Can velmanase alfa be the next widespread potential therapy for alpha-mannosidosis?

Alpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.

First experience of combined enzyme replacement therapy and hematopoietic stem cell transplantation in alpha-mannosidosis.

We describe the first case of bridge therapy in alpha-mannosidosis (AM) in an infant diagnosed at only 5 months of life who underwent enzyme replacement therapy (ERT) in the pre- and peri-transplant phases. Eight ERT infusions were administered before hematopoietic stem cell transplantation (HSCT) and continued for additional 90 days until complete engraftment. The clinical and laboratory data after 3 years post-HSCT show that the early combined intervention may reduce the disease progression and the urine and plasma content of mannosyl-oligosaccharides (OS) monitored by liquid chromatography tandem mass spectrometry (LC-MS/MS). This report highlights that early diagnosis and prompt initiation of such treatments in AM are the best chance to minimize the progression of symptoms.

Comprehensive cardiopulmonary assessment in α mannosidosis.

INTRODUCTION: α Mannosidosis is an extremely rare, progressive, and complex lysosomal storage disease, characterized by mental retardation, hearing impairment, coarse facial features, skeletal abnormalities, and pulmonary involvement. While bone marrow transplantation has been the only therapeutic option to date, nowadays new treatment options are being explored, which may affect pulmonary and exercise capacity. AIM AND METHODS: To assess cardiopulmonary involvement in patients with α mannosidosis by pulmonary function tests, cardiopulmonary exercise testing, and low irradiation chest computed tomography (CT). RESULTS: Five patients aged 11 to 28 years were followed in our Respiratory-Metabolic Clinic. All five had pulmonary symptoms and received inhaled therapy. Three patients underwent bone marrow transplantation. Parenchymal lung disease was evident in 3/5 chest CT tests. Pulmonary function tests were abnormal in all patients and showed obstructive/restrictive impairment with air trapping. All five patients showed reduced peak oxygen uptake (median 23.1; range 20.4-32.2 mL/minute/kg, median %predicted 62; range %predicted 59-79). CONCLUSIONS: Pulmonary involvement is a known complication in this rare disease. Comprehensive cardiopulmonary evaluation is feasible among these patients and may help in assessing disease progression and response to new treatment modalities.

Alpha-Mannosidosis: Therapeutic Strategies.

Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.

Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis.

INTRODUCTION: Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). METHODS: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). RESULTS: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. CONCLUSIONS: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis.

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.

Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.

INTRODUCTION: This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. METHODS: Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT). RESULTS: Mean relative change in S-oligo in the VA arm was -77.6% [95% confidence interval (CI) -81.6 to -72.8] at week 52 and -62.9% (95% CI -85.8 to -40.0) at LO; mean relative change in the placebo arm was -24.1% (95% CI -40.3 to -3.6) at week 52 and -55.7% (95% CI -76.4 to -34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was -1.1% (95% CI -9.0 to 7.6) and - % (95% CI -13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI -5.5 to 13.2) in the VA arm and 9.0% (95% CI -10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. CONCLUSIONS: These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.

Clinical Improvement of Alpha-mannosidosis Cat Following a Single Cisterna Magna Infusion of AAV1.

Lysosomal storage diseases (LSDs) are debilitating neurometabolic disorders for most of which long-term effective therapies have not been developed. Gene therapy is a potential treatment but a critical barrier to treating the brain is the need for global correction. We tested the efficacy of cisterna magna infusion of adeno-associated virus type 1 (AAV1) expressing feline alpha-mannosidase gene in the postsymptomatic alpha-mannosidosis (AMD) cat, a homologue of the human disease. Lysosomal alpha-mannosidase (MANB) activity in the cerebrospinal fluid (CSF) and serum were increased above the control values in untreated AMD cats. Clinical neurological signs were delayed in onset and reduced in severity. The lifespan of the treated cats was significantly extended. Postmortem histopathology showed resolution of lysosomal storage lesions throughout the brain. MANB activity in brain tissue was significantly above the levels of untreated tissues. The results demonstrate that a single cisterna magna injection of AAV1 into the CSF can mediate widespread neuronal transduction of the brain and meaningful clinical improvement. Thus, cisterna magna gene delivery by AAV1 appears to be a viable strategy for treatment of the whole brain in AMD and should be applicable to many of the neurotropic LSDs as well as other neurogenetic disorders.

