Hurler Syndrome Research Articles

Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs.

Hurler syndrome, a type of Mucopolysaccharidosis type I, is an inherited disorder caused by the accumulation of glycosaminoglycans (GAG) due to a deficiency in lysosomal α-L-iduronidase (IDUA), resulting in multiorgan dysfunction. In many patients with Hurler syndrome, IDUA proteins are not produced due to nonsense mutations in their genes; therefore, readthrough-inducing compounds, such as gentamycin, are expected to restore IDUA proteins by skipping the premature termination codon. In the present study, we synthesized a series of chromenopyridine derivatives to identify novel readthrough-inducing compounds. The readthrough-inducing activities of synthesized compounds were examined by measuring cellular IDUA activities and GAG concentrations in Hurler syndrome patient-derived cells. Compounds with a difluorophenyl group at the 2-position of chromenopyridine, a cyclobutyl group at the 3-position, and a basic side chain or basic fused ring exhibited excellent readthrough-inducing activities. KY-640, a chromenopyridine derivative with a tetrahydroisoquinoline sub-structure, increased the cellular IDUA activities of patient-derived cells by 3.2-fold at 0.3 µM and significantly reduced GAG concentrations, and also significantly increased enzyme activity in mouse models, suggesting its therapeutic potential in patients with Hurler syndrome.

Increasing Palliative Care Team Involvement in Pediatric Hematopoietic Stem Cell Transplant Patients

Background/Objectives: Palliative care facilitates communication, helps with physical and psychological symptom management, and assists in goals of care and advance care planning discussions. Multiple organizations including the World Health Organization, American Academy of Pediatrics and the American Society of Clinical Oncology encourage palliative care involvement. Palliative care involvement with hematopoietic stem cell transplant (HSCT) patients has been shown to be beneficial as HSCT is associated with a high degree of morbidity and possible mortality. We sought to increase the frequency of palliative care consultations for patients planning to undergo HSCT for targeted diagnoses. The outcome measure was percentage of patients who underwent HSCT for a targeted diagnosis who had a Palliative Care Team (PaCT) consult. Baseline data revealed 48 patients underwent HSCT from July 2020 to July 2022, 25 of whom had a targeted diagnosis. PaCT met 12 of the 25 patients (48%). Our goal is to increase the number of PaCT consults for patients receiving HSCT for our targeted diagnoses from 48% to 75% by December 2023. Methods: Chart review was conducted for patients who underwent HSCT from July 2020 to July 2022. Demographics documented included reason for HSCT, if PaCT was consulted, date of transplant, date of PaCT consult and living status. A targeted diagnosis list was compiled based on which patients were felt to benefit most from palliative care involvement: relapsed or refractory leukemias and lymphomas, myelodysplastic syndrome, high risk acute myeloid leukemia and metabolic disorders, such as Hurler syndrome. The first plan-do-study-act (PDSA) cycle included discussion of the project at division meetings, posting flyers in the clinic provider workrooms, and education regarding palliative care and evidence of its involvement in HSCT patients. The second PDSA cycle implemented involved revision of the HSCT referral form to include the question “Is PaCT consulted.” If the provider answers “no,” further elaboration is requested. Results: From 1/1/23 to 7/31/23 ten patients with a targeted diagnosis underwent HSCT. Five patients (50%) received a PaCT consult prior to HSCT. Conclusions: Palliative care involvement in pediatric oncology is well established, but its role in HSCT patients continues to be explored. As HSCT patients receive more intense therapy, have frequent deaths in intensive care units and can have limited opportunity for end of life planning due to rapidly changing clinical courses, early integration of PaCT could allow for decreased symptom burden and distress for both patients and families. Future PDSA cycle interventions include adding PaCT consultation to the transplant evaluation order set in the electronic medical record and review of the comments on the completed HSCT referral forms to identify possible barriers in the PaCT consultation process.

