RARE DISEASE
Rhizomelic chondrodysplasia punctata
Rhizomelic chondrodysplasia punctata
Rhizomelic chondrodysplasia punctata
Synonyms: RCDP
Synonyms: RCDP
Synonyms: RCDP
Drug discovery
1
drug
With orphan designation
Overview
Rhizomelic chondrodysplasia punctata (RCDP) is a rare autosomal recessive peroxisomal disorder characterized by rhizomelic limb shortening, chondrodysplasia punctata, congenital cataracts, severe intellectual disability, seizures, and respiratory compromise. Caused by mutations in PEX7 (type 1), GNPAT (type 2), or AGPS (type 3), RCDP results from impaired plasmalogen biosynthesis. Prognosis is poor, with most patients dying by age 10 due to respiratory complications, though milder forms may survive into adulthood [1][7][14].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
32 drug discovery papers about Rhizomelic chondrodysplasia punctata, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
32 drug discovery papers about Rhizomelic chondrodysplasia punctata, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-05-01 | Novel PEX7 gene variant-associated rhizomelic chondrodysplasia punctata type 1: a clinico-radio-biochemical diagnosis
A male child in late infancy, born at 38 weeks of gestation in a hospital to healthy parents in their late 20s (first pregnancy, non-consanguineous marriage) with an uneventful perinatal history, was referred to our tertiary care centre for evaluation of short stature and global developmental delay
2025-08-25 | A diagnostic and management odyssey of a rare case of rhizomelic chondrodysplasia punctata.
Rhizomelic chondrodysplasia punctata (RCDP) is one of the rare inherited peroxisomal disorders that belongs to the heterogeneous group of chondrodysplasias presenting with proximal shortening of the limbs and distinctive punctate calcifications of bones and cartilages. This disorder occurs due to mutations in the genes responsible for peroxisomal biosynthesis inherited commonly as autosomal recessive, though a few are reported as x-linked dominant and recessive. The diagnosis can be made on clinical findings along with a skeletal survey; however, sonography and genetic analysis are crucial for a definitive prenatal diagnosis in cases where RCDP is inherited within a family as there is no definitive cure for RCDP and the treatment revolves around the management of its manifestations and complications. We hereby report the case of a neonate with features of RCDP. Significant respiratory involvement in RCDP babies is linked with high mortality which was also observed in this case.
2024-10-03 | Biallelic Deletion of PEX26 Exon 4 in a Boy with Phenotypic Features of both Zellweger Syndrome and Infantile Refsum Disease.
Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy. The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype. Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient's clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein's ability to facilitate essential cellular processes related to peroxisome biogenesis and function. The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations.
2016-07-12 | A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform.
Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.
2006-02-15 | Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance
In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant. We tested whether these features could be related to the known role of microtubules in peroxisome trafficking in mammalian cells. We found that remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype, and a less-pronounced effect was observed for fibroblasts from an infantile Refsum patient who was homozygous for a milder PEX1 mutation. By contrast, such changes were not seen for patients with peroxisomal disorders characterized by normal peroxisome abundance and size. Stable overexpression of PEX11β to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells. In D-BP-deficient cells, peroxisome division was apparently driven to completion, as induced peroxisomal structures were similar to the spherical parental structures. By contrast, in PEX1-null cells the majority of induced peroxisomal structures were elongated and tubular. These structures were apparently blocked at the division step, despite having recruited DLP1, a protein necessary for peroxisome fission. These findings indicate that the increased size, reduced abundance, and disturbed cytoplasmic distribution of peroxisomal structures in PEX1-null and D-BP-deficient cells reflect defects at different stages in peroxisome proliferation and division, processes that require association of these structures with, and dispersal along, microtubules.
small molecules
2025-03-14 | First-In-Human Safety, Tolerability, and Pharmacokinetics of PPI-1011, a Synthetic Plasmalogen Precursor.
