Here you will find a regular update of the latest information on clinical trials and scientific publications on the different forms of NCL.
Last update: July 2024
BDSRA. The BDSRA Foundation announced its Clinical Center of Excellence & Affiliate members and the formation of the Batten Disease Global Research Initiative during this year`s annual family conference in July in St. Louis, Missouri . The research grant program aims to invest in the most promising research worldwide that addresses key research questions and areas of unmet need in all forms of Batten disease. We as CLN3 NCL Foundation have expressed our interest to evaluate upcoming common funding opportunities that address research specifically focused on CLN3 disease.
Arzt + Kind. A series of articles (note, all in German) co-authored by some of our SAB (Angela Schulz, Robert Steindeld) and NCL team members (Frank Stehr, Herman van der Putten) on NCL clinical and research aspects have been published in the Austrian pediatric Journal “Arzt + Kind”. You can download the pdf version here.
For regular updates on NCL clinical trials please consult the BDSRA site and the ClinicalTrials.gov websites.
CLN1 gene therapy: In February 2024, the news came that a patient with CLN1 disease was treated with the investigational gene therapy candidate TSHA-118 under an individual-patient investigator-initiated Investigational New Drug (IND) at RUSH University Medical Center in Chicago, Illinois. Dr. Elizabeth Berry-Kravis is the principal investigator and sponsor of the investigator-initiated IND and the material was provided by Taysha Gene Therapies.
Koster et al
2023 report a crucial role for Ppt1 in AMPAR trafficking and show that impeded proteostasis of palmitoylated synaptic proteins drives maladaptive homeostatic plasticity and abnormal
recruitment of cortical activity in CLN1.
Puhl et al 2024 identified new modulators and inhibitors of Palmitoyl-Protein
Thioesterase 1 for CLN1 Batten Disease and Cancer.
Bagh et al
2024 reveal a previously unrecognized role of Cln1/Ppt1 in regulating mTORC1-activation and suggest that IGF1/PI3K/Akt may be a targetable pathway for CLN1 disease.
Jansen et al 2023 report that Bowel dysmotility and enteric neuron
degeneration in CLN1 and CLN2 mice is prevented by gene therapy.
Koster et al 2024 performed a palmitoyl-proteomic screen and discovered that Akap5 is
excessively palmitoylated at Ppt1−/− synapses. This causes an excessive upregulation of GluA1 and was associated with exacerbated disease pathology. The FDA-approved calcineurin inhibitor FK506
(Tacrolimus) modestly improved neuroinflammation in Ppt1−/− mice.
Fyke et al 2024 show therapeutic potential of a small molecule PPT1 mimetic, N-tert-butyl hydroxylamine
(NtBuHA), in a Cln1−/− mouse model. Treatment with NtBuHA reduced neuroinflammation, mitigated epileptic episodes, normalized motor function. and partially rescued aberrant synaptic calcium
dynamics in primary cortical neurons.
Bishnu et al 2023 show that AAVrh.10hCLN2 delivered by intracisternal route in
non-human primates is safe and widely distributes TPP-1 in brain and CSF at levels that are potentially therapeutic.
Wawrzynski et al 2024 report a first in man study of
intravitreal tripeptidyl peptidase 1 (rhTPP1) ERT for CLN2 retinopathy that appears to be safe and efficacious when started early. For discussion see also a review by Rodriguez-Martinez et al 2024.
Latus Bio, a Philadelphia-based biotechnology company, develops a novel gene therapy candidate for CLN2 and plans for first-in-human dosing in late 2025.
Spaull et al 2024 report on the
evolution and slowing of movement disorders in CLN2 patients treated with ERT.
Schulz et al 2024 report on safety and efficacy of ERT using Cerliponase alfa in an open-label extension
study of children with CLN2 disease and over a mean treatment period of more than 5 years. The authors report a clinically meaningful slowing of decline of motor and language function.
Gaur et al 2024: Using MRI, the authors
show that ERT in their CLN2 cohort showed a significantly slower rate of brain parenchymal volume loss compared to a natural history cohort in several anatomical regions. These results complement
prior clinical data which found a positive response to ERT.