Implementation and results of a risk-sharing scheme for enzyme replacement therapy in lysosomal storage diseases

ObjectiveTo describe a risk-sharing program's implementation and results on enzyme replacement therapy for lysosomal diseases. MethodThe program was designed and implemented in a referral hospital for congenital metabolic diseases. The conclusion of agreements required the following phases: 1) To define and agree on response variables and criteria to treatment; 2) to assign discount percentage to each stage of effectiveness; 3) to prepare and sign the agreement by all parties; 4) to implement the agreement; 5) to individualize purchases management; 6) to evaluate clinical results, and 7) to issue an annual report. ResultsEight patients were included in the program (four with Hurler's disease, two with Pompe and two with Gaucher), five of them were women and three were men. After analyzing the defined variables and response criteria, all patients presented full effectiveness after two or three years of follow-up except one of them that could not be evaluated. Given the effectiveness achieved, the hospital made full payment of all administered therapies. ConclusionsThe implanted risk-sharing program is Spain's first published event of paying for clinical results using orphan drugs. Economic impact has been limited, and program implementation has gone through a complex process of formulation and management. However, the greatest achievement has been to reduce the knowledge gap between efficacy and effectiveness, stating that the therapies administered have shown the optimal benefits for which the funder is willing to pay.

Utilizing AAV-mediated LEAPER 2.0 for programmable RNA editing in non-human primates and nonsense mutation correction in humanized Hurler syndrome mice

BackgroundThe endogenous adenosine deaminases acting on RNA (ADAR) have been harnessed to facilitate precise adenosine-to-inosine editing on RNAs. However, the practicability of this approach for therapeutic purposes is still ambiguous due to the variable expression of intrinsic ADAR across various tissues and species, as well as the absence of all-encompassing confirmation for delivery methods.ResultsIn this study, we demonstrate that AAV-mediated delivery of circular ADAR-recruiting RNAs (arRNAs) achieves effective RNA editing in non-human primates at dosages suitable for therapy. Within a time frame of 4 to 13 weeks following infection, the editing efficiency in AAV-infected cells can reach approximately 80%, with no discernible toxicity, even at elevated dosages. In addition, when AAV-delivered circular arRNAs are systematically administered to a humanized mouse model of Hurler syndrome, it rectifies the premature stop codon precisely and restores the functionality of IDUA enzyme encoded by the Hurler causative gene in multiple organs.ConclusionsThese discoveries considerably bolster the prospects of employing AAV-borne circular arRNAs for therapeutic applications and exploratory translational research.

Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.

Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of -0.0401 [p = 0.069] and -0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Hurler Syndrome Glycosaminoglycans Decrease in Cerebrospinal Fluid without Brain-Targeted Therapy.

Novel therapies for Hurler syndrome aim to cross the blood-brain barrier (BBB) to target neurodegeneration by degrading glycosaminoglycans (GAG). BBB penetration has been assumed with decreased cerebrospinal fluid (CSF) GAG, yet little is known about CSF GAG without brain-targeting therapies. We compared pre-transplant CSF GAG in patients who were treatment naïve (n = 19) versus receiving standard non-BBB penetrating enzyme replacement therapy (ERT, n = 12). In the ERT versus treatment naïve groups, CSF GAG was significantly lower across all content assayed, raising questions about using CSF GAG decrements to show BBB penetration. Future studies should compare GAG reduction in standard versus novel therapies. ANN NEUROL 2023;94:1182-1186.

Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity.

The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control

Suppression of premature termination codons (PTCs) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two potent readthrough promoters-NVS1.1 and NVS2.1-that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to other readthrough promoters that affect stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, and activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

