High-Dose Ambroxol Therapy in Type 1 Gaucher Disease Focusing on Patients with Poor Response to Enzyme Replacement Therapy or Substrate Reduction Therapy.

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103/L, lumbar spine bone density T-score < -2.0, and/or LysoGb1 > 200 ng/mL, and for a group of naïve patients who had abnormal values in two of these three parameters. We enrolled 40 patients: 28 ERT- or SRT-treated, and 12 naïve. There were no severe adverse effects (AEs). There were 24 dropouts, mostly due to AEs (n = 12), all transient, and COVID-19 (n = 7). Among the 16 completers, 5 (31.2%) had a >20% increase in platelet count, 6 (37.5%) had a >0.2 increase in T-score, and 3 (18.7%) had a >20% decrease in Lyso-Gb1. This study expands the number of patients exposed to high-dose ABX, showing good safety and satisfactory efficacy, and provides an additional rationale for adding off-label ABX to the arsenal of therapies that could be offered to patients with GD1 and a suboptimal response or those unable to receive ERT or SRT.

Challenges and strategies with international recruitment in early phase gene therapy trials

The Children's NIHR Clinical Research Facility at Royal Manchester Children's Hospital has been involved in numerous early phase gene therapy trials for diseases such as GM1 gangliosidosis, Gaucher disease, MPSIIIA and MPSII. These trials have necessitated international recruitment which brings challenges for both site and families. In addition, we also actively recruited participants during the Covid-19 global pandemic, amplifying these challenges. A typical patient journey on one of these trials would involve being approached soon after diagnosis due to the rapid progression of these diseases and the need for early intervention. The family would then relocate to the UK with relatively short notice and commence an intensive period of screening involving a lot of extensive information for them to retain and invasive procedures for the patient. Some of these families will speak no English at all which is an additional barrier to managing the parental anxiety and expectations of the trial and its outcome. Once eligibility is confirmed the families are then faced with an extended stay in the UK without the support of their extended family/community. This impacts parent's employment and other siblings who may or may not be with them and who may also be affected by the same disease. Following administration of the gene therapy, participants then commence intensive follow up often associated with immunosuppressants. Close working with the local clinicians is essential for patient safety and trial integrity. Good engagement with families once they have returned to their home country is vital in obtaining continuing trial data and ensuring retention and compliance with attending future visits. Follow up visits are essential for safety and efficacy data for the progression of gene therapy trials. Travel restrictions brought about by the covid 19 pandemic exacerbated these challenges but with good communication and engagement we have mostly overcome them.

Ambroxol therapy for patients with Gaucher disease type 1, either poor responders to enzyme replacement therapy/substrate reduction therapy (ERT/SRT) or untreated

Ambroxol hydrochloride is an oral mucolytic drug, available over-the-counter for many years as cough medicine, which was found to also act as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Proof-of-concept reports have been published over the past decade in all three forms of Gaucher disease (GD). The current study aimed to assess the safety and efficacy of 12-months ambroxol 600 mg/day in 3 groups of type 1 GD patients with sub-optimal response, after a minimum of 3 years, to enzyme replacement therapy (ERT)/substrate reduction therapy (SRT) defined as lumbar spine bone density <−2.0 t-score, or platelet count<100 × 10−3/L, or LysoGb1 > 200 ng/ml, and for a group of naïve patients, i.e., never treated or stopped therapy >12 months prior to enrollment, who had abnormal values in 2 of the 3 above-mentioned parameters. Forty patients were enrolled: 28 ERT/SRT treated and 12 naïve;21 (52%) males, mean age 52 years (range 24–84). Safety aspects included several adverse effects (mainly gastrointestinal, excessive saliva, and vertigo) all mild and transient in nature, but led to drug discontinuation in 14 patients, additional dropouts were 7 patients due to COVID19 pandemic and 3 due to personal reasons. Of the remaining 16 patients, 14 have completed 12 months, and 2 are ongoing. Of the 14 completers, 5 (~36%) achieved significant improvement in at least one of the three parameters, and nine did not demonstrate any improvement nor deterioration. The interpretation of the results must take into account the fact that most of the enrolled patients have had poor response to ERT/SRT (including 10 of the 12 naïve patients) and therefore may not represent the majority of the patients. Further studies are needed in never-treated patients as well as an oral, less expensive, alternative to unselected stable patients currently treated with ERT/SRT with a favorable response.

