4 December 2023
In 2020, Sondhi and colleagues published results from an investigative gene therapy study for the treatment of CLN2 disease. In that study, 8 children with mild to moderate CLN2 disease were treated with intraparenchymal administration (infusion of drug into the brain tissue via burr holes in the skull) of an AAV viral serotype encoding the human CLN2 gene, known as AAVrh.10hCLN2. Researchers concluded that the treatment "slowed the progression of disease in children with CLN2 disease, [however], improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy." In their latest study, Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten disease, published in August, the research team assessed whether the less invasive intracisternal delivery route (infusion into cisterna magna compartment at the base of the skull) would be safe and provide a wider distribution of the TPP-1 enzyme. The study was conducted in nonhuman primates (NHP) with intracisternal delivery to cerebral spinal fluid of AAVrh.10hCLN2. Overall, results indicate that delivery of the investigational gene therapy via the intracisternal route is safe and the doses administered led to widely distributed TPP-1 in the brain and cerebrospinal fluid (CSF) at levels that are potentially therapeutic.
Lysosomes play a crucial role in maintaining neuronal health in childhood and in age-related neurodegenerative diseases. Lysosomal function is potently enhanced by an enigmatic lipid known as bis(monoacylglycero)phosphate (BMP). Alterations in BMP levels are linked to neurodegeneration, and its accumulation is increasingly recognized as a ‘firefighter’ response to lysosomal dysfunction. However, the enzyme responsible for BMP production has remained unknown for decades, hindering understanding and translational potential. In this study, The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase, Uche Medoh and colleagues now show that the gene CLN5, the loss of which causes CLN5 Batten disease, encodes the long-sought BMP synthase. This discovery establishes the groundwork for future research on the fundamental aspects of BMP and its therapeutic applications in CLN5 disease, other NCL subtypes and potentially other neurodegenerative conditions.
Recurrent non-epileptic episodes of frightened facial and body expression reportedly occur in more than half of post-adolescent patients with CLN3 disease. Clinically, the episodes look similar to the seizures normally seen following acute traumatic brain injury (TBI), known as paroxysmal sympathetic hyperactivity (PSH). This review entitled Treatment of non-epileptic episodes of anxious, fearful behavior in adolescent juvenile neuronal ceroid lipofuscinosis (CLN3 disease) by Prof. John Ostergaard at Aarhus University Hospital Denmark, suggests episodes in patients with CLN3 disease are often triggered by separation (eg. from primary carer), loud sounds or the exposure to ‘uncomfortable stimuli’ such as lifting the patient against gravity, bathing or brushing teeth. Like PSH following TBI, the attacks are difficult to prevent and/or treat. According to this review, published in Frontiers in Neurology, the underlying mechanisms causing these episodes in the degenerative process of CLN3 disease, are three-fold: (1) disturbed somatosensory modulation leading to a reduced threshold of pain; (2) degeneration within the neural anxiety/fear circuit leading to an imbalance of inhibition and excitation pathways; and (3) with advancing age, there appears a significant dominance of the sympathetic “fight or flight” neural system. Based on these observations, Prof. Ostergaard discusses a rational approach to prevent and/or treat the attacks. Read more here.
Major facilitator superfamily domain-containing protein 8 (MFSD8) is a transmembrane protein that has been reported to function as a lysosomal chloride channel. In humans, homozygous mutations in MFSD8 cause a late-infantile form of NCL, CLN7 disease. Here, researcher Robert Huberman and colleagues at Trent University Ontario, Canada, used the amoeba Dictyostelium discoideum, to examine the effect of mfsd8-deficiency on the ‘secretome’ (the overall secretory factors and proteins released from the cells) during the early stages of multicellular development. Results revealed mfsd8 deregulates and disrupts protein secretion and protein localization within the cell, and/or causes the release of proteins not normally secreted by healthy cells. Interestingly, loss of mfsd8 was shown to alter release of proteins also known to interact with Cln5, and loss of mfsd8 or Cln3 affected the release of common proteins. Together, this study published in the European Journal of Cell Biology, reveals the impact of mfsd8 loss on the secretome and lays the foundation for follow up work that investigates the role of altered protein release in CLN7 disease. Read more here.
Rus CM, Polla DL, Di Bucchianico S, Fischer S, Hartkamp J, Hartmann G, Alpagu Y, Cozma C, Zimmermann R, Bauer P. Sci Rep. 2023 Oct 29;13(1):18550. Abstract Neuronal ceroid lipofuscinosis 6 (CLN6) is a rare and fatal autosomal recessive disease primarily affecting the nervous system in children. It is caused by a pathogenic mutation in the CLN6 gene for which no therapy is available. Employing an untargeted metabolomics approach, we analyzed the metabolic changes in CLN6 subjects to see if this system could potentially yield biomarkers for diagnosis and monitoring disease progression. Neuronal-like cells were derived from human fibroblast lines from CLN6-affected subjects (n = 3) and controls (wild type, n = 3). These were used to assess the potential of a neuronal-like cell-based metabolomics approach to identify CLN6 distinctive and specific biomarkers. The most impacted metabolic profile is associated with sphingolipids, glycerophospholipids metabolism, and calcium signaling. Over 2700 spectral features were screened, and fifteen metabolites were identified that differed significantly between both groups, including the sphingolipids C16 GlcCer, C24 GlcCer, C24:1 GlcCer and glycerophospholipids PG 40:6 and PG 40:7. Of note, these fifteen metabolites were downregulated in the CLN6 disease group. This study is the first to analyze the metabolome of neuronal-like cells with a pathogenic mutation in the CLN6 gene and to provide insights into their metabolomic alterations. This could allow for the development of novel biomarkers for monitoring CLN6 disease. Read the full article here.
