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CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-disease mice on the same genetic background from multiple animal facilities in an attempt to better define a surrogate marker of CLN3-Batten disease. Interestingly, we found that significant differences between Batten and non-disease mice found at one site were generally not maintained across different facilities. Our results suggest that colony variation in the Cln3Δex7/8 mouse model of CLN3-Batten disease can influence potential biomarkers of the disease.

Ataxia telangiectasia (AT) is a progressive multisystem autosomal recessive disorder caused by mutations in the AT-mutated (ATM) gene. Early onset AT in children is characterized by cerebellar degeneration, leading to motor impairment. Lung disease and cancer are the two most common causes of death in AT patients. Accelerated thymic involution may contribute to the cancer, and recurrent and/or chronic respiratory infections may be a contributing factor to lung disease in AT. AT patients have fertility issues, are highly sensitive to ionizing radiation and they present oculocutaneous telangiectasia. Current treatments only slightly ameliorate disease symptoms; therapy that alters or reverses the course of the disease has not yet been discovered. Previously, we have shown that ATM-/- pigs, a novel model of AT, present with a loss of Purkinje cells, altered cerebellar cytoarchitecture and motor coordination deficits. ATM-/- porcine model not only recapitulates the neurological phenotype, but also other multifaceted clinical features of the human disease. Our current study shows that ATM-/- female pigs are infertile, with anatomical and functional signs of an immature reproductive system. Both male and female ATM-/- pigs show abnormal thymus structure with decreased cell cycle and apoptosis markers in the gland. Moreover, ATM-/- pigs have an altered immune system with decreased CD8+ and increased natural killer and CD4+CD8+ double-positive cells. Nevertheless, ATM-/- pigs manifest a deficient IgG response after a viral infection. Based on the neurological and peripheral phenotypes, the ATM-/- pig is a novel genetic model that may be used for therapeutic assessments and to identify pathomechanisms of this disease.

Importance:Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. Objective:To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. Design, Setting, and Participants:A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Main Outcomes and Measures:Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. Results:There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. Conclusions and Relevance:This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. The NCLs result in premature death due to the absence of curative therapies. Nevertheless, preclinical and clinical trials exist for various therapies. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. The genotype of the original mouse model of CLN2 disease, Cln2-/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2R208X. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Molecular assessment of Cln2R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. This reduction leads to the development of neurological impairment (e.g. tremors) and neuropathology (e.g. astrocytosis). Collectively, these assessments indicate that the Cln2R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies.

The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative genetic diseases that primarily affect children and have no known cure. A unified clinical rating scale for the juvenile form of NCL (JNCL) has been developed, but it has not been validated in other subtypes and does not give a true measure of the pathophysiological changes that may be occurring during disease progression. In this study, we have identified candidate biomarkers in blood plasma of NCL disease using multiple proteomic approaches, with the aim of developing a panel of biomarkers that could serve as a metric for therapeutic response. Candidate biomarkers were identified as proteins with levels that significantly differed between patients and controls in both sample sets. The seven candidates identified have previously been associated with neurodegenerative and inflammatory diseases. Multiplex immunoassay based testing was the most efficient and effective evaluation technique and could be employed on a broad scale to track patient response to treatment.

The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile, late-infantile, juvenile and adult forms based on their age of onset. Though the disease phenotypes may vary in their age and order of presentation, all typically include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures. Pathological hallmarks of NCLs include the accumulation of storage material or ceroid in the lysosome, progressive neuronal degeneration and massive glial activation. Advances have been made in genetic diagnosis and counseling for families. However, comprehensive treatment programs that delay or halt disease progression have been elusive. Current disease management is primarily targeted at controlling the symptoms rather than “curing” the disease. Recognizing the growing need for transparency and synergistic efforts to move the field forward, this review will provide an overview of the therapeutic approaches currently being pursued in preclinical and clinical trials to treat different forms of NCL as well as provide insight to novel therapeutic approaches in development for the NCLs.