RARE DISEASE
FKRP-related limb-girdle muscular dystrophy R9
FKRP-related limb-girdle muscular dystrophy R9
FKRP-related limb-girdle muscular dystrophy R9
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2I, FKRP-related LGMD R9, LGMD due to FKRP deficiency, LGMD type 2I, LGMD2I, Limb-girdle muscular dystrophy due to FKRP deficiency, Limb-girdle muscular dystrophy type 2I
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2I, FKRP-related LGMD R9, LGMD due to FKRP deficiency, LGMD type 2I, LGMD2I, Limb-girdle muscular dystrophy due to FKRP deficiency, Limb-girdle muscular dystrophy type 2I
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2I, FKRP-related LGMD R9, LGMD due to FKRP deficiency, LGMD type 2I, LGMD2I, Limb-girdle muscular dystrophy due to FKRP deficiency, Limb-girdle muscular dystrophy type 2I
Drug discovery
3
drugs
With orphan designations
Overview
FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) is an autosomal recessive disorder caused by FKRP mutations, impairing α-dystroglycan glycosylation. It manifests with progressive proximal muscle weakness (pelvic > shoulder girdle), calf hypertrophy, cardiomyopathy (23–55% prevalence), and respiratory insufficiency [1][4][15]. Disease severity varies, ranging from childhood-onset rapidly progressive forms to adult-onset slow progression, influenced by genotype (homozygous c.826C>A founder mutation correlates with milder phenotypes) [2][6][9].
Population
Prevalence: 1–9/100,000 globally; up to 2.84/100,000 in Norway due to a founder mutation [1][2]
Bimodal onset: Adolescence/adulthood (homozygous c.826C>A) vs. childhood (compound heterozygotes) [2][6]
Gender disparities: Females show higher rates of wheelchair dependency (46% vs 27%) and earlier ventilatory needs, males exhibit increased cardiomyopathy risk [2][15]
Burden
24.6% progress to wheelchair dependence; 33% require ventilatory support before ambulation loss [4][6]
Cardiomyopathy (median onset: 54 years in c.826C>A homozygotes) and respiratory failure drive mortality [2][15]
High morbidity: 85% report chronic pain, 65% experience fatigue interfering with daily function [10][12]
This structured format prioritizes clinically actionable insights while aligning with current evidence from global registries, natural history studies, and therapeutic pipelines [1][6][7][10].
Therapies
Supportive care: Ventilatory assistance, cardiac monitoring (β-blockers/ACE inhibitors), mobility aids, and physiotherapy [1][9]
Experimental therapies: Gene therapy (AAV vectors) and substrate supplementation (BBP-418/ribitol) in Phase 2/3 trials (e.g., FORTIFY trial NCT05775848) [3][7][11]
Surveillance: Annual echocardiograms and pulmonary function tests recommended [4][15]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
69 drug discovery papers about FKRP-related limb-girdle muscular dystrophy R9, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
69 drug discovery papers about FKRP-related limb-girdle muscular dystrophy R9, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-30 | Safety, Tolerability, Pharmacokinetics, Food Effect of Ribitol, and Its Effect on QTcF in Healthy Adults: First-in-Human, Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Studies.
Limb-girdle muscle dystrophy Type R9 (LGMDR9), also known as LGMD Type 2I, is a rare genetic disease caused by partial loss of function of fukutin-related protein (FKRP) enzyme which glycosylates alpha-dystroglycan, thereby stabilizing myocytes during contraction. Hypoglycosylation leads to progressive muscle injury and impaired function including loss of ambulation. Ribitol is an endogenous pentose alcohol and precursor to CDP-ribitol, the substrate of FKRP. This first-in-human study demonstrated that ribitol was well tolerated when administered as single or multiple oral doses over 6 days to healthy adults. PK demonstrated dose-proportional increases in exposure from 0.5 to 15 g (therapeutic dose 9 and 12 g BID for patients weighing >30 to ≤50 kg and >50 kg, respectively); t½ was 9-13 h. A high-fat meal did not affect overall oral bioavailability; indicating ribitol may be taken without regard to food intake. A dedicated QT study using ribitol 21 g revealed no concentration-dependent QTcF prolongation and clinically significant QTcF prolongation was excluded over the entire range of exposures in the study, up to 351.9 µg/mL. Assay sensitivity was demonstrated with the expected effect of moxifloxacin. These results support further development of ribitol for the treatment of LGMDR9.