Hepatic adenoma in a 7-year-old girl: a case report and literature review

BackgroundHepatocellular adenomas (HCAs) are rare benign tumors of the liver that occur predominantly in women taking oral contraceptives. In children, HCAs comprise < 5% of hepatic tumors. We report a case of HCAs in a 7-year-old girl with estrogen and glucose imbalance.Case presentationA 7-year-old girl was presented to our hospital with bilateral breast enlargement for 2 months, polydipsia, polyuria, polyphagia, hyperglycemia, and significant weight gain. Computed tomography (CT) showed a 7.2 cm×6.9 cm×5.3 cm round-shaped mass in the left inner lobe of the liver, ovarian ultrasound showed multiple follicles in the ovaries bilaterally, and cranial magnetic resonance imaging (MRI) showed an enlarged superior pituitary. Hematological and biochemical results were as follows: fasting glucose was 19.7 mmol/L, estradiol was 122.9 pmol/L, follicle-stimulating hormone 10.81 IU/L, luteinizing hormone 10.99 IU/L, insulin-like growth factor 1,513 ng/mL, glutamine aminotransferase 86 U/L, and alkaline phosphatase 362 U/L. Thyroid functions, methemoglobin, fetal protein, carcinoembryonic antigen, and chorionic gonadotropin were normal. The patient had a complete surgical resection of the liver tumor, and the postoperative histopathological diagnosis was HCAs. After the surgery, insulin was injected and the glucose levels were stable. During the 36-month follow-up period, neither tumor recurrence nor significant abnormalities were detected using color Doppler ultrasound of the liver. The child’s precocious puberty is currently under control.ConclusionsHCAs are particularly rare in children with liver tumors, and risk factors for the development of HCAs in children include sex hormone imbalance, obesity, Fanconi anemia (FA), glycogen storage diseases (GSDs) type I, III, and IV, galactosemia, immunodeficiency, congenital portosystemic shunts (CPSS), cardiac hepatopathy status-post Fontan procedure, Hurler syndrome, familial adenomatous polyposis, germline HNF1A mutations, and maturity-onset diabetes of the young type 3. Most HCAs are detected during a physical examination without clinical symptoms, and some patients may present with symptoms such as abdominal pain, abdominal distension, and abdominal masse. Serum liver function tests can show increased alkaline phosphatase (ALP) and γ- glutamyl transferase (GT), whereas α-Fetoprofein (AFP) levels are normal. The definitive diagnosis relies mainly on histopathological examination. Because HCAs can rupture and bleed and become malignant. Early surgical treatment is recommended after detection.

Incidence of Bloodstream Infections after Hematopoietic Stem Cell Transplantation for Hurler Syndrome

Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder characterized by the deficiency of the alpha-L-iduronidase enzyme necessary for the degradation of glycosaminoglycans (GAG) in the lysosome. Hurler syndrome is the most severe form of MPS I, manifesting as multiorgan dysfunction, cognitive delay, and death, usually within ten years if left untreated. Hematopoietic stem cell transplantation (HSCT) is the optimal treatment option, providing a permanent solution to enzyme deficiency and halting cognitive decline; however, the HSCT complications transplantation-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD) are known risk factors for bloodstream infection (BSI). BSI is a serious complication of HSCT, contributing to poor outcomes and transplantation-related morbidity. There are little data evaluating BSI after HSCT in the Hurler syndrome population. We performed a retrospective analysis of patients with Hurler syndrome who underwent HSCT at our center between 2013 and 2020 to determine the incidence of BSI within the first year post-transplantation. Patient BSI data were collected through the first year post-HSCT. Variables including patient demographics and transplantation-related characteristics were collected, including information on BSI and mortality. Twenty-five patients with a total of 28 HSCTs were included in the analysis; the majority (n=17; 68%) were male, with a median age of 1.1 years (interquartile range, .35 to 1.44 years) at the time of transplantation. The most common graft source was cord blood (n=15; 54%), followed by bone marrow (n=13; 46%), with the majority from matched unrelated donors (n=14; 52%) and mismatched unrelated donors (n=13; 44%). Sixteen BSIs were diagnosed in 12 patients (48%). Most infections (n=7; 43.8%) were diagnosed in the first 20 days post-transplantation, with fewer infections observed at later time points. Seven of the 9 Hurler patients diagnosed with TA-TMA (78%) also had a BSI. The incidence rate of BSIs in Hurler patients (n=12; 48%) was higher than the rates reported in the general pediatric HSCT population at 1-year post-transplantation (15% to 35%). Given the high rate of both TA-TMA and a BSI in Hurler patients, we suspect a possible correlation between the 2. Additionally, due to the time it takes for GAG levels to normalize post-HSCT in Hurler patients, it is reasonable to suspect that the high BSI rates in these patients are linked to their Hurler diagnosis. These findings bring awareness to possible disease-related factors contributing to high BSI rates in the Hurler population post-HSCT.