Recommendations on the follow-up of patients with Gaucher disease in Spain: Results from a Delphi survey.

Management of Gaucher disease (GD) is challenging due to its wide genotypic and phenotypic variability and changing clinical manifestations due to effective treatment. Sixteen face-to-face meetings with experts were held in order to discuss daily clinical practice and identify controversies regarding the management of GD. With this information, a questionnaire with 93 recommendations for different clinical scenarios was designed, and a Delphi survey among 86 physicians with experience in GD was conducted. Consensus was reached on 73 out of the 93 items. Recommendations on follow-up of adult and pediatric patients were in line with current guidelines, and underscored the importance of a patient-tailored approach. For the follow-up of stable patients receiving long-term treatment, consensus was reached on the importance of multidisciplinary care that involves pediatricians, internal medicine, and primary care, specialized radiologists, orthopedic surgeons, and hematologists when required. Degree of pain, use of painkillers and antidepressants, and quality of life should be evaluated at every follow-up visit or at least once per year. In general, a closer follow-up was recommended for untreated patients or patients who underwent a treatment change (every 3 months during the first year) and during pregnancy. For pregnant patients, hemostasis and risk of hemorrhage should be assessed, but no consensus was reached for initiation of treatment in asymptomatic pregnant patients. Lastly, recommendations on how to adapt GD management during a COVID-19 pandemic were collected. This expert consensus may help decision-making during the management of GD in specific clinical scenarios.

Impact of COVID-19 on the management of patients with Lysosomal Storage Disorders

Lysosomal storage disorders (LSDs) are a group of inborn errors of metabolism (IEM) characterized by multisystemic involvement with multi-organ complications. The recent Covid-19 pandemic had a major impact on the management and treatment of patients with LSDs, who also experienced significant psychological distress following the pandemic. Several experiences described so far demonstrate that telemedicine and home therapy programs are valid tools for the follow-up and care of patients suffering from these complex chronic diseases.

Measurement of glycosylated ferritin with Concanavalin A: Assay design, optimization and validation.

INTRODUCTION: Ferritin is the major iron-storage glycoprotein found in all tissues. Ferritin glycosylation can be assessed by the differential affinities of ferritin glycoforms for Concanavalin A (ConA), a lectin. The fraction of serum ferritin bound to ConA is called "glycosylated ferritin" (GF). Low GF reflects macrophagic activation and is an essential biomarker used in adult-onset Still's disease (AOSD), macrophage activation syndrome (MAS) and Gaucher disease diagnosis and therapeutic management. To date, no complete assay description and method validation according to the ISO 15189 standard has been published. This study aimed to describe and validate our method used for GF measurement and describe GF values observed in patients. MATERIALS AND METHODS: Ferritin glycoforms were separated based on their affinities for ConA using commercially available TRIS-barbital buffer, Sepharose and ConA/Sepharose 4B gels. Ferritin concentrations were measured on the Siemens Dimension Vista 1500®. We analysed 16,843 GF values obtained between 2000 and 2021 from our database of patients. RESULTS: Optimal separation of ferritin glycoforms was obtained by 15-min incubation of serum with ConA/Sepharose at pH 8. The optimized volume were 0.4 mL for total serum ferritin (TSF) 30-1000 µg/L and 0.5 mL for TSF 1000-2500 µg/L. Serum with higher TSF should be pre-diluted in the TRIS-barbital buffer. Reproducibility of ferritin measurement in the TRIS-barbital buffer matrix was excellent (intra-assay CV < 1%; inter-assay CV < 4%). Reproducibility of GF assay was good (intra-assay CV < 10% for low and high ferritin samples, respectively; and inter-assay CV < 10%). Inter-operator variability was 21.6% for GF < 20%. Ferritin was stable for up to 3 days in the TRIS-barbital buffer. An inter-laboratory exchange program conducted with another French hospital showed good agreement between results. In our database, <20% GF levels were scarce, compatible with the low prevalence of Still's disease, MAS, and Gaucher disease. The 95% confidence interval for GF was [26-58]%, lower than values described in the literature for healthy individuals. CONCLUSION: Thanks to good performances, this technique can become readily available for laboratories servicing patients with AOSD, MAS (including severe COVID-19 patients) and Gaucher disease patients.