2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle
Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.
2026-04-27 | Heart Transplant in a Patient with Fukutin-Related-Protein Limb-Girdle-Muscular-Dystrophy and Severe Cardiomyopathy: A Case Study
Background/Purpose: Limb-Girdle-Muscular-Dystrophy R9 (LGMD R9) is caused by autosomal recessive mutations of the Fukutin-related protein (FKRP), leading to defective glycosylation of Alpha-dystroglycan. Patients with compound heterozygote mutations have a more severe course. Dilated cardiomyopathy (DCM) is frequent and can precede loss of ambulation by many years. Methods: A boy (10 years old) presented with difficulties in climbing stairs, fatigue, and limited walking distance. Serum-CK: 10.600 U/L. Genetic testing revealed compound heterozygote mutations in FKRP (c.947C>G and c.826C>A). Echocardiography showed DCM. Over 5 years. period muscle weakness progressed (6-minute walking test 200 m, North Star Ambulatory Assessment [NSAA]-score 20), increasing shortness of breath (SOB) on mild exercise (with normal pulmonary function tests and sleep studies), severe fatigue, and weight loss. This was accompanied by deterioration of his ejection fraction (LVEF) from 45 to 25% and progression of severe left ventricular dilatation from 45 to 69 mm despite maximal heart failure treatment (fourfold anticongestive medical treatment and regular Levosimendan infusions). Results: Decision for HTx was made following multidisciplinary and ethical discussion. The patient (15 years) underwent HTx with an uncomplicated course. Four months post-HTx, walking distance and motor activities improved (NSAA-Score +8). Cardiac function was normal. Six months after HTx, immunosuppressive therapy showed severe side effects (neutropenia, mucositis, weight loss) and motor function decline. Twelve months after HTx therapy with Vamorolon was started, followed by a reduction of CK level. Conclusion: HTx can be an option in patients with LGMD R9. SOB, loss of walking distance, and fatigue can be caused by heart failure due to DCM. In patients with mild neuromuscular involvement and end-stage DCM, long-term prognosis is closely linked to the possibility of a heart transplant. The long-term effect of corticosteroids on motor function needs to be further investigated in LGMD R9. Publication History Article published online: 27 April 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-08-20 | Ribitol treatment rescues dystroglycanopathy mice with common L276I mutation.
Matriglycan of alpha dystroglycan (α-DG) serves as a receptor for extracellular matrix proteins. Hypoglycosylation of α-DG underlies specific types of muscular dystrophy, dystroglycanopathy. Fukutin Related Protein (FKRP) gene encodes a glycosyltransferase that adds ribitol-5-phosphate to the core glycan of α-DG and enables the synthesis of matriglycan. Mutations in the FKRP gene are a common cause of dystroglycanopathies. Ribitol is able to restore matriglycan in diseased muscles with FKRP mutations, but this effect relies on partial function of mutant FKRPs. Different mutations affect FKRP function differently, which could affect the efficiency of ribitol treatment. Here we examined the long-term effect of ribitol in mice with FKRP C826A (L276I) mutation, the most common genotype in patient population of LGMD2I/R9. Oral administration of ribitol significantly enhances expression of matriglycan in both cardiac and skeletal muscles up to 40% of normal muscle levels. Importantly, matriglycan is homogeneously expressed in almost all muscle fibers with similar levels especially in cardiac muscle. Consistently, muscle degeneration and regeneration are greatly attenuated with reduced central nucleation and fibrosis especially in the diaphragm. This is associated with improvements in muscle functions, although the diseased mice only show limited deficiency when compared to wild type C57 mice. The higher level of restoration in matriglycan in L276I mice than in P448L mice is consistent with the hypothesis that therapeutic potential of ribitol treatment may depend on the remaining function of mutant FKRPs. These results support clinical trials of ribitol to the majority of patients with FKRP mutations.
2025-01-09 | Ribitol and ribose treatments differentially affect metabolism of muscle tissue in FKRP mutant mice.