Murray SJ, Wellby MP, Barrell GK, Russell KN, Deane AR, Wynyard JR, Gray SJ, Palmer DN, Mitchell NL. Front Pharmacol. 2023 Oct 24;14:1212235. Abstract Mutations in the CLN5 gene cause the fatal, pediatric, neurodegenerative disease CLN5 neuronal ceroid lipofuscinosis. Affected children suffer progressive neuronal loss, visual failure and premature death. Presently there is no treatment. This study evaluated dual intracerebroventricular (ICV) and intravitreal (IVT) administration of a self-complementary adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) into CLN5 affected sheep (CLN5-/-) at various disease stages. CLN5 disease progression was slowed in pre-symptomatic sheep who received a moderate dose of scAAV9/oCLN5, whilst a higher ICV dose treatment in early and advanced symptomatic animals delayed or halted disease progression. Intracranial (brain) volume loss was attenuated in all treatment cohorts, and visual function was also sustained in both the early and advanced symptomatic treated sheep over the 24-month duration of the study. Robust CLN5 protein expression was detected throughout the brain and spinal cord, and improvements in central nervous system and retinal disease correlates were observed. These findings hold translational promise for extending and improving the quality of life in both pre-symptomatic and symptomatic CLN5 patients, and prompted the initiation of the first in-human Phase I/II clinical trial testing ICV/IVT administration of scAAV9 encoding human CLN5 (https://clinicaltrials.gov/; NCT05228145). Read the full article here.
N. Gammaldi, F. Pezzini, E. Michelucci, N. Di Giorgi, A. Simonati, S. Rocchiccioli, F.M. Santorelli, S. Doccini. Neurobiology of Disease. 2023, 189: 106349 Abstract Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative disorders whose molecular mechanisms remain largely unknown. Omics approaches are among the methods that generate new information on modifying factors and molecular signatures. Moreover, omics data integration can address the need to progressively expand knowledge around the disease and pinpoint specific proteins to promote as candidate biomarkers. In this work, we integrated a total of 62 proteomic and transcriptomic datasets originating from humans and mice, employing a new approach able to define dysregulated processes across species, stages and NCL forms. Moreover, we selected a pool of differentially expressed proteins and genes as species- and form-related biomarkers of disease status/progression and evaluated local and spatial differences in most affected brain regions. Our results offer promising targets for potential new therapeutic strategies and reinforce the hypothesis of a connection between NCLs and other forms of dementia, particularly Alzheimer's disease. Read the full article here.
Nickel M, Gissen P, Greenaway R, Cappelletti S, Hamborg C, Ragni B, Ribitzki T, Schulz A, Tondo I, Specchio N. Neuropediatrics. 2023 Dec;54(6):402-406. Abstract Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric disorder associated with rapid neurodegeneration, and premature death in adolescence. An effective enzyme replacement therapy (cerliponase alfa) has been approved that can reduce this predictable neurological decline. The nonspecific early symptoms of CLN2 disease frequently delay diagnosis and appropriate management. Seizures are generally recognized as the first presenting symptom of CLN2 disease, but emerging data show that language delay may precede this. An improved understanding of language deficits in the earliest stage of CLN2 disease may support the early identification of patients. In this article, CLN2 disease experts examine how language development is affected by CLN2 disease in their clinical practices. The authors' experiences highlighted the timings of first words and first use of sentences, and language stagnation as key features of language deficits in CLN2 disease, and how deficits in language may be an earlier sign of the disease than seizures. Potential challenges in identifying early language deficits include assessing patients with other complex needs, and recognizing that a child's language abilities are not within normal parameters given the variability of language development in young children. CLN2 disease should be considered in children presenting with language delay and/or seizures to facilitate earlier diagnosis and access to treatment that can significantly reduce morbidity. Read the full article here.
Kovács AD, Gonzalez Hernandez JL, Pearce DA. Sci Rep. 2023 Nov 6;13(1):19229. Abstract Batten disease is a group of mostly pediatric neurodegenerative lysosomal storage disorders caused by mutations in the CLN1-14 genes. We have recently shown that acidified drinking water attenuated neuropathological changes and improved motor function in the Cln1R151X and Cln3-/- mouse models of infantile CLN1 and juvenile CLN3 diseases. Here we tested if acidified drinking water has beneficial effects in Cln2R207X mice, a nonsense mutant model of late infantile CLN2 disease. Cln2R207X mice have motor deficits, muscle weakness, develop tremors, and die prematurely between 4 and 6 months of age. Acidified water administered to Cln2R207X male mice from postnatal day 21 significantly improved motor function, restored muscle strength and prevented tremors as measured at 3 months of age. Acidified drinking water also changed disease trajectory, slightly delaying the death of Cln2R207X males and females. The gut microbiota compositions of Cln2R207X and wild-type male mice were markedly different and acidified drinking water significantly altered the gut microbiota of Cln2R207X mice. This suggests that gut bacteria might contribute to the beneficial effects of acidified drinking water. Our study demonstrates that drinking water is a major environmental factor that can alter disease phenotypes and disease progression in rodent disease models. Read the full article here.