On the cusp of cures: Breakthroughs in Batten disease research

Brudvig, Jon; Weimer, Jill M.

doi:10.1016/j.conb.2021.08.003

Cited by 14 publications

(14 citation statements)

References 70 publications

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“…Likewise, little is known regarding upstream disease etiology, and reliable, specific biomarkers of disease status have not been reported. 3 With several potential therapies in clinical trials, sensitive, minimally invasive biomarkers could facilitate a faster path to regulatory approval.…”

Section: Introductionmentioning

confidence: 99%

Glycerophosphoinositol is Elevated in Blood Samples From CLN3^Δex7-8 pigs, Cln3^Δex7-8 Mice, and CLN3-Affected Individuals

et al. 2022

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Introduction: CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants in CLN3. Despite decades of intense research, specific biofluid biomarkers of disease status have not been reported, hindering clinical development of therapies. Thus, we sought to determine whether individuals with CLN3 Batten disease have elevated levels of specific metabolites in blood. Methods: We performed an exhaustive metabolomic screen using serum samples from a novel minipig model of CLN3 Batten disease and validated findings in CLN3 pig serum and CSF and Cln3 mouse serum. We further validate biomarker candidates with a retrospective analysis of plasma and CSF samples collected from participants in a natural history study. Plasma samples were evaluated from 22 phenotyped individuals with CLN3 disease, 15 heterozygous carriers, and 6 non-affected non-carriers (NANC). Results: CLN3 pig serum samples from 4 ages exhibited large elevations in 4 glycerophosphodiester species: glycerophosphoinositol (GPI), glycerophosphoethanolamine (GPE), glycerophosphocholine (GPC), and glycerophosphoserine (GPS). GPI and GPE exhibited the largest elevations, with similar elevations found in CLN3 pig CSF and Cln3 mouse serum. In plasma samples from individuals with CLN3 disease, glycerophosphoethanolamine and glycerophosphoinositol were significantly elevated with glycerophosphoinositol exhibiting the clearest separation (mean 0.1338 vs 0.04401 nmol/mL for non-affected non-carriers). Glycerophosphoinositol demonstrated excellent sensitivity and specificity as a biomarker, with a receiver operating characteristic area under the curve of 0.9848 ( P = .0003). Conclusions: GPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. This raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies.

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Section: Introductionmentioning

confidence: 99%

Glycerophosphoinositol is Elevated in Blood Samples From CLN3^Δex7-8 pigs, Cln3^Δex7-8 Mice, and CLN3-Affected Individuals

et al. 2022

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“…NCLs have been subclassified according to age at onset and clinical features into congenital (CNCL), infantile (INCL), late-infantile (LINCL), juvenile (JNCL), and adult (ANCL) neuronal ceroid lipofuscinoses. Thirteen genes with NCL associated variants have been established to date, named CLN1-CLN8 and CLN10-CLN14 [ 10 , 11 ]. Additionally, a new subtype of NCL (CLN15) has been proposed [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Rus

Weissensteiner

Pereira

et al. 2022

Orphanet J Rare Dis

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Background Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. Results We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. Conclusions Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.

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“…Milasen was developed in less than a year to treat Mila Makovec’s CLN7 gene mutation leading to the development of Batten disease. This is a rare disease caused by one of at least 13 known mutations to the CLN gene that affects the cell’s ability to remove waste, such as excess proteins and lipids [ 115 ]. This disease is eventually fatal if left untreated.…”

Section: Rna Therapeuticsmentioning

confidence: 99%

Current Advances in RNA Therapeutics for Human Diseases

Zogg

Singh

2022

IJMS

102

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Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairly rapidly once administered; this has led to the development of novel delivery mechanisms, such as nanoparticles to increase stability as well as to prevent off-target effects of these molecules. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology similarly to traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely comprise promising RNA therapeutics. This review focuses on the current advances of RNA therapeutics and addresses current challenges with their development.

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On the cusp of cures: Breakthroughs in Batten disease research

Cited by 14 publications

References 70 publications

Glycerophosphoinositol is Elevated in Blood Samples From CLN3^Δex7-8 pigs, Cln3^Δex7-8 Mice, and CLN3-Affected Individuals

Glycerophosphoinositol is Elevated in Blood Samples From CLN3^Δex7-8 pigs, Cln3^Δex7-8 Mice, and CLN3-Affected Individuals

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Current Advances in RNA Therapeutics for Human Diseases

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On the cusp of cures: Breakthroughs in Batten disease research

Cited by 14 publications

References 70 publications

Glycerophosphoinositol is Elevated in Blood Samples From CLN3Δex7-8 pigs, Cln3Δex7-8 Mice, and CLN3-Affected Individuals

Glycerophosphoinositol is Elevated in Blood Samples From CLN3Δex7-8 pigs, Cln3Δex7-8 Mice, and CLN3-Affected Individuals

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Current Advances in RNA Therapeutics for Human Diseases

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Product

Resources

About

Glycerophosphoinositol is Elevated in Blood Samples From CLN3^Δex7-8 pigs, Cln3^Δex7-8 Mice, and CLN3-Affected Individuals

Glycerophosphoinositol is Elevated in Blood Samples From CLN3^Δex7-8 pigs, Cln3^Δex7-8 Mice, and CLN3-Affected Individuals