Phenotypic characterisation of the Mucopolysaccharidosis Type I (MPSI) Idua-W392X mouse model reveals increased anxiety-related traits in female mice.

Mucopolysaccharidosis Type I (MPSI) is a rare inherited lysosomal storage disease that arises due to mutations in the IDUA gene. Defective alpha-L-iduronidase (IDUA) enzyme is unable to break down glucosaminoglycans (GAGs) within the lysosomes and, as a result, there is systemic accumulation of undegraded products in lysosomes throughout the body leading to multi-system disease. Here, we characterised the skeletal/craniofacial, neuromuscular and behavioural outcomes of the MPSI Idua-W392X mouse model. We demonstrate that Idua-W392X mice have gross craniofacial abnormalities, showed signs of kyphosis, and show signs of hypoactivity compared to wild-type mice. X-ray imaging analysis revealed significantly shorter and wider tibias and femurs, significantly wider snouts, increased skull width and significantly thicker zygomatic arch bones in Idua-W392X female mice compared to wild-type mice at 9 and 10.5months of age. Idua-W392X mice display decreased muscle strength, especially in the forelimbs, which is already apparent from 3months of age. Female Idua-W392X mice display hypoactivity in the open-field test from 9months of age and anxiety-like behaviour at 10months of age. As these behaviours have been identified in Hurler children, the MPSI Idua-W392X mouse model may be important for the investigation of new therapeutic approaches for MPSI-Hurler.

First Three Years’ Experience of Mucopolysaccharidosis Type-I Newborn Screening in California

To report on the first 3years of mucopolysaccharidosis type I (MPS I) newborn screening (NBS) in the large and diverse state of California. The California Genetic Disease Screening Program began universal NBS for MPS I on August 29, 2018. The screening uses a 2-tiered approach: an α-L-iduronidase (IDUA) enzyme activity assay followed by DNA sequencing for variants in the IDUA gene. As of August 29, 2021, 1 295 515 California newborns were screened for MPS I. In tier 1 of screening, 329 (0.025%) had an IDUA enzyme measurement below the cutoff and underwent tier-2 IDUA DNA sequencing. After tier 2, 146 (0.011%) newborns were screen positive, all of whom were referred to a metabolic Special Care Center for follow-up. After long-term follow-up, 7 cases were resolved as severe MPS I (Hurler syndrome) and 2 cases as attenuated MPS I for an MPS I birth prevalence of 1/143 946. DNA sequencing identified 107 unique IDUA variants among a total of 524 variants; 65% were known pseudodeficiency alleles, 25% were variants of uncertain significance, and 10% were pathogenic variants. As a result of a 2-tiered NBS approach, 7 newborns diagnosed with Hurler syndrome had received early treatment for MPS I. Continuation of California's long-term follow-up program will be crucial for further understanding the complex genotype-phenotype relationships of MPS I.

Extensive mongoloid spots in mucopolysaccharidosis Type I Hurler syndrome

Lysosomal storage diseases are inherited metabolic disorders that are caused by enzyme deficiencies within the lysosomes. The most common lysosomal storage disorder associated with Mongolian spots (MSs) is GM1 gangliosidosis Type-1. We are reporting a case of Hurler disease with extensive MS. A 9-month-old girl, born to a consanguineously married couple, presented with a developmental delay with uneventful birth history. The presence of multiple mongoloid spots over the lumbosacral region and lateral abdominal wall was noticed since birth. Examination showed coarse facies with a depressed nasal bridge and a low-set ear. Multiple mongoloid macules were noted in the lumbosacral region. Serum enzyme assay level had decreased activity of alpha-L-iduronidase (IDUA). Exome sequencing revealed a homozygous mutation in exon 8 of the IDUA gene. Extensive MS can be seen in mucopolysaccharidosis (MPS) Type 1 in addition to commonly described GM1 gangliosidosis. The early diagnosis helps to start enzyme replacement therapy in MPS Type I, compared to currently no specific treatment available for GM1 gangliosidosis.

