmembrane protein that appears to be localized predominantly in endolysosomal compartments. Apart from some cells in specific tissues including retina and brain, CLN3 function seems not to be essential for the function and survival of most cells in our body. In retina and brain, it is still not quite clear whether the detrimental consequences of a lack of CLN3 are caused by its absence in all or only specific neurons, glial cells or other support cells such as the pigment epithelial cells in the retina. At this year’s international NCL meeting in Boston it was reported that restoring CLN3 function in only brain endothelial cells or neurons of CLN3-deficient mice is insufficient to rescue phenotypes. Therefore, the perfect cure for CLN3 disease may require the transduction of a functional copy of the gene in most if not all cells. Alternatively, repairing the defect in specific cell types might suffice to rescue some of the main defects in this disease. Recently published exciting preclinical results were obtained with an intravenously administered gene therapy vector that directs prominent expression mainly in central neurons of CLN3 mice. These results laid the foundation for Abeona to go ahead and try pave the way for a clinical trial in CLN3 patients. As highlighted by Dr. Alberto Auricchio (Napels, Italy) and Prof. Gustavo Aguirre (Philadelphia, USA), using photoreceptor and RPE targeted gene therapies several retinal diseases have been successfully treated in dogs, and taken forward to the clinic. Dr. Alexander Smith (London, United Kingdom) showed that photoreceptor function in CLN6-deficient mice can be restored by specifically expressing CLN6 in non-photoreceptor retinal neurons. Whether the same principle can apply to rescuing the CLN3 retina needs to be seen. Many open questions remain. Nonetheless, the altogether encouraging findings raise hope that gene therapy may offer chances to reduce disease burden, also in CLN3 patients. Also the therapeutic potential of antisense oligonucleotides (ASOs) has been widely recognized. ASOs are being tested to correct gene defects in patients suffering e.g. from Huntington’s disease, Spinal Muscular Atrophy and Duchenne Muscular Dystrophy. Erwin van Wijk (Nijmegen, The Netherlands) showed how ASOs can restore USH2A transcripts in USH2A-patient cells and gave an outlook for genetic therapy to treat USH2A-associated retinal dystrophy. With gene and ASO-based therapy, we are still largely stepping into unknown territory.


DGKJ 2016 (annual meeting of the German Society of Paediatricians)


The NCL Foundation informs ophthalmologists and paediatricians to prevent false diagnoses. We collaborate with organizers of different medical meetings. Like in former years we were responsible for putting together a programme which was included in the annual meeting of the Society of paediatricians. This time we focused on diagnostics and therapy options in childhood dementia (R. Steinfeld, Göttingen), intracerebroventricular CLN2 therapy (A. Schulz, Hamburg), palliative care for CLN3 patients as well as neurodegeneration in Brain Iron Accumulation (NBIA) (T. Klopstock, Munich) and respective patient perspective (A. Klucken, Velbert). More than 80 guests followed the talks. Here you can find the programme (p. 58).


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 Recent Publications



AJNR Am J Neuroradiol. 2016 Oct 20 "MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis." This research provides a study on the reduction of brain volume during INCL and identifies the order of involvements of cerebrum, thalamus, cerebellum and brain stem. It also points out the beneficial effects of phosphocysteamine and N-acetyl cysteine on the patients.



AJNR Am J Neuroradiol. 2016 May 26 "Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression." Recently the lab of Dr. Schulz proved the strong relation between the brain volume loss and the age of CLN2 patients. MR imaging volumetry allows the assessment of brain atrophy during late stages of the disease.


Mol Genet Metab. 2016 Sep "Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis." This article deals with possibilities of an early detection of CLN2 by assessing the activity of TPP1-Enzyms with symptom- or disease-based gene panels.


Exp Eye Res. 2016 Nov "Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis." This review is about an ex vivo gene therapy using autologous stem cells as an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.



Ann Neurol. 2016 Nov "Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)." Three phosphodiesterase-4 (PDE4) inhibitors were tested and proved to be able to mitigate behavioural deficits and cell-specific pathology in the Cln3ex7/8 mouse model of JNCL.


Br J Ophthalmol. 2016 Jun "Novel morphological macular findings in juvenile CLN3 disease." This publication deals with the analysis of the retinal phenotype of patients with CLN3 disease via OCT. All patients showed a specific macular striation pattern on optical coherence tomography that was independent of age and progression of the disease. Particularly in early disease cases, macular striae can potentially help to discriminate CLN3 disease from other inherited forms of retinitis pigmentosa.


PLoS One. 2016 Jun "Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)." The research provides information on the knock-down of CLN3 in zebrafish which recapitulates disease symptoms like reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase and epileptic seizure. 


J Neurochem. 2016 Nov "Revisiting the neuronal localization and trafficking of CLN3 in juvenile neuronal ceroid lipofuscinosis." This publication deals with a constitutive active mutant of Rab7. It traps CLN3 in enlarged endosomes and influences the localization and subcellular targeting of CLN3 to late endosomal-lysosomal compartment. The expression maxima in the developing thalamus and cerebral cortex and outside of the central nervous system in the gastrointestinal tract and other peripheral organs was analysed. In differentiated primary neurons CLN3-protein shows mainly a somatodendritic localization. In primary neurons, they thoroughly revisit the subcellular localization of CLN3 and find a predominant localization in late endosomal-lysosomal compartments. This project was funded by the NCL Foundation.