Rogers et al 2024 report
peripheral retinal findings in CLN2 patients using fluorescein angiography and the authors propose that these may represents an early vasodegenerative phase of the disease that leads to the
vascular attenuation seen later in the disease.
Felczak et al 2024 investigated a rectal mucosa biopsy of young CLN2
patient for mitochondrial abnormalities and report aside from curvilinear profiles wads of osmophilic material and atypically damaged mitochondria.
Specchio et al 2024: To validate the CLN2 Clinical Rating Scale
(CRS) the authors used clinical trial data from patients treated with cerlopinase alpha and compared outcomes with the Pediatric Quality of Life Inventory (PedsQL). CRS motor ratings had the
highest correlation to PedsQL but the remaining domains lacked good correlations suggesting that additional disease-specific measures may be needed to fully capture the quality of life impact of
CLN2 disease.
Takahashi et al 2024 provide compelling experimental data using
GABAergic interneuron-specific deletion of TPP1 suggesting that modulating interneuron activity exerts a key influence over epileptiform abnormalities in CLN2 disease.
Olkhovych et al 2024 analysed phenotypes and genotypes of 48 CLN2
Ukraine patients thereby augmenting existing data on genotype-phenotype correlations and confirming that predicting the type and clinical course of CLN2 disease based on genotype is very
complicated.
Miglustat: Theranexus and the
Beyond Batten Disease Foundation recently confirmed positive results in their Phase I/II trial to evaluate Batten-1 (Miglustat) in CLN3 disease after 18 months of treatment. The results indicate
a decline in serum neurofilament light chain, and suggest therapeutic potential of Miglustat in CLN3 disease.
CLN3 Gene Therapy: Amicus decided to return the rights to all Batten programs to The Abigail Wexner Research Institute at Nationwide Children’s Hospital (NCH). These include the CLN3 and CLN6
clinical programs and the CLN8 preclinical program. NCH is now responsible for determining the next steps in developing those programs and for all follow-up with the CLN3 and CLN6 clinical trial
participants and their families.
Nyama et al 2024 demonstrate that glycerphosphodiesters (GPDs)
that accumulate in CLN3 lysosomes act as potent inhibitors of glycerophospholipid catabolism. GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2 and inhibit the
rate-limiting lysophospholipase activity of these phospholipases. This explains why lysosomes of CLN3-deficient cells accumulate toxic lysophospholipids and the work establishes that GPD storage
directly disrupts lysosomal lipid homeostasis.
Sareela et al 2024 present a“tagless LysoIP method” to enable
rapid enrichment of lysosomes via immunoprecipitation. The method is based on using an antibody recognizing the endogenous lysosomal membrane protein TMEM192. The authors enriched lysosomes from
freshly isolated peripheral blood mononuclear cells (PBMCs) from CLN3 patients with CLN3 disease, and confirmed the massive accumulation of glycerophosphodiesters (GPDs) in patients’ lysosomes. A
patient with a milder and mostly retinal phenotype displayed lower accumulation of lysosomal GPDs, consistent with their potential role as disease biomarkers.
Yasa et al 2024 show that loss of CLN3 function in microglia leads to
cell autonomous defects in CLN3-deficient microglia that impacts the ability of these cells to support neuronal cell health. Pathological proteomic signatures implicate defects in lysosomal
function and lipid metabolism processes at an early disease stage and CLN3-deficient microglia were unable to efficiently turnover myelin and metabolize its associated lipids. Defects in lipid
droplet formation and cholesterol accumulation were corrected by treatment with autophagy inducers and cholesterol lowering drugs.
Heins-Marroquin et al 2024 generated CLN3 mutant lines in zebrafish and
performed in-depth metabolomics and lipidomics analyses revealing significant accumulation of several glycerophosphodiesters (GPDs) and cholesteryl esters, and a global decrease in
bis(monoacylglycero)phosphate species (BMPs). These results mimic the results seen in CLN3-deficient human cells and mouse models and suggest that the zebrafish may serve as a model for
therapeutic drug testing.
Domingues et al
2024 identified the transcriptional regulator YAP1 as a major driver of the transcriptional changes observed in CLN3-KO cells. Loss of CLN3 activates YAP1 and leads to perturbations in the
lipid content of the nuclear envelope. This results in increased numbers of DNA lesions and activation of c-Abl, which phosphorylates YAP1, stimulating its pro-apoptotic signaling.