Dystroglycanopathy is characterized by reduced or lack of matriglycan, a cellular receptor for laminin as well as other extracellular matrix proteins. Recent studies have delineated the glycan chain structure of the matriglycan and the pathway with key components identified. FKRP functions as ribitol-5-phosphate transferase with CDP-ribitol as the substrate for the extension of the glycan chain. Supplement of ribitol and ribose have been reported to increase the levels of CDP-ribitol in both cells and in muscles in vivo. Clinical trials with both ribitol and ribose have been reported for treating LGMD2I caused by mutations in the FKRP gene. Here we compared the comprehensive metabolite profiles of the skeletal muscle between ribitol-treated and ribose-treated FKRP mutant mice. The closely related pentose and pentitol show clearly differential impacts on metabolisms despite their similarity in enhancing the levels of CDP-ribitol and matriglycan synthesis. Supplement of ribitol changes lysophospholipid sub-pathway metabolite profiling with a trend towards normalization as reported in the muscle after AAV9-FKRP gene therapy. Ribose treatment significantly increases level of ribonate and elevates levels of advanced glycation end products. Further analysis is required to determine which metabolite is prudent to use for long-term daily treatment of dystroglycanopathies.
oligonucleotides
2023-10-01 | O19 Preliminary results from MLB-01-003: an open label phase 2 study of BBP-418 in patients with limb-girdle muscular dystrophy type 2I/R9
S192gene.Currently no disease-modifying therapies exist.AOC 1001, as an antibody oligonucleotide conjugate (AOCTM) comprised of a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1, was designed for functional delivery to muscle cells, where it can reduce the toxic mutant DMPK mRNA and potentially address the pathology of DM1.The MARINA phase 1/2 study (NCT05027269) is a randomized, placebo-controlled, double-blind trial in two parts.Part A was a single dose design.Part B was a multiple-ascending dose design with 3 cohorts (dose levels), with quarterly doses and 1 booster after the first 6 weeks.The cohorts were initiated in a staggered fashion based on a safety data review of the preceding cohort(s).The primary objective is safety and tolerability.Secondary objectives include spliceopathy, pharmacokinetics, and pharmacodynamics.Exploratory objectives include efficacy measures and patientreported outcomes.The study enrolled 38 adults aged 18-65 years with a genetic diagnosis of DM1.As the first complete trial of AOC 1001, the MARINA data analysis includes safety, tolerability, and functional endpoints.This includes investigation of a single serious adverse event reported as a related event of thalamic hemorrhage observed in a participant after their first dose at 4mg/kg.AOC 1001 was found to be delivered to the muscle, reduce DMPK mRNA, modify splicing profiles, and improve multiple functional endpoints.AOC 1001 represents a novel potential therapy addressing the underlying cause of DM1.
gene therapies
2026-05-22 | Discordant Cardiomyopathy Phenotypes in Siblings With Homozygous FKRP c.1100T>C.
Pathogenic FKRP variants cause limb-girdle muscular dystrophy R9, with variable cardiac involvement. How genotype influences the cardiac phenotype remains poorly defined for non-European founder variants. We report 2 siblings of South African Afrikaner descent, both homozygous for FKRP c.1100T>C (p.Ile367Thr), with discordant cardiac phenotypes. The brother (age 25 years) presented at age 17 with nondilated cardiomyopathy (left ventricular ejection fraction [LVEF]: 41%) that progressed to dilated cardiomyopathy, with fibrosis involving 12 to 14 of 17 AHA (American Heart Association) segments late gadolinium enhancement segments over 7 years despite partial reverse remodeling. His sister (age 30 years) had nondilated cardiomyopathy with preserved LVEF (59%) and stable fibrosis in 4 lateral segments over 2 years. Serial cardiac magnetic resonance revealed dissociation between functional recovery and fibrosis progression: LVEF improved on guideline-directed therapy, while fibrosis burden remained extensive. Ejection fraction alone underestimates disease progression in FKRP-related cardiomyopathy. Serial cardiac magnetic resonance with late gadolinium enhancement should guide surveillance, especially in non-c.826C>A genotypes where cardiac onset occurs decades earlier.
2025-12-25 | Transgene-induced cardiotoxicity in high-dose AAV gene transfer.