Alpha-mannosidosis - a review of genetic, clinical findings and options of treatment.

Alpha-mannosidosis (OMIM 248500) is a rare, autosomal recessive, multisystemic, progressive lysosomal storage disorder caused by a deficiency of alpha-mannosidase. It has been described in humans, cattle, domestic cats, mice and guinea pigs. In humans, alpha-mannosidosis results in progressive facial- and skeletal abnormalities, motor impairment, hearing impairment, intellectual disability, recurrent infections and immune deficiency. This review provides detailed information regarding the variability of manifestations and a description of current treatment and treatment under investigation for alpha-mannosidosis. The pathology, genetics and clinical pictures, including impairments in the activity of daily living are discussed.

Successful unrelated bone marrow transplantation in two siblings with alpha-mannosidosis.

Alpha-mannosidosis is a rare lysosomal storage disorder with an autosomal recessive inheritance. Deficient alpha-mannosidase activity leads to lysosomal accumulation of mannose-rich oligosaccharides. The disease characterized by mental retardation, skeletal changes, hearing impairment, and recurrent infections. Stem cell transplantation has been shown to be an effective treatment. It works by providing increased levels of α-mannosidase in the localized extracellular milieu to provide improvements in skeletal malformations, neurocognitive, and sensorineural function. In this case report, we describe a pair of siblings with α-mannosidosis who successfully underwent HSCT from matched unrelated donors. In both siblings, enzyme levels reached to normal limits and improvements in clinical symptoms were recognized early after HSCT. We conclude that HSCT should be considered as a therapeutic approach in patients with alpha-mannosidosis before disease-related complications have developed.

Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.

Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.

Alpha-mannosidosis.

Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.

Survival and engraftment of mouse embryonic stem cell-derived implants in the guinea pig brain.

alpha-Mannosidosis is a lysosomal storage disease resulting from a deficiency of the enzyme alpha-D-mannosidase. A major feature of alpha-mannosidosis is progressive neurological decline, for which there is no safe and effective treatment available. We have a guinea pig model of alpha-mannosidosis that models the human condition. This study investigates the feasibility of implanting differentiated mouse embryonic stem cells in the neonatal guinea pig brain in order to provide a source of alpha-mannosidase to the affected central nervous system. Cells implanted at a low dose (1.5 x 10(3)cells per hemisphere) at 1 week of age were found to survive in very low numbers in some immunosuppressed animals out to 8 weeks. Four weeks post-implantation, cells implanted in high numbers (10(5) cells per hemisphere) formed teratomas in the majority of the animals implanted. Although implanted cells were found to migrate extensively within the brain and differentiate into mature cells of neural (and other) lineages, the safety issue related to uncontrolled cell proliferation precluded the use of this cell type for longer-term implantation studies. We conclude that the pluripotent cell type used in this study is unsuitable for achieving safe engraftment in the guinea pig brain.

Over-expression of human lysosomal alpha-mannosidase in mouse embryonic stem cells.

Alpha-mannosidosis is a lysosomal storage disorder characterised by the lysosomal accumulation of mannose-containing oligosaccharides and a range of pathological consequences, caused by a deficiency of the lysosomal enzyme alpha-mannosidase. One of the major features of alpha-mannosidosis is progressive neurological decline, for which there is no safe and effective treatment. Implantation of stem cells into the central nervous system has been proposed as a potential therapy for these disorders. We report the construction and characterisation of mouse embryonic stem cell lines for the sustained over-expression of recombinant human lysosomal alpha-mannosidase (rhalphaM). Two vectors (involving recombinant human alpha-mannosidase expression driven by either the chicken beta-actin promoter/CMV enhancer or by the elongation factor 1-alpha promoter) were constructed and used to transfect mouse D3 embryonic stem cells. Selected clonal cell lines were isolated and tested to evaluate their expression of recombinant human alpha-mannosidase. Stem cell clones transfected with the chicken beta-actin promoter/CMV enhancer maintained rhalphaM expression levels throughout differentiation. This expression was not markedly elevated above background. In contrast, the vector incorporating the elongation factor 1-alpha promoter facilitated substantial over-expression of alpha-mannosidase when analysed out to 21 days of differentiation in stably transfected cell lines. The highest expressing cell line was found to qualitatively retain a similar differentiation potential to untransfected cells, and to secrete alpha-mannosidase that could mediate a reduction in the level of oligosaccharides stored by human alpha-mannosidosis skin fibroblasts. These results suggest potential for the use of this cell line for investigation of a stem cell therapy approach to treat alpha-mannosidosis.