Han et al 2024 show that CLN3-deficient human iPSC-derived RPE cells
as well as RPE cells from a CLN3 miniswine model display reduced binding and decreased uptake of POS. Lipofuscin autofluorescence was decreased in CLN3 miniswine RPE at 36 months-of-age and was
followed by almost complete loss of photoreceptors at 48 months of age. The results suggest that both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis
in CLN3 disease.
Reith et al 2024 discovered a
recessive CLN3 variant that is responsible for delayed-onset retinal degeneration in Hereford cattle, a phenotype that is similar to patients with non-syndromic CLN3 mutations.
Brima et al 2024 describe insufficiencies in auditory cortical
dysfunction in individuals with later-stage CLN3 disease when measuring the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) using three stimulation rates. Their
data suggest that MMN of the ERP might serve as a brain-based bio marker of progressively atypical cortical processing in CLN3 patients.
Kane et al 2024 report on a large cohort PiezoSleep study in CLN3
mutant mice that reveals sleep abnormalities during the light period (LP) in male Cln3KO mice compared to WT male. More subtle differences were observed in Cln3KO female mice throughout the dark
period (DP) compared to WT female, recapitulating sleep abnormalities seen in CLN3 disease patients.
Schulz et al 2024 conducted an observational study describing the
parent and family impact of CLN3 disease. The study demonstrated clear patterns of disease progression, a strong desire for therapies to treat symptoms related to vision and cognition, and a
powerful family impact driven by the unrelenting nature of disease progression.
Kim and Kim 2024 report that Resorcinol upregulates nuclear PPARγ
levels in CLN3 patient-derived cells thereby reducing ROS levels, upregulating autophagy and reducing lipid accumulation.
TRPML1 and CLN3
Gan et al 2024 report TRPML1
gating modulation by allosteric mutations and lipids. The authors identified Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function
channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible
to agonist or antagonist modulation.They also identified a phospholipid (spingomylein) in the PI(4,5)P2-bound TRPML1 structure at the same hotspot for agonists and antagonists, providing a
plausible structural explanation for the inhibitory effect of sphingomyelin on agonist activation as described earlier by Prat Castro et al 2022. In the latter paper lysosomal patch experiments were carried out on iPSC-derived neurons with different CLN3
mutations. It was noted that in neurons with syndromic Batten mutations, ML-SA1(agonist)-mediated activation of TRPML1 is severely impaired, whereas this was not seen in neurons carrying a
non-syndromic CLN3 mutation (R405W) that is known to give rise mainly to a retinal phenotype in patients. Also note, in CLN3 KO ARPE-19 cells ML-SA1-mediated activation of TRPML1 was not impaired
as shown by Wünkaus et al 2023. It
will be interesting to see if these differential effects on agonist-mediated TRPML1 activation are caused by differences in lipids accumulating in different cell types and/or different CLN3
mutations.
Barker et al 2024: Mutations in CLN4 (DNAJC5 gene encodes CSPα) cause autosomal dominant, adult-onset NCL. Given that null mutations in animal models similarly result in neurodegeneration, the authors employed proximity labelling to identify CSP client proteins that are (e.g. SNAP-25 and STXBP1/Munc18-1), or are not affected (e.g. Hsc70) by the autosomal dominant L115R mutation.
Medoh and Abu-Remaileh 2024: After their
recent discovery that CLN5 encodes the lysosomal BMP synthase, the autors provide a comprehensive review of the current knowledge of BMP metabolism in mammalian cells, identifying gaps and
discussing, based on the available literature, how BMP modulation might cure intractable lysosome-associated diseases.
Huber et al 2024 examined the pathways and cellular components that regulate the
intracellular trafficking and the release of the D. discoideum homologs of CLN5 and CTSD.
Ofrim et al 2024 present two new CLN5 iPSC lines generated from skin
fibroblasts of CLN5 disease patients. The lines exhibit trilineage differentiation potential and successfully differentiate into neurons.