The need for home enzyme replacement therapy for patients with lysosomal disease in Japan

[Introduction and Aim] In Europe, Australia, and North and South America, enzyme replacement therapy (ERT) at home is a common practice for patients with lysosomal diseases. In Japan, on the other hand, patients need to visit a specialized hospital every one to two weeks for regular ERT. For the past 10 years, we have been proposing to the government, authorities, and academic societies to realize ERT at home, and under the circumstances of the spread of the COVID-19 in 2020, the need for ERT at home has increased. The purpose of this study was to investigate the patient burden of ERT in Japan for patients with lysosomal diseases (Fabry disease, Gaucher disease, Pompe disease, and MPS) who belong to four major lysosomal disease patient groups in Japan, and to clarify the need for enzyme replacement therapy at home. [Results] In January 2021, we conducted a questionnaire survey of lysosome disease patients and their families via four lysosome disease patient organizations (194 patients in total). Among the patients with lysosomal disease, 57% of them needed to be accompanied by their families. In addition, it took about 40 min each way to visit a specialized hospital and 246 min to stay in the hospital. In Japan, 67% of the patients preferred to receive ERT at a place other than a specialized hospital (home, clinic, school, office, etc.). [Conclusions] It is clear that lysosomal disease patients and their families in Japan are burdened by ERT. As a result of our work to date, in March 2021, 11 enzymes approved in Japan for lysosomal disease will be available for use by home physicians. Were approved to be administered by nurses under the direction of home physicians.

Spanish Fabry and Gaucher disease patients show striking differences in Beliefs about Medicines (BMQ) and Brief Illness Perception (BIPQ) questionnaires

During the last 2 years of Coronavirus SARS-CoV-2 pandemic we witnessed a more personalized approach between lysosomal disease (LD) patients and healthcare professionals. Indeed, in many specialized units of inborn errors of metabolism (IEM) there has been an extraordinary effort to adjust telemedicine and home therapy to the increasing needs of LD patients. Furthermore, in our Spanish Association of IEM (AECOM) a new section (AECOM&Sociedad) was created with the aim to attend the increasing needs of communication, and education in partnership with patient's associations. Along the end of 2020 and first months of 2021 a combined quest including knowledge about the disease, beliefs about medicines (BMQ), and illness perception (BIPQ) was opened on-line among Gaucher (GD) and Fabry (FD) Spanish populations. We obtained 40 GD (55.7% males) and 49 FD (53% males) anonymous responses. The proportion of adults was 87.5% and 96% for GD and FD cohorts, respectively. Results: The Batalla test of knowledge about the own disease showed a very good and similar result for both cohorts (94% GD and 92% FD). However, striking differences were observed concerning disease control (71% GD vs 44% FD), concern about the disease (75% GD vs 90% FD), and emotional affectation (37% GD vs 65% FD). In addition, these results were compared with 35 PKU/HPA patients referring clinical symptoms in 20% of cases compared to 65% GD and 57% FD, high level of disease knowledge and control (94 and 88%, respectively), and lower percentages for disease concern (63%) and emotional affectation (34%). Conclusions: Compared to GD, FD patients report lower perception of disease control, and higher levels of disease concern and emotional affectation. Differences were still wider when comparing FD with PKU patients. These self-reported results add evidence to the high complexity of FD and the need of multidisciplinary care for LD population.

Recommendations on the follow-up of patients with Gaucher disease in Spain: Results from a Delphi survey

Management of Gaucher disease (GD) is challenging because of its wide genotypic and phenotypic variability. In addition, the appearance of effective therapies for GD1 (enzyme replacement therapy, ERT and later substrate reduction therapy, SRT) has shifted the paradigm of care, and recommendations for GD management should now include strategies for patients without treatment, long-term treated patients, reproductive health, and transition of care from children to adults. Here we present the results of a Delphi survey on the follow-up of GD patients in specific clinical situations in Spain. Sixteen face-to-face meetings with experts were held to discuss daily clinical practice and to identify controversies regarding the management of GD. With this information, a questionnaire with 93 recommendations for different clinical scenarios was designed, and a Delphi survey among 86 physicians with experience in GD patient care was conducted. Results show consensus in 73 out of the 93 items. Recommendations on follow-up of adult and pediatric patients were in line with current guidelines, and underscored the importance of a patient-tailored approach. For the follow-up of stable patients receiving long-term treatment, consensus was reached on the importance of multidisciplinary team collaborating with the expert physician in GD, and specialists with GD knowledge (nurses, primary care, specialized radiologists, etc.), when required. Consensus was reached on the frequency of follow-up depending on the disease evolution time, whether or not patients received treatment, clinical disease stability, and specific recommendations for pregnant patients were also stated. Experts stressed on the importance of asking about symptoms reflecting quality of life such as pain, use of analgesics, antidepressants, etc. Lastly, recommendations on how to adapt GD management during a COVID-19 pandemic were collected. This expert consensus will help decision-making during the management of GD in specific clinical scenarios.