A glycomic workflow for LC–MS/MS analysis of urine glycosaminoglycan biomarkers in mucopolysaccharidoses

In recent years, several rational designed therapies have been developed for treatment of mucopolysaccharidoses (MPS), a group of inherited metabolic disorders in which glycosaminoglycans (GAGs) are accumulated in various tissues and organs. Thus, improved disease-specific biomarkers for diagnosis and monitoring treatment efficacy are of paramount importance. Specific non-reducing end GAG structures (GAG-NREs) have become promising biomarkers for MPS, as the compositions of the GAG-NREs depend on the nature of the lysosomal enzyme deficiency, thereby creating a specific pattern for each subgroup. However, there is yet no straightforward clinical laboratory platform which can assay all MPS-related GAG-NREs in one single analysis. Here, we developed and applied a GAG domain mapping approach for analyses of urine samples of ten MPS patients with various MPS diagnoses and corresponding aged-matched controls. We describe a nano-LC–MS/MS method of GAG-NRE profiling, utilizing 2-aminobenzamide reductive amination labeling to improve the sensitivity and the chromatographic resolution. Diagnostic urinary GAG-NREs were identified for MPS types IH/IS, II, IIIc, IVa and VI, corroborating GAG-NRE as biomarkers for these known enzyme deficiencies. Furthermore, a significant reduction of diagnostic urinary GAG-NREs in MPS IH (n = 2) and MPS VI (n = 1) patients under treatment was demonstrated. We argue that this straightforward glycomic workflow, designed for the clinical analysis of MPS-related GAG-NREs in one single analysis, will be of value for expanding the use of GAG-NREs as biomarkers for MPS diagnosis and treatment monitoring.

Posterior Fossa Horns in Hurler Syndrome: Prevalence and Regression.

Posterior fossa "horns" caused by internal hypertrophy of the occipitomastoid sutures are one of the more recently defined cranial abnormalities described in mucopolysaccharidoses, especially in Hurler Syndrome. However, details of this finding, including the development and natural history, are not well-understood. Two hundred eighty-six brain MR imaging studies of 61 patients with mucopolysaccharidosis I-Hurler syndrome treated at single institution between 1996 and 2015 were studied. Posterior fossa horn height was measured as the perpendicular distance from the tip of the horn to the expected curvature of the occipital inner table. Fifty-seven of the 61 patients (93.4%) had evidence of posterior fossa horns on at least one occasion. The initial average height of the right horn was 4.5 mm, and the left horn, 4.7 mm. Most of the posterior horns regressed before transplantation in our cohort, though the exact age was variable among the patients. Nearly all patients in our cohort had posterior fossa horns, and these horns regressed with age. The regression of the horns frequently started before transplantation. This trend has not been previously described, and it may suggest unknown effects of mucopolysaccharidosis on skull development.

Increased pituitary volumes in patients with Sanfilippo syndrome (mucopolysaccharidosis type 3, MPS III).

To evaluate apparent pituitary gland enlargement in patients with Sanfilippo syndrome observed at our institution. Twelve patients with Sanfilippo syndrome with brain MRI were studied. Anterior, posterior, and whole pituitary volumes were estimated using the prolate ellipsoid volume calculation method (π/6 × L × W × H). Convexity along the upper pituitary margin (Elster's grade) was also measured. These values were compared to two age- and sex-matched groups (normal controls and patients with Hurler syndrome) using one-way ANOVA followed by Tukey's post hoc analysis for multiple comparisons. In the Sanfilippo cohort, the mean whole pituitary volume was 529.9 mm, the mean anterior pituitary volume was 333.4 mm, and the mean posterior pituitary volume was 59.1 mm with Elster's grade of 4.2. In the control cohort, the mean whole pituitary volume was 217.4 mm, the mean anterior pituitary volume was 154.8 mm, and the mean posterior pituitary volume was 28.4 mm with Elster's grade of 2.5. In the Hurler syndrome cohort, the mean whole pituitary volume was 310.0 mm, the mean anterior pituitary volume was 178.2 mm, and the mean posterior pituitary volume was 35.4 mm with Elster's grade of 3.5. In our cohort of patients with Sanfilippo syndrome, whole, anterior, and posterior pituitary volumes and degree of convexity along the upper pituitary border were all significantly greater than controls. The cause of these morphological changes is unclear, as is clinical correlation of the findings.