PPI-1011 is a synthetic plasmalogen precursor designed to augment plasmalogen levels in patients with Rhizomelic chondrodysplasia punctata (RCDP), an ultra-rare genetic disorder caused by a plasmalogen deficiency that results in significant physical and mental delays. We report here a Phase I, randomized, double-blind, placebo-controlled study that evaluated the safety, tolerability, and pharmacokinetics (PK) of single (10-100 mg/kg) and multiple (75 and 100 mg/kg/day) ascending doses of PPI-1011 in healthy adults. All treatment-emergent adverse events (TEAEs) were mild, monitorable, and resolved without intervention, suggesting no significant safety concerns. The most common TEAEs were gastrointestinal in both the placebo and PPI-1011 groups, suggesting they were likely related to the oil-based nature of the formulation. PK analysis confirmed that both single (25, 50, 75 and 100 mg/kg) and multiple-dose (75 and 100 mg/kg, once daily) administration of PPI-1011 significantly increased serum levels of the target plasmalogen (PlsEtn 16:0/22:6). With a once-daily regimen, PPI-1011 administration resulted in a sustained increase of PlsEtn 16:0/22:6 serum concentrations in healthy participants over a duration of 14 days and beyond.
2023-12-01 | Revolutionizing memory improvement: KIT‐13, a novel Plasmalogen analog, inhibits neuroinflammation and boosts memory in mice
Abstract Background A decrease in cell plasmalogens often links with an inflammatory state. Our previous study discovered that natural plasmalogens (specific types of phospholipids) extracted from scallops inhibited neuroinflammation and improved memory function in mice 1 . The subsequent randomized clinical trials also showed significant improvements in patients with Alzheimer’s disease by natural plasmalogens 2 . In order to increase the stability and achieve greater cellular plasmalogens, we developed a new plasmalogen derivative and examined if it would produce similar effects in mice. Method In our current study, we investigated the alkyl‐type plasmalogen analog, KIT‐13 (1‐0‐octadecyl‐2‐arachidonoyl‐sn‐glycerol‐3‐phosphoethanolamine), to evaluate its potential effect on neuroinflammation (in vitro, in vivo), neurogenesis (in vitro), and memory improvement (in vivo). In our in vitro studies, mice microglial cell lines (BV2 and MG6) were used for evaluation of the anti‐inflammatory effects, and neuronal‐like cells (SH‐SY5Y) were used to assess the effect of KIT‐13 on the regulation of brain‐derived neurotrophic factor (BDNF) and the neurogenesis marker DCX. In in vivo studies, learning and memory were assessed by Morris Water Maze (MWM) tests. The neuroinflammation was induced by LPS injection (i.p.), which increased activated glial cells and reduced memory in 12‐week‐old adult male (B6) mice. KIT‐13 (0.2 mg/kg/day) was administered orally for four weeks before LPS injection. Result In vitro experiments demonstrated that KIT‐13 attenuated the LPS‐induced upregulation of NOS2 expression in microglial cells and increased BDNF and DCX expression in neuronal‐like cells. Also, KIT‐13 pre‐treatment reduced LPS‐induced neuroinflammation and memory disturbance in mice, indicating that, similar to natural plasmalogens, KIT‐13 may improve memory by decreasing neuroinflammation and increasing BDNF‐mediated neurogenesis in the mouse brain. Conclusion These findings suggested that KIT‐13 can be a therapeutic drug candidate for diseases associated with plasmalogen reduction, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and rhizomelic chondrodysplasia punctata (RCDP). Reference : 1. Ifuku et al. J Neuroinflammation 2012, 9:197 2. Fujino et al. EBioMedicine 2017, 17:199‐205 3. Fujino et al. J Alzheimers Dis Parkinsonism 2019, 9:4 4. Hossain et al. Front Cell Dev Biol 2022, 10:828282
2022-02-24 | Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment.
The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer's and Parkinson's disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS.
2020-05-22 | Oral batyl alcohol supplementation rescues decreased cardiac conduction in ether phospholipid‐deficient mice
Abstract Plasmalogens (Pls) are a class of membrane phospholipids which serve a number of essential biological functions. Deficiency of Pls is associated with common disorders such as Alzheimer's disease or ischemic heart disease. A complete lack of Pls due to genetically determined defective biosynthesis gives rise to rhizomelic chondrodysplasia punctata (RCDP), characterized by a number of severe disabling pathologic features and death in early childhood. Frequent cardiac manifestations of RCDP include septal defects, mitral valve prolapse, and patent ductus arteriosus. In a mouse model of RCDP, reduced nerve conduction velocity was partially rescued by dietary oral supplementation of the Pls precursor batyl alcohol (BA). Here, we examine the impact of Pls deficiency on cardiac impulse conduction in a similar mouse model ( Gnpat KO). In‐vivo electrocardiographic recordings showed that the duration of the QRS complex was significantly longer in Gnpat KO mice than in age‐ and sex‐matched wild‐type animals, indicative of reduced cardiac conduction velocity. Oral supplementation of BA for 2 months resulted in normalization of cardiac Pls levels and of the QRS duration in Gnpat KO mice but not in untreated animals. BA treatment had no effect on the QRS duration in age‐matched wild‐type mice. These data suggest that Pls deficiency is associated with increased ventricular conduction time which can be rescued by oral BA supplementation.