Hum Gene Ther. 2016 Jul "Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration." AAV2-CLN3 was successful in restoring full-length CLN3 transcript and protein in patient-specific fibroblasts and iPSC-derived retinal neurons. When injected into the subretinal space of wild-type mice, purified AAV2-CLN3 did not show any evidence of retinal toxicity. This study provides proof-of-principle for initiation of a clinical trial using AAV-mediated gene augmentation for the treatment of children with CLN3-associated retinal degeneration.


Ophthalmic Genet. 2016 Aug "Ocular morphology and function in juvenile neuronal ceroid lipofuscinosis (CLN3) in the first decade of life." Three unrelated children aged from 5.6 to 8.8 years were analysed. It was shown that CLN3 causes predominantly a degeneration of the first and second neuron compared to other macular and generalized retinal dystrophies.


J Neurosci. 2016 Sep "Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)." Gene delivery approach for JNCL by generating two self-complementary adeno-associated virus 9 (scAAV9) constructs to address CLN3 dosage effects using the methyl-CpG-binding protein 2 (MeCP2) and ß-actin promoters to drive low versus high transgene expression, respectively. Only the scAAV9 construct driving low CLN3 expression (scAAV9/MeCP2-hCLN3) corrected motor deficits and attenuated microglial and astrocyte activation and lysosomal pathology. Systemic delivery route to restore CLN3 in vivo using scAAV9 and highlights the importance of promoter selection for disease modification in juvenile animals.


Cell Adh Migr. 2016 Sep "Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis." In the social amoeba Dictyostelium discoideum, loss of Cln3 results in an aberrant mid-to-late stage multicellular development. Cln3-deficiency causes aberrant adhesion and aggregation during the early stages of Dictyostelium development.


J Inherit Metab Dis. 2016 Oct "Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease." This reviw delas with the use of the XT7 complete cln-3 knockout strain of C. elegans to evaluate the therapeutic effect of calcium channel antagonist therapy. Therapeutic effects of five calcium channel antagonists were evaluated on XT7 animal lifespan and in vivo mitochondrial physiology. Flunarizine rescued the short lifespan of XT7 worms and prevented their pathophysiologic mitochondrial accumulation.



J Vet Intern Med. 2016 Jul "Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies." The identification of the molecular genetic cause of Australian Cattle Dog NCL has shown that the whole-genome sequence contained a homozygous nonsense mutation: CLN5:c.619C>T.



Mol Genet Metab. 2016 Aug "Neuronal ceroid lipofuscinosis associated with an MFSD8 mutation in Chihuahuas." This group developed a new CLN7-dog model that could be used for the research on NCL.


Invest Ophthalmol Vis Sci. 2016 Sep "Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7." Early onset and rapidly progressing degeneration of photoreceptor cells in CLN7-deficient mice results in the loss of more than 70% rod photoreceptors in 4-month-old animals. This was accompanied by reactive astrogliosis and microgliosis. Immunohistochemical and immunoblot analyses revealed accumulation of subunit c of mitochondrial ATP synthase and saposin D in mutant retinas, and electron microscopic analyses demonstrated the presence of curvilinear bodies or fingerprint-like profiles in various cell types of CLN7-deficient retinas.



Neurobiol Aging. 2016 May "Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation." The family heterozygous relatives presented behavioural variant of frontotemporal dementia (FTD). Symptoms of the homozygous progranulin mutation included rapidly progressive visual deficit, slightly dysarthria, and cerebellar ataxia.


Mol Neurodegener. 2016 Jun "Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia." This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat multiple neurodegenerative diseases.



Am J Pathol. 2016 Oct "Lysosomal Storage of Subunit c of Mitochondrial ATP Synthase in Brain-Specific Atp13a2-Deficient Mice." These medicals analysed brain tissues of Atp13a2 conditional-knockout mice, which exhibited characteristic features of neuronal ceroid lipofuscinosis, including accumulation of lipofuscin positive for subunit c of mitochondrial ATP synthase, suggesting that a common pathogenic mechanism underlies both neuronal ceroid lipofuscinosis and Parkinson disease.


CLN13 (Kufs disease (KD) type B)

Neurobiol Aging. 2016 Oct "Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation." Two consanguineous siblings were clinically diagnosed with early onset Alzheimer's disease (AD). The exome in one of these siblings was sequenced and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygots. This proved an overlap of NCL and AD.

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Grants, Awards and Open Positions


NCL Foundation and Belgian NCL contact organization co-sponser project.

The Belgian Contactpunt NCL organization, and the NCL Foundation decided to co-sponsor a series of experiments aimed at completing the characterization of the function of the CLN3 protein in lysosomal ion mobilization.

The project is conducted by Dr. Luke Haslett and principle investigator Dr. Emyr Lloyd-Evans at Cardiff University in the UK, in collaboration with co-IP Dr. Samantha Pitt at St. Andrews in Scotland.


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Kayak Team from the Netherlands fights 5500 km of waters to support Batten Research.


Three courageous Dutch friends, Fenna Bergsma (24), Willem Leefers (25), and Feike van Weperen (24) started at the end of August 2016 on an altogether 7 months lasting heroic kayak trip from Amsterdam in the Netherlands all the way to Pesaro in Italy. Their goal, together with the Dutch Batten Research Fonds, is to collect money to support research and help find and advance a cure for Batten Disease. With this extraordinary act of physical and mental endurance they plead for more support and awareness of the high unmet medical need and the research that is needed to fight and beat this horrible disease. We would like to encourage everyone, also in neighboring countries, to welcome and support this team by visiting their website and donate. They are also on facebook. On their website you will find further details in Dutch, French and Italian.


                                                   Fenna Bergsma, Willem Leefers and Feike Weperen



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