CLN5 relevant BMP homeostasis papers
Nyama et al demonstrate that the
lysosomal phospholipase PLA2G15 efficiently hydrolyzes bis(monoacylglycero)phosphate (BMP), which is a key to lipid catabolism, a stimulator of lipid-degrading enzymes in the lysosome, and a
major lipid constituent of intralysosomal vesicles. Of therapeutic relevance, increasing BMP levels by targeting PLA2G15 reverses the cholesterol accumulation phenotype in Niemann Pick Disease
Type C (NPC1) patient fibroblasts and significantly ameliorate diseases pathologies in NPC1-deficient mice leading to extended lifespan.
Abe et al 2024 also provide results indicating
that LPLA2 (PLA2G15) degrades BMP isomers with different substrate specificities under acidic conditions and may be the key enzyme associated with BMP accumulation in drug-induced
phospholipidosis.
Bulfon et al 2024 show that the
endolysosomal phospholipid BMP is synthesized via intra- as well as extracellular pathways and that cytosolic and secreted enzymes enhance BMP synthesis independently of CLN5. Extracellularly,
acyl-PG and BMP are generated by endothelial lipase in cooperation with other serum enzymes of the pancreatic lipase family. The intracellular acylation of PG is catalyzed by members of the
cytosolic phospholipase A2 group IV (PLA2G4) family. Overexpression of secreted or cytosolic transacylases was sufficient to correct BMP deficiency in HEK293 cells lacking CLN5 suggesting
functionally overlapping pathways promoting BMP synthesis in mammalian cells.
Singh et al 2024 report that
phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where the enzymes are highly expressed
(PLD3 in brain; PLD4 in spleen), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants are associated with neurodegenerative diseases, including Alzheimer’s disease risk. These show
diminished PLD3 catalytic activity.
Otero et al 2024 developed several new iPSC lines from CLN6 patients
with neuroimaging profiles consistent with leukodystrophy and present experimental evidence for iPSC-neurons developing storage phenotypes and had >1300 differentially-expressed genes
reminiscent of significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways.
O`Niel et al 2024 present the largest
international study that monitors the longitudinal natural history and progression of CLN6 disease in 25 patients with late-infantile-onset CLN6. These data may serve as a template for future
interventional trials.
Gene Therapy: In January, Elpida Therapeutics gave an online presentation with an update on the ongoing Phase I stage gene therapy trial and further plans for treating CLN7
Batten disease, which has been led by the University of Texas Southwestern Medical Center. For more information on the CLN7 gene therapy program please reach out to Souad Messahel, Head of
Clinical Operations at Souad@elpidatx.com.
Kayashi et al 2024 performed a single-center cross sectional data
collection along with retrospective medical chart review in a total of 8 CLN7 patients between the ages of 4 to 6 years and either homozygous or compound heterozygous. Onset of clinical symptoms
was as early as two years of age and all patients followed a progressive course of language, motor, and neurocognitive deterioration.
Marchese et al 2024 generated a novel CLN8 model in zebrafish and showed that CLN8 dysfunction impairs autophagy. The authors used autophagy modulators that are able to attenuate the pathological phenotype in mutant larvae.
Reich et al 2024 developed an
adeno-associated virus targeting the liver and achieved sustained peripheral expression of a transferrin receptor binding, brain-penetrant PGRN variant. The authors show that the gene therapy
ameliorates aberrant TDP-43, lysosomal dysfunction, and neuronal loss in Grn knockout and GrnxTmem106b double knockout mice, and shows therapeutic effects in an iPSC-based microglia-neuronal cell
model of GRN-FTD.
Sevigny et al 2024 report interim results of a PR006 (Prevail
Therapeutics) investigational gene therapy phase I/II open label trial of a low-dose and mid-dose cohort and delivering the granulin gene (GRN) using AAV9 into the cisterna magna. The one-time
administration of PR006 intowas generally safe and well tolerated but longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006 (see
ClinicalTrials.gov identifier: NCT04408625). For a more detailed discussion on both gene therapy studies see Alzforum.
Collela et al 2024 report that bone marrow
transplant of progranulin- deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid
metabolism. These experiments confirm that the bone-marrow derived microglial cells produce and secrete sufficient progranulin to cross-correct and rescue also neuronal GRN-deficiency.
