Here you will find a regular update of the latest scientific publications on the different forms of NCL.
Last update: December 2021.
Taysha Gene Therapies is working on a CLN1 infantile Batten disease gene therapy program
(currently open IND) that was licensed from Abeona Therapeutics and is now designated TSHA-118 (formerly ABO-202).
Sadhukhan et al. report that ablation of miR-155, which upregulation was seen in CLN1 KO mouse brain, does not alter the neuroinflammation trajectory in the brains of these mice.
Augustine et al. reported limited evidence base for treatment and clinical manage-ment guidelines for CLN1 disease. A survey and a meeting of experts was conducted to ascertain points of consensus.
Schaefers et al. studied cerliponase alfa ERT in two siblings, one symptomatic and one asymptomatic, and propose that ERT is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease.
Lourenco et al. reported on the
clinical phenotype of 30 Latin American patients with atypical CLN2 disease at 6, rather than the common onset between 2-4 years of age. The authors reinforce an inclusion of CLN2 in differential
diagnosis of children presenting with seizures, behavioral disorders and language abnormalities to allow early initiation of therapy.
Domowicz et al. analyzed transcriptional changes in the brain of aging TPP1-defi-cient mice and report several astrocytic and microglial genes showing increased ex-pression starting after 2 months of age, noted earliest in cerebellum, and associated with disease progression.
Gissen et al. demonstrate how utility studies enable preference-based quantifica-tion of a disease`s impact on health-related quality-of-life of CLN2 patients.
Helman et al. present a case study showing that RNA sequencing is a useful comple-mentary tool to DNA sequencing to inform on variants of unknown or uncertain sig-nificance, in particular variants caused by aberrant splicing.
Banning and Tikkanen used minigene approaches and patient cells to show that substances like methylxanthine derivatives and luteonin may be able to modulate splicing of one of the most common TPP1 gene variants.
Thompson et al. reported ERG and OCT findings in a cohort of atypical and typical CLN2 patients showing symmetrical cone-rod dysfunction but a broad range of ages when ERG function is preserved.
Gall et al. used next-generation sequencing-based panels including copy-number variant detection in a cohort of 211 patients (24-60 months of age) with a first un-provoked seizure at/after 24 months. In 14% of these patients CLN2 was diagnosed. This is 12-24 months earlier than reported by natural history of disease supporting NGS as a tool to identify patients early.
CLN2 gene therapy: REGENXBIO reported that it is continuing to evaluate the path forward for their RGX-181 (CNS) and RGX-381 (ocular) CLN2 gene therapy programs and plans to provide an update in 2022.
Exicure announced at their virtual R&D-day
a CLN3 program using its proprietary Spherical Nucleic Acid (SNA) technology to deliver synthetic nucleic acids.
Theranexus & BBDF announced in September receipt of Investigational New Drug approval from the FDA to launch a Phase I/II clinical trial of their drug candidate BBDF-101.
Soldati et al. described increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and developed a cell-based high content imaging screening assay for the repurposing of FDA-approved compounds able to reduce this accumulation within BD cells. Tamoxifen reduced lysosomal Gb3 accumulation in CLN3 and CLN7 cell models through a mechanism that involves activation of TFEB. Tamoxifen reduced Gb3 and SCAMS accumulation in the CLN7Δex2 mouse model and improved neuroinflammation and motor coordination.
Morsy et al. provide an overview of available
iPSC models for different NCLs and highlight findings in these models that may spur target identification and drug de-velopment.
Ostergaard studied gait phenotype in CLN1, CLN2 and CLN3 Batten disease. He re-ported for CLN3 patients a reduction in walking speed at age 7-8 years, a parkin-sonian gait phenotype in the mid-teens, and peripheral nerve involvement, neuro-genic musculoskeletal atrophy and loss of tendon reflexes and postural control in the late-teens and early-twenties.
Yasa et al. showed that CLN5 and CLN3 function as a complex to regulate endolyso-some function.
Masten et al. created a reliable diagnostic confidence scheme for CLN3 disease and discuss its utility for future clinical research studies.
Kuper et al. showed that in CLN3 disease, as compared to early-onset Stargardt dis-ease, visual acuity loss is more rapid. Also, severe colour vision abnormalities and abnormal dark-adapted ERG responses are main differentiating features of CLN3 dis-ease.
Do et al. showed that neurofilament light chain levels in CSF and serum correlate with clinical measures in CLN3 disease.
Minnis et al. used yeast-based assays to show that the minor 1-kb deletion transcript both loses and retains functions and acquires abnormal characteristics.
Rechtzigel et al. reported substantial overlap in the protein interactomes of CLN3, CLN6, and CLN8 suggesting a shared etiology. The absence of CLN3, CLN6 and CLN8 leads to synaptic depletion of key SNARE proteins and tethers, and aberrant synaptic SNARE dynamics.
Neurogene working with Lincoln University
researchers announced FDA clearance of IND for NGN-101 gene therapy to treat CLN5.
Basak et al. used CRISPR-based genome editing to generate CLN5-deficient iPSC-derived neurons and describe neutralized lysosomal acidity, reduced lysosomal en-zyme activity, and impaired lysosomal movement.
Russell et al. employed ERG and characterized progressive physiological
changes in the degenerating retina of CLN5 and CLN6 forms of ovine NCL.