Butorphanol and Ketamine Use in Patients with a Diagnosis of Hurler Syndrome Undergoing Bone Marrow Transplantation (BMT) (Sch415)

Butorphanol and Ketamine Use in Patients with a Diagnosis of Hurler Syndrome Undergoing Bone Marrow Transplantation (BMT) (Sch415)

IMPROVEMENT IN HURLER SYNDROME WITH AYURVEDIC MANAGEMENT: A CASE REPORT

Hurler syndrome is a rare lysosomal storage disorder occurring due to the deficiency of the lysosomal enzyme alpha L Iduronidase and has an autosomal recessive inheritance [1]. Ayurveda explains this condition as aavaranajanya vatavyadhi (obstructive pathology) [2]. This is the case of Hurler Syndrome of a female child of 13yrs with a relevant family history (her sister had the same syndrome). The patient had dysmorphic facies, pain and stiffness over multiple joints, dysmorphic facies, difficulty in walking, and mild speech impairment. She visited the outpatient department of our tertiary Ayurvedic health centre three times. She took OP and IP management along with dietary recommendations for about two months and ten days, and significant improvement was noted such as a reduction in contractures, ability to walk independently, self-feeding and the ability for normal schooling. The assessment was done with Cerebral Palsy Quality of Life (CPQOL). The values changed from 330 to 445 before and after treatment, respectively and gradings of spasticity as per the Modified Ashworth scale changed from 2+ to 1+ in both upper limbs and from 3+ to 2+ in both lower limbs.

Triamterene Functions as an Effective Nonsense Suppression Agent for MPS I-H (Hurler Syndrome).

Mucopolysaccharidosis I-Hurler (MPS I-H) is caused by the loss of α-L-iduronidase, a lysosomal enzyme that degrades glycosaminoglycans. Current therapies cannot treat many MPS I-H manifestations. In this study, triamterene, an FDA-approved, antihypertensive diuretic, was found to suppress translation termination at a nonsense mutation associated with MPS I-H. Triamterene rescued enough α-L-iduronidase function to normalize glycosaminoglycan storage in cell and animal models. This new function of triamterene operates through premature termination codon (PTC) dependent mechanisms that are unaffected by epithelial sodium channel activity, the target of triamterene's diuretic function. Triamterene represents a potential non-invasive treatment for MPS I-H patients carrying a PTC.

In vivo adenine base editing corrects newborn murine model of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is a severe disease caused by loss-of-function mutation variants in the α-L-iduronidase (Idua) gene. In vivo genome editing represents a promising strategy to correct Idua mutations, and has the potential to permanently restore IDUA function over the lifespan of patients. Here, we used adenine base editing to directly convert A > G (TAG>TGG) in a newborn murine model harboring the Idua-W392X mutation, which recapitulates the human condition and is analogous to the highly prevalent human W402X mutation. We engineered a split-intein dual-adeno-associated virus 9 (AAV9) adenine base editor to circumvent the package size limit of AAV vectors. Intravenous injection of the AAV9-base editor system into MPS IH newborn mice led to sustained enzyme expression sufficient for correction of metabolic disease (GAGs substrate accumulation) and prevention of neurobehavioral deficits. We observed a reversion of the W392X mutation in 22.46 ± 6.74% of hepatocytes, 11.18 ± 5.25% of heart and 0.34 ± 0.12% of brain, along with decreased GAGs storage in peripheral organs (liver, spleen, lung and kidney). Collectively, these data showed the promise of a base editing approach to precisely correct a common genetic cause of MPS I in vivo and could be broadly applicable to the treatment of a wide array of monogenic diseases.