An 18-month report on the safety and efficacy of rapid intravenous velaglucerase alfa infusions in naïve patients with Gaucher disease

The introduction of enzyme replacement therapy (ERT) has revolutionized the management of patients with Gaucher disease (GD). To improve the patients' quality of life, we have studied and published the safety and efficacy of a rapid 10-min infusion of high-dose velaglucerase-alfa, instead of one hour as labeled, in 15 previously treated patients. We herein present the 18-month results of the investigator-initiated research in naïve patients with GD (defined by at least one year off ERT or SRT). All patients received bi-weekly infusions of 60 unit/kgBW velaglucerase-alfa;the infusion rate was gradually reduced from 60 to 10 min over six infusions in the hospital setup, followed by home infusions. Each infusion was followed for safety, and efficacy parameters were assessed every 3 months. We enrolled 15 patients (77% males) at a median age (range) of 40 (10–72) years. Thirteen patients were never treated, and two patients were off-ERT for over one year. Ten-minute rapid infusions were well tolerated with no reported related severe or non-severe adverse events (AEs). Two patients reported a non-related SAE and another a non-related AE. Two patients dropped out due to unwillingness to attend follow-up visits during the COVID-19 pandemic. In addition, in 3 patients the infusion rate was increased back to 30 or 60 min due to different causes (2 due to sub-optimal response and one due to AE). All 13 remaining patients reached the 18-month time-point. The platelet counts increased by a median (range) of 75.1% [15.6%–206.9%] and the lyso-GB1 levels decreased by 60.15% [25.7%–85.6%]. Shortening the infusion time has shown to be safe and effective in both previously treated (Zimran et al., AJH2018) and in treatment-naïve patients (this report) and could therefore improve the quality-of-life of patients with GD who have a long-life commitment to this therapy.

Angiotensin converting enzyme (ACE).

BACKGROUND: Angiotensin converting enzyme (ACE) was isolated as a 'hypertensinconverting enzyme'. There have been considerable advances in understanding the metabolic role of ACE in the body. This review attempts to highlight the role of ACE enzyme in the physiological and pathological processes occurring in the organs in which it is localized. METHODS: The literature was searched from the websites of the National Library of Medicine (http://www.ncbi.nlm.nih.gov/) and Pub Med Central, the U.S. National Library of Medicine's digital archive of life sciences journal literature. RESULTS: The involvement of ACE in regulation of blood pressure forms its central action but it has a role to play in a variety of physiological processes occurring in the organs in which it is localized like the lungs, macrophages, brain, pancreas, liver etc. It has also been implicated in the pathogenesis of a number of diseases including COVID-19. CONCLUSIONS: More studies need to be carried out in order to validate the use of ACE levels in the diagnosis and monitoring of the diseases associated, and facilitate the use of ACE inhibitors and Angiotensin Receptor Blockers in the management of the same, so this wonder molecule can be utilized to its full potential.

Gaucher's Disease in an Adult Female: A Rare Entity.

Gaucher's disease is a rare inborn error of metabolism with an autosomal recessive pattern of inheritance. With over 26 million births occurring per annum, extrapolation of this figure would give us an estimated burden of 17,000 babies born with lysosomal storage disorder (LSD). Given the large population of India and the high rates of consanguineous marriage that takes place in the subcontinent, LSD might not be as rare as we perceive it to be. We report a rare occurrence of type-1 Gaucher's disease in an adult female patient born of a non-consanguineous marriage, belonging to the tropical area of Chhattisgarh, India where there is a predominance of malaria, thalassemia, and sickling. The diagnosis was challenging in this case since we needed to work out all the differential diagnoses of pancytopenia with hepatomegaly and massive splenomegaly. The key part was her medical history where there was documentation of her elder brother's death due to some mental illness of undiagnosed etiology. Being a difficult time due to coronavirus disease 2019 ( COVID-19) , we were able to diagnose the patient with a bone marrow biopsy followed by glucocerebrosidase enzyme level suggestive of Gaucher's disease.