Robinson Kick et al. described visual system pathology and function (ERG and visual evoked potentials) in a canine model that shows pronounced visual impairment by 21-22 months of age. They highlight the utility of the model because of the similari-ties with changes seen in CLN5 patients.
McLaren et al. describe findings that support a role for CLN5 in autophagy during the life cycle of Dictyostelium.
Barry et al. generated sheep from
ovine wildtype and CLN6 embryo aggregation chimeras and studied degrees of neurodegeneration. These varied from affected, normal-like to recovering-like. In the latter two cases there was a lack
of glial activa-tion and storage bodies. The authors propose that intercellular communication af-fects pathology.
Shiro et al. employed an earlier finding that CLN6 displays anti-aggregate activity of the myopathy-causing R120G alpha-B-crystallin mutant and showed that this activity is compromised and/or nullified depending on which pathogenic or combination of pathogenic CLN6 mutations are present. These findings may bear on patients that are compound heterozygous for different mutant CLN6 alleles.
Nicolaou et al. report clinical and genetic findings in three patients with a juvenile onset of CLN6 disease which remarkably lack vision loss at presentation.
Cherian et al. report on a CLN6 patient with type B Kufs disease who showed a first documented remarkable life-changing response to levodopa.
Koh et al. show that CLN6 interacts with a CRMP2-KLC4 complex to regulate ante-rograde axonal transport in developing neurons. CRMP2 fails to properly associate with key neuronal protein partners in the absence of CLN6. Some of these deficits can be rescued in cultured neurons and in vivo by treatment with the CRMP2 modu-lator lanthionine ketimine ester.
Taysha Gene Therapies has secured an exclusive option from the
University of Texas Southwestern to license worldwide rights to a clinical-stage gene therapy pro-gram for CLN7 disease that is currently being evaluated in a Phase 1 clinical trial
Neurogene Inc. currently sponsers a Natural History Study for both CLN5 and CLN7 to help advance gene therapy for these two diseases.
Wang et al. identified CLN7 as a novel endolysosomal chloride channel that mainly transports chloride from the lysosomal lumen to the cytoplasm. When overex-pressed, CLN7 increases chloride currents and enlarges endolysosomes in a Ca2+/cal-modulin-dependent way. CLN7 regulates lysosomal chloride conductance, luminal pH, lysosomal membrane potential, and promotes lysosomal Ca2+ release through TRPML1. CLN7 KO mice show pathological features similar to those of patients in-cluding retinal degeneration and accumulation of lipofuscin storage material. CLN7 pathogenic mutations decrease chloride permeability with more severe mutations showing more serious defects in chloride channel function.
Pesaola et al. used CLN8 knockdown to show increased size of the Golgi,
lysosomal alkalization, and decreased complexity and size of the somatodendritic compart-ment in primary rat hippocampal neurons.
Salpeter et al. generated CLN8-/- mice using CRISPR/Cas9 genome editing and pro-vide a detailed clinical characterization of retinopathy in adult mice. The retinal find-ings are consistent with those seen in CLN8 patients.
Logan et al. showed that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), and an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. PGRN protein replacement enhanced CNS biodistribution of PGRN and its delivery rescued various phenotypes in primary murine macrophages and human iPSC-derived microglia. It also rescued BMP levels, and had beneficial effects on glucosylsphingosine levels, microgliosis, lipofuscinosis, and neuronal damage disease pathology in the Grn-/- mouse CNS.
Zin et al. characterized retinal degeneration in CLN11 (progranulin) knockout mice showing that retinal PGRN gene therapy outcome is time-sensitive and depends on route of administration (systemic versus intravitreal).
Takahashi et al. characterized the retinal phenotype (ERG and histology) in mature PGRN knockout (Grn−/−) mice. Microglial cells accumulated on the retinal pigment epithelium (RPE) apical layer, and in Grn+/+ mice, strongest PGRN signals were detected in the RPE-choroid. The authors suggest that subretinal translocation of microglia is a characteristic phenotype in the retina of mature PGRN knockout mice.
Boland et al. showed that levels of bis(monoacylglycero)phosphate (BMP), a lysosomal lipid required for ganglioside catabolism, were markedly reduced in PGRN-deficient cells and patient brain tissue. These data indicate that granulins are required to maintain BMP levels which regulate ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis.
Reifschneider et al. generated Grn/TREM2 double knockout mice and used antibody-mediated TREM2 modulation showing that loss of TREM2 reduces hyperactivation of PGRN-deficient microglia but not lysosomal pathology. Accordingly, miroglia hyperactivation is not necessarily contributing to neurotoxicity in PGRN-deficiency.
Devireddy and Ferguson identified an interaction between prosaposin and Surf4 and show that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER.
Lan et al. reviewed the role of progranulin in immune-mediated diseases and its potential as a therapeutic target.
Mateeva et al. provided a structural
and catalytic mechanism model of ATP13A2 (PARK9) from simulations implicating roles of the conserved Arg686 and Lys859 cata-lytic residues. When missense mutations occur near an active site
residue, they can interfere with the barrier height of the reaction, which can halt the normal enzymatic rate of the protein.
Tillinghast et al. provided structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2. These provide a foundation to under-stand ATP13A2 mutations associated with disease.
Sim et al. generated a high-resolution cryo-EM structure and provide a structural basis of polyamine transport by human ATP13A2. Five distinct conformational inter-mediates are described which together represent a near-complete polyamine transport cycle of ATP13A2.