proteins
2026-05-01 | Novel PEX7 gene variant-associated rhizomelic chondrodysplasia punctata type 1: a clinico-radio-biochemical diagnosis
A male child in late infancy, born at 38 weeks of gestation in a hospital to healthy parents in their late 20s (first pregnancy, non-consanguineous marriage) with an uneventful perinatal history, was referred to our tertiary care centre for evaluation of short stature and global developmental delay
2025-08-25 | A diagnostic and management odyssey of a rare case of rhizomelic chondrodysplasia punctata.
Rhizomelic chondrodysplasia punctata (RCDP) is one of the rare inherited peroxisomal disorders that belongs to the heterogeneous group of chondrodysplasias presenting with proximal shortening of the limbs and distinctive punctate calcifications of bones and cartilages. This disorder occurs due to mutations in the genes responsible for peroxisomal biosynthesis inherited commonly as autosomal recessive, though a few are reported as x-linked dominant and recessive. The diagnosis can be made on clinical findings along with a skeletal survey; however, sonography and genetic analysis are crucial for a definitive prenatal diagnosis in cases where RCDP is inherited within a family as there is no definitive cure for RCDP and the treatment revolves around the management of its manifestations and complications. We hereby report the case of a neonate with features of RCDP. Significant respiratory involvement in RCDP babies is linked with high mortality which was also observed in this case.
2024-10-03 | Biallelic Deletion of PEX26 Exon 4 in a Boy with Phenotypic Features of both Zellweger Syndrome and Infantile Refsum Disease.
Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy. The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype. Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient's clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein's ability to facilitate essential cellular processes related to peroxisome biogenesis and function. The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations.
2016-07-12 | A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform.
Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.
2006-02-15 | Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance
In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant. We tested whether these features could be related to the known role of microtubules in peroxisome trafficking in mammalian cells. We found that remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype, and a less-pronounced effect was observed for fibroblasts from an infantile Refsum patient who was homozygous for a milder PEX1 mutation. By contrast, such changes were not seen for patients with peroxisomal disorders characterized by normal peroxisome abundance and size. Stable overexpression of PEX11β to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells. In D-BP-deficient cells, peroxisome division was apparently driven to completion, as induced peroxisomal structures were similar to the spherical parental structures. By contrast, in PEX1-null cells the majority of induced peroxisomal structures were elongated and tubular. These structures were apparently blocked at the division step, despite having recruited DLP1, a protein necessary for peroxisome fission. These findings indicate that the increased size, reduced abundance, and disturbed cytoplasmic distribution of peroxisomal structures in PEX1-null and D-BP-deficient cells reflect defects at different stages in peroxisome proliferation and division, processes that require association of these structures with, and dispersal along, microtubules.
small molecules
2025-03-14 | First-In-Human Safety, Tolerability, and Pharmacokinetics of PPI-1011, a Synthetic Plasmalogen Precursor.
PPI-1011 is a synthetic plasmalogen precursor designed to augment plasmalogen levels in patients with Rhizomelic chondrodysplasia punctata (RCDP), an ultra-rare genetic disorder caused by a plasmalogen deficiency that results in significant physical and mental delays. We report here a Phase I, randomized, double-blind, placebo-controlled study that evaluated the safety, tolerability, and pharmacokinetics (PK) of single (10-100 mg/kg) and multiple (75 and 100 mg/kg/day) ascending doses of PPI-1011 in healthy adults. All treatment-emergent adverse events (TEAEs) were mild, monitorable, and resolved without intervention, suggesting no significant safety concerns. The most common TEAEs were gastrointestinal in both the placebo and PPI-1011 groups, suggesting they were likely related to the oil-based nature of the formulation. PK analysis confirmed that both single (25, 50, 75 and 100 mg/kg) and multiple-dose (75 and 100 mg/kg, once daily) administration of PPI-1011 significantly increased serum levels of the target plasmalogen (PlsEtn 16:0/22:6). With a once-daily regimen, PPI-1011 administration resulted in a sustained increase of PlsEtn 16:0/22:6 serum concentrations in healthy participants over a duration of 14 days and beyond.