Root et al 2023 report that
AAV-mediated expression of single granulins, either granulin 2 or 4, in mouse brain is sufficient to rescue the full spectrum of disease pathology in mice with complete PGRN deficiency. This
supports the idea that individual granulins are the functional units of PGRN and likely mediate neuroprotection within the lysosome.
Ondaro et al 2024 studied fibroblasts from FTD patients carrying a
distinctive GRN mutation (c.709-1G>A). The reported findings findings highlight an association between GRN deficiency and altered lysosomal-mitochondrial interactions, influencing lipid
metabolism and contributing to GRN-FTD pathogenesis.
Dominguez et al 2023 tested the impact of full deletion and partial
reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency and conclude that TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and
mouse models.
Swift et al 2024 provide a systematic review of progranulin
concentrations in biofluids in over 7,000 people. The results support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene and
further highlight the importance of considering factors such as mutation type, sex and age when interpreting PGRN concentrations.
Zhou et al 2024 investigated expression levels of progranulin in the tears of
patients with diabetic retinopathy versus healthy controls and suggest it might serve as a noninvasive Biomarker for monitoring corneal innervation changes in patients with type 2 Diabetes
Mellitus.
Smith et al 2024 conducted a
biochemical, biomarker, and behavioral characterization of the GrnR493X mouse model of FTD. In contrast to homozygous GrnR493X mice, the hets lack increased TDP-43 phosphorylation and
plasma and CSF NFL and GFAP levels, but hets do exhibit limited increases in lysosomal and inflammatory gene expression, and show behavioral social and emotional deficits similar to the
homozygous mutant mice.
Robinson et al 2024 demonstrate
that PGRN slows the maturation and limits the proteolytic activity of the lysosomal protease legumain (LGMN), and that LGMN activity is strongly elevated in Grn KO mice, in human iPSC-derived GRN
KO microglia, and in FTLD-GRN patients’ brain. LGMN secreted by microglia is internalized by neurons, where it mediates pathological processing of TDP-43. The authors identify LGMN as a
link between PGRN haploinsufficiency and TDP-43 pathology in FTLD-GRN.
Hasan et al 2023 designed a combination of in vitro and in situ
proximity labeling, lysosome immunopurification, and dynamic SILAC proteomic approaches to map the organellar and cellular architectures of neuronal PGRN deficiency, as well as a neuron dynamic
SILAC proteomic method to calculate protein half-lives in i3-Neurons. Accordingly, they discovered that PGRN deficiency had a severe impact on the lysosomes’ ability to properly acidify
thereby impairing hydrolytic activity, and also broadly influenced proteostasis by altering the half-lives of over 15% and 25% neuron proteins in GRN mutant and KO neurons.
Overby et al 2023 show that NSG1
reduced sortilin cell surface expression in neurons, causing significant reductions in uptake of progranulin. NSG1-dependent reduction of cell surface sortilin occurred via proteolytic processing
by ADAM10 with a concomitant increase in shedding of sortilin ectodomain to the extracellular space.
Erb et al 2024 selectively deleted ATP13A2 in the adult mouse brain
by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. The authors show that this adult-onset
homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration.
Croucher and Fleming 2024 review the role of ATP13A2 in basal ganglia function and dysfunction, and
discuss potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.
Chia et al 2024 identified four significantly associated risk
loci for multiple system atrophy (MSA) using a genome-wide association study approach. One of these includes KCTD7. Of note, Sharma et al 2023 showed that CRISPR-Cas9-mediated knockout of Kctd7 in mice phenotypically recapitulated human KCTD7 deficiency
and resulted in calpain hyperactivation, behavioral impairments, and neurodegeneration; these pheno- types were largely prevented by pharmacological inhibition of calpains. Also of note, Wang et
al 2022 revealed an unrecognized role of KCTD7-mediated CLN5 proteolysis in lysosomal homeostasis and demonstrate that KCTD7 and CLN5 are biochemically linked and function in a common
neurodegenerative pathway.
Yoganathan et al 2024 report on 42 patients with KCTD7-related progressive myoclonic
epilepsy and present a systematic review on the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe
neurological sequalae are common phenotypes.