Gene delivery technologies based on adeno-associated virus (AAV) vectors have yielded promising results for the treatment of monogenic diseases. Preclinical studies and clinical trials have highlighted that infusing high AAV vector doses can induce cytotoxicity, resulting in the death of the patient in a few cases. In the wake of signs of cardiac symptoms in several human patients after gene transfer, we investigated the effects on the heart of systemic administration of high doses of AAV vectors expressing three different transgenes, corresponding to Duchenne muscular dystrophy, γ-sarcoglycanopathy, and fukutin-related protein deficiency. In all these cases, we observed the possibility of cardiotoxicity with high-dose injections that we related to transgene expression. Consequently, strategies reducing or preventing expression in the heart prevented the appearance of such cardiotoxicity and were also confirmed to be safe in non-human primates. Dissection of the mechanisms at stake revealed activation of stress cascades, leading to cardiomyocyte death due to protein overload or abnormal homeostasis of location or function of the specific protein. Our data highlighted a particular sensitivity of the heart to transgene expression, suggesting the importance of finely regulating the expression of transgenes in this vital organ in any gene therapy approach.
small molecules
2026-07-30 | Safety, Tolerability, Pharmacokinetics, Food Effect of Ribitol, and Its Effect on QTcF in Healthy Adults: First-in-Human, Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Studies.
Limb-girdle muscle dystrophy Type R9 (LGMDR9), also known as LGMD Type 2I, is a rare genetic disease caused by partial loss of function of fukutin-related protein (FKRP) enzyme which glycosylates alpha-dystroglycan, thereby stabilizing myocytes during contraction. Hypoglycosylation leads to progressive muscle injury and impaired function including loss of ambulation. Ribitol is an endogenous pentose alcohol and precursor to CDP-ribitol, the substrate of FKRP. This first-in-human study demonstrated that ribitol was well tolerated when administered as single or multiple oral doses over 6 days to healthy adults. PK demonstrated dose-proportional increases in exposure from 0.5 to 15 g (therapeutic dose 9 and 12 g BID for patients weighing >30 to ≤50 kg and >50 kg, respectively); t½ was 9-13 h. A high-fat meal did not affect overall oral bioavailability; indicating ribitol may be taken without regard to food intake. A dedicated QT study using ribitol 21 g revealed no concentration-dependent QTcF prolongation and clinically significant QTcF prolongation was excluded over the entire range of exposures in the study, up to 351.9 µg/mL. Assay sensitivity was demonstrated with the expected effect of moxifloxacin. These results support further development of ribitol for the treatment of LGMDR9.
2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle
Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.
2026-04-27 | Heart Transplant in a Patient with Fukutin-Related-Protein Limb-Girdle-Muscular-Dystrophy and Severe Cardiomyopathy: A Case Study
Background/Purpose: Limb-Girdle-Muscular-Dystrophy R9 (LGMD R9) is caused by autosomal recessive mutations of the Fukutin-related protein (FKRP), leading to defective glycosylation of Alpha-dystroglycan. Patients with compound heterozygote mutations have a more severe course. Dilated cardiomyopathy (DCM) is frequent and can precede loss of ambulation by many years. Methods: A boy (10 years old) presented with difficulties in climbing stairs, fatigue, and limited walking distance. Serum-CK: 10.600 U/L. Genetic testing revealed compound heterozygote mutations in FKRP (c.947C>G and c.826C>A). Echocardiography showed DCM. Over 5 years. period muscle weakness progressed (6-minute walking test 200 m, North Star Ambulatory Assessment [NSAA]-score 20), increasing shortness of breath (SOB) on mild exercise (with normal pulmonary function tests and sleep studies), severe fatigue, and weight loss. This was accompanied by deterioration of his ejection fraction (LVEF) from 45 to 25% and progression of severe left ventricular dilatation from 45 to 69 mm despite maximal heart failure treatment (fourfold anticongestive medical treatment and regular Levosimendan infusions). Results: Decision for HTx was made following multidisciplinary and ethical discussion. The patient (15 years) underwent HTx with an uncomplicated course. Four months post-HTx, walking distance and motor activities improved (NSAA-Score +8). Cardiac function was normal. Six months after HTx, immunosuppressive therapy showed severe side effects (neutropenia, mucositis, weight loss) and motor function decline. Twelve months after HTx therapy with Vamorolon was started, followed by a reduction of CK level. Conclusion: HTx can be an option in patients with LGMD R9. SOB, loss of walking distance, and fatigue can be caused by heart failure due to DCM. In patients with mild neuromuscular involvement and end-stage DCM, long-term prognosis is closely linked to the possibility of a heart transplant. The long-term effect of corticosteroids on motor function needs to be further investigated in LGMD R9. Publication History Article published online: 27 April 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-08-20 | Ribitol treatment rescues dystroglycanopathy mice with common L276I mutation.