The clinical spectrum of SARS-CoV-2 infection in Gaucher disease: Effect of both a pandemic and a rare disease that disrupts the immune system.

INTRODUCTION: The impact of SARS-CoV-2 in rare disease populations has been underreported. Gaucher disease (GD) is a prototype rare disease that shares with SARS-CoV-2 a disruption of the lysosomal pathway. MATERIALS-METHODS: Retrospective analysis of 11 patients with Type 1 GD who developed COVID-19 between March 2020 and March 2021. RESULTS: Seven male and 4 female patients with Type 1 GD developed COVID-19. One was a pediatric patient (8 years old) while the remainder were adults, median age of 44 years old (range 21 to 64 years old). Two patients required hospitalization though none required intensive care or intubation. All 11 patients recovered from COVID-19 and there were no reported deaths. CONCLUSIONS: Our case series suggests that GD patients acquired COVID-19 at a similar frequency as the general population, though experienced a milder overall course despite harboring underlying immune system dysfunction and other known co-morbidities that confer high risk of adverse outcomes from SARS-CoV-2 infection.

Gaucher disease and SARS-CoV-2 infection: Experience from 181 patients in New York.

SARS-CoV-2 infection carries high morbidity and mortality in individuals with chronic disorders. Its impact in rare disease populations such as Gaucher disease (GD) is unknown. In GD, decreased acid ß-glucosidase activity leads to the accumulation of inflammatory glycosphingolipids and chronic myeloid cell immune activation which a priori could predispose to the most severe effects of SARS-CoV-2. To evaluate the determinants of SARS-CoV-2 infection in GD, we conducted a cross-sectional study in a large cohort. 181 patients were enrolled, including 150 adults and 31 children, with a majority of patients on treatment (78%). Information on COVID-19 exposure, symptoms, and SARS-CoV-2 nucleic acid and/or antibody testing was obtained during the peak of the pandemic in the New York City metropolitan area. Forty-five adults reported a primary exposure to someone with COVID-19 and 17 (38%) of these patients reported at least one COVID-19 symptom. A subset of adults was tested (n = 88) and in this group 18% (16/88) were positive. Patients testing positive for SARS-CoV-2 had significantly more symptoms (4.4 vs 0.3, p < 0.001) than patients testing negative. Among patients who were antibody-positive, quantitative titers indicated moderate to high antibody response. In GD adults, male gender, older age, increased BMI, comorbidities, GBA genotype, prior splenectomy and treatment status were not associated with the probability of reporting symptoms or testing positive. No patient required COVID-19-specific treatments and there were no deaths. Our data suggests that GD does not confer a heightened risk for severe effects of SARS-CoV-2 infection feared based on the known chronic inflammatory state in these patients.

Direct and indirect effects of the SARS-CoV-2 pandemic on Gaucher Disease patients in Spain: Time to reconsider home-based therapies?

OBJECTIVE: An analysis of the SARS-CoV-2 pandemic impact in the Spanish Gaucher Disease (GD) community is presented here. PATIENTS & METHODS: The Spanish GD foundation (FEETEF) surveyed 113 GD patients from March 30 to April 27; all patients provided a verbal consent. RESULTS: 110 surveys were analyzed. The median age was 47 years old (y.o.), 31 patients were ≥ 60 y.o.; and 34% of patients reported comorbidities. 46% (51/110) of patients were treated by enzyme replacement therapy (ERT), 48 of them at hospitals; 45.1% (45/110) were on substrate reduction therapy (SRT) and 9% (10/110) receive no therapy. 25% (11/48) of ERT-hospital-based patients reported therapy interruptions, while SRT-patients did not report missing doses. No bone crises were reported. However, 50% (55/110) of patients reported being worried about their predisposition to a severe SARS-COV-2 infection and 29% (16/55) of them took anxiolytics or antidepressants for this. While 6 patients reported to have contact with an infected person, another two confirmed SARS-CoV-2 infections were reported in splenectomyzed patients, one of them (a 79-year-old diabetic) died. CONCLUSIONS: One quarter of the patients treated at hospitals reported dose interruptions. Home-based therapy may need to be considered in order to minimize the impact of the COVID-19 pandemic.