2023-12-01 | Revolutionizing memory improvement: KIT‐13, a novel Plasmalogen analog, inhibits neuroinflammation and boosts memory in mice
Abstract Background A decrease in cell plasmalogens often links with an inflammatory state. Our previous study discovered that natural plasmalogens (specific types of phospholipids) extracted from scallops inhibited neuroinflammation and improved memory function in mice 1 . The subsequent randomized clinical trials also showed significant improvements in patients with Alzheimer’s disease by natural plasmalogens 2 . In order to increase the stability and achieve greater cellular plasmalogens, we developed a new plasmalogen derivative and examined if it would produce similar effects in mice. Method In our current study, we investigated the alkyl‐type plasmalogen analog, KIT‐13 (1‐0‐octadecyl‐2‐arachidonoyl‐sn‐glycerol‐3‐phosphoethanolamine), to evaluate its potential effect on neuroinflammation (in vitro, in vivo), neurogenesis (in vitro), and memory improvement (in vivo). In our in vitro studies, mice microglial cell lines (BV2 and MG6) were used for evaluation of the anti‐inflammatory effects, and neuronal‐like cells (SH‐SY5Y) were used to assess the effect of KIT‐13 on the regulation of brain‐derived neurotrophic factor (BDNF) and the neurogenesis marker DCX. In in vivo studies, learning and memory were assessed by Morris Water Maze (MWM) tests. The neuroinflammation was induced by LPS injection (i.p.), which increased activated glial cells and reduced memory in 12‐week‐old adult male (B6) mice. KIT‐13 (0.2 mg/kg/day) was administered orally for four weeks before LPS injection. Result In vitro experiments demonstrated that KIT‐13 attenuated the LPS‐induced upregulation of NOS2 expression in microglial cells and increased BDNF and DCX expression in neuronal‐like cells. Also, KIT‐13 pre‐treatment reduced LPS‐induced neuroinflammation and memory disturbance in mice, indicating that, similar to natural plasmalogens, KIT‐13 may improve memory by decreasing neuroinflammation and increasing BDNF‐mediated neurogenesis in the mouse brain. Conclusion These findings suggested that KIT‐13 can be a therapeutic drug candidate for diseases associated with plasmalogen reduction, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and rhizomelic chondrodysplasia punctata (RCDP). Reference : 1. Ifuku et al. J Neuroinflammation 2012, 9:197 2. Fujino et al. EBioMedicine 2017, 17:199‐205 3. Fujino et al. J Alzheimers Dis Parkinsonism 2019, 9:4 4. Hossain et al. Front Cell Dev Biol 2022, 10:828282
2022-02-24 | Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment.
The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer's and Parkinson's disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS.
2020-05-22 | Oral batyl alcohol supplementation rescues decreased cardiac conduction in ether phospholipid‐deficient mice
Abstract Plasmalogens (Pls) are a class of membrane phospholipids which serve a number of essential biological functions. Deficiency of Pls is associated with common disorders such as Alzheimer's disease or ischemic heart disease. A complete lack of Pls due to genetically determined defective biosynthesis gives rise to rhizomelic chondrodysplasia punctata (RCDP), characterized by a number of severe disabling pathologic features and death in early childhood. Frequent cardiac manifestations of RCDP include septal defects, mitral valve prolapse, and patent ductus arteriosus. In a mouse model of RCDP, reduced nerve conduction velocity was partially rescued by dietary oral supplementation of the Pls precursor batyl alcohol (BA). Here, we examine the impact of Pls deficiency on cardiac impulse conduction in a similar mouse model ( Gnpat KO). In‐vivo electrocardiographic recordings showed that the duration of the QRS complex was significantly longer in Gnpat KO mice than in age‐ and sex‐matched wild‐type animals, indicative of reduced cardiac conduction velocity. Oral supplementation of BA for 2 months resulted in normalization of cardiac Pls levels and of the QRS duration in Gnpat KO mice but not in untreated animals. BA treatment had no effect on the QRS duration in age‐matched wild‐type mice. These data suggest that Pls deficiency is associated with increased ventricular conduction time which can be rescued by oral BA supplementation.
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Drug Discovery Landscape
1 orphan drug designation for Rhizomelic chondrodysplasia punctata.
1 orphan drug designation for Rhizomelic chondrodysplasia punctata.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
1-(((Z)-hexadec-1-en-1-yl)oxy)-3-((2-oxido-1,3,2-oxazaphospholidin-2-yl)oxy)propan-2-yl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate | small molecules | FDA | Med-Life Discoveries, LP |
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