Matriglycan of alpha dystroglycan (α-DG) serves as a receptor for extracellular matrix proteins. Hypoglycosylation of α-DG underlies specific types of muscular dystrophy, dystroglycanopathy. Fukutin Related Protein (FKRP) gene encodes a glycosyltransferase that adds ribitol-5-phosphate to the core glycan of α-DG and enables the synthesis of matriglycan. Mutations in the FKRP gene are a common cause of dystroglycanopathies. Ribitol is able to restore matriglycan in diseased muscles with FKRP mutations, but this effect relies on partial function of mutant FKRPs. Different mutations affect FKRP function differently, which could affect the efficiency of ribitol treatment. Here we examined the long-term effect of ribitol in mice with FKRP C826A (L276I) mutation, the most common genotype in patient population of LGMD2I/R9. Oral administration of ribitol significantly enhances expression of matriglycan in both cardiac and skeletal muscles up to 40% of normal muscle levels. Importantly, matriglycan is homogeneously expressed in almost all muscle fibers with similar levels especially in cardiac muscle. Consistently, muscle degeneration and regeneration are greatly attenuated with reduced central nucleation and fibrosis especially in the diaphragm. This is associated with improvements in muscle functions, although the diseased mice only show limited deficiency when compared to wild type C57 mice. The higher level of restoration in matriglycan in L276I mice than in P448L mice is consistent with the hypothesis that therapeutic potential of ribitol treatment may depend on the remaining function of mutant FKRPs. These results support clinical trials of ribitol to the majority of patients with FKRP mutations.
2025-01-09 | Ribitol and ribose treatments differentially affect metabolism of muscle tissue in FKRP mutant mice.
Dystroglycanopathy is characterized by reduced or lack of matriglycan, a cellular receptor for laminin as well as other extracellular matrix proteins. Recent studies have delineated the glycan chain structure of the matriglycan and the pathway with key components identified. FKRP functions as ribitol-5-phosphate transferase with CDP-ribitol as the substrate for the extension of the glycan chain. Supplement of ribitol and ribose have been reported to increase the levels of CDP-ribitol in both cells and in muscles in vivo. Clinical trials with both ribitol and ribose have been reported for treating LGMD2I caused by mutations in the FKRP gene. Here we compared the comprehensive metabolite profiles of the skeletal muscle between ribitol-treated and ribose-treated FKRP mutant mice. The closely related pentose and pentitol show clearly differential impacts on metabolisms despite their similarity in enhancing the levels of CDP-ribitol and matriglycan synthesis. Supplement of ribitol changes lysophospholipid sub-pathway metabolite profiling with a trend towards normalization as reported in the muscle after AAV9-FKRP gene therapy. Ribose treatment significantly increases level of ribonate and elevates levels of advanced glycation end products. Further analysis is required to determine which metabolite is prudent to use for long-term daily treatment of dystroglycanopathies.
oligonucleotides
2023-10-01 | O19 Preliminary results from MLB-01-003: an open label phase 2 study of BBP-418 in patients with limb-girdle muscular dystrophy type 2I/R9
S192gene.Currently no disease-modifying therapies exist.AOC 1001, as an antibody oligonucleotide conjugate (AOCTM) comprised of a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1, was designed for functional delivery to muscle cells, where it can reduce the toxic mutant DMPK mRNA and potentially address the pathology of DM1.The MARINA phase 1/2 study (NCT05027269) is a randomized, placebo-controlled, double-blind trial in two parts.Part A was a single dose design.Part B was a multiple-ascending dose design with 3 cohorts (dose levels), with quarterly doses and 1 booster after the first 6 weeks.The cohorts were initiated in a staggered fashion based on a safety data review of the preceding cohort(s).The primary objective is safety and tolerability.Secondary objectives include spliceopathy, pharmacokinetics, and pharmacodynamics.Exploratory objectives include efficacy measures and patientreported outcomes.The study enrolled 38 adults aged 18-65 years with a genetic diagnosis of DM1.As the first complete trial of AOC 1001, the MARINA data analysis includes safety, tolerability, and functional endpoints.This includes investigation of a single serious adverse event reported as a related event of thalamic hemorrhage observed in a participant after their first dose at 4mg/kg.AOC 1001 was found to be delivered to the muscle, reduce DMPK mRNA, modify splicing profiles, and improve multiple functional endpoints.AOC 1001 represents a novel potential therapy addressing the underlying cause of DM1.
gene therapies
2026-05-22 | Discordant Cardiomyopathy Phenotypes in Siblings With Homozygous FKRP c.1100T>C.
Pathogenic FKRP variants cause limb-girdle muscular dystrophy R9, with variable cardiac involvement. How genotype influences the cardiac phenotype remains poorly defined for non-European founder variants. We report 2 siblings of South African Afrikaner descent, both homozygous for FKRP c.1100T>C (p.Ile367Thr), with discordant cardiac phenotypes. The brother (age 25 years) presented at age 17 with nondilated cardiomyopathy (left ventricular ejection fraction [LVEF]: 41%) that progressed to dilated cardiomyopathy, with fibrosis involving 12 to 14 of 17 AHA (American Heart Association) segments late gadolinium enhancement segments over 7 years despite partial reverse remodeling. His sister (age 30 years) had nondilated cardiomyopathy with preserved LVEF (59%) and stable fibrosis in 4 lateral segments over 2 years. Serial cardiac magnetic resonance revealed dissociation between functional recovery and fibrosis progression: LVEF improved on guideline-directed therapy, while fibrosis burden remained extensive. Ejection fraction alone underestimates disease progression in FKRP-related cardiomyopathy. Serial cardiac magnetic resonance with late gadolinium enhancement should guide surveillance, especially in non-c.826C>A genotypes where cardiac onset occurs decades earlier.
2025-12-25 | Transgene-induced cardiotoxicity in high-dose AAV gene transfer.
Gene delivery technologies based on adeno-associated virus (AAV) vectors have yielded promising results for the treatment of monogenic diseases. Preclinical studies and clinical trials have highlighted that infusing high AAV vector doses can induce cytotoxicity, resulting in the death of the patient in a few cases. In the wake of signs of cardiac symptoms in several human patients after gene transfer, we investigated the effects on the heart of systemic administration of high doses of AAV vectors expressing three different transgenes, corresponding to Duchenne muscular dystrophy, γ-sarcoglycanopathy, and fukutin-related protein deficiency. In all these cases, we observed the possibility of cardiotoxicity with high-dose injections that we related to transgene expression. Consequently, strategies reducing or preventing expression in the heart prevented the appearance of such cardiotoxicity and were also confirmed to be safe in non-human primates. Dissection of the mechanisms at stake revealed activation of stress cascades, leading to cardiomyocyte death due to protein overload or abnormal homeostasis of location or function of the specific protein. Our data highlighted a particular sensitivity of the heart to transgene expression, suggesting the importance of finely regulating the expression of transgenes in this vital organ in any gene therapy approach.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for FKRP-related limb-girdle muscular dystrophy R9.
3 orphan drug designations for FKRP-related limb-girdle muscular dystrophy R9.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno associated vector (serotype AAV MYO2) encoding the fukutin related protein (ssAAVMYO2.tMCK.FKRP) | gene therapies | FDA | 2025-09-08 | — | Cure Rare Disease |
adeno-associated virus serotype 9 (AAV9) vector containing a linear, self-complementary DNA genome encoding a codon-optimized, CpG motif-depleted, human fukutin-related protein (FKRP) gene under the control of a Syn100 promoter (scAAV9.Syn100.coHuFKRP) | gene therapies | FDA | 2024-10-17 | — | Asklepios Biopharmaceutical, Inc. |
Adeno-associated virus serotype 9 carrying the human Fukutin-Related protein gene and target sequence of the miR-208a | gene therapies | FDA | 2022-01-31 | — | Atamyo Therapeutics |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.