Unmanipulated HLA-haploidentical bone marrow transplantation for the treatment of fatal, nonmalignant diseases in children and adolescents.

Fetomaternal microchimerism has been demonstrated, and immunologic tolerance to unshared HLA antigens between mother and offspring may be suggested. We used T-cell-repleted bone marrow transplantation (BMT) from their HLA-haploidentical mothers to treat 6 patients with fatal nonmalignant diseases. The number of mismatched HLA loci in the graft-versus-host disease (GVHD) direction was 3 in 4 patients and 2 in 2 patients. The number in the host-versus-graft direction was 3 in 4 patients, 2 in 1 patient, and 1 in 1 patient. Microchimerism of inherited paternal antigens was demonstrated in 5 donors, and microchimerism of noninherited maternal antigens was detected in 3 recipients. GVHD prophylaxis consisted of short-course methotrexate, tacrolimus, and mycophenolate mofetil (3 patients) or short-course methotrexate, tacrolimus, and methylprednisolone (1 patient). Engraftment was achieved in 5 patients who had received preconditioning, and T-cell engraftment was confirmed in 1 patient with severe combined immunodeficiency. Acute GVHD developed in 3 patients: grade 1 in 2 patients and grade 2 in 1 patient. Chronic GVHD was observed in 5 patients: localized type in 3 patients and extended type in 2 patients. Five patients were alive 11 to 30 months after BMT and 1 patient died of chronic GVHD. Unmanipulated haploidentical BMT from a maternal donor may be the treatment of choice of poor-prognosis nonmalignant diseases.

Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of alpha-mannosidosis. STUDY DESIGN: Four patients with alpha-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was established by assay of leukocyte alpha-mannosidase activity level. Physical features, donor engraftment, leukocyte alpha-mannosidase activity, neuropsychologic function, and hearing were monitored before and after transplantation, with follow-up ranging from 1 to 6 years. RESULTS: All 4 patients showed slowing of their neurocognitive development and sensorineural hearing loss before HCT. All patients are alive, with normalization of leukocyte enzyme activity after HCT. Intellectual function has stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Hearing has improved to normal or near normal for speech frequencies in 3 patients. No new skeletal abnormalities have developed. CONCLUSIONS: HCT can halt the progressive cognitive loss in patients with alpha-mannosidosis. Early diagnosis and treatment with HCT is critical for optimal results.

Late occurrence of chronic immune-mediated axonal polyneuropathy following bone marrow transplant for juvenile-onset alpha-mannosidosis.

A 23-year-old woman with juvenile-onset alpha-mannosidosis developed an axonal polyneuropathy more than a year following successful unrelated donor (URD) BMT complicated by chronic graft-versus-host disease (GVHD). Progressive muscle weakness and paresthesias developed over at least 4 months, and made her nonambulatory. Nerve conduction and EMG studies demonstrated an axonal sensorimotor neuropathy. Cerebral spinal fluid (CSF) IgG was elevated with two peaks not identified in serum. Strength improved after a single course of plasma exchange and continued to improve over 12 months. The response to plasma exchange, elevated CSF IgG production, and evidence of a serum IgM peak suggest an immune-mediated mechanism. Chronic polyneuropathies following BMT are rare and are usually temporally related to GVHD or infection. This patient's disease was unusual because of its late occurrence and chronic onset in the face of resolved GVHD and in the absence of infection.

T-cell-depleted peripheral blood stem cell transplantation for alpha-mannosidosis.

Alpha-mannosidosis (alpha-mannosidosis) is a lysosomal storage disease characterized by accumulation of oligosaccharides in various tissues leading to symptoms such as coarse facial features, dysostosis multiplex, hearing disabilities, mental developmental delay and skeletal involvement (dysostosis multiplex). Without treatment, the severe infantile onset form of this autosomal recessive disease leads to progressive neurodegeneration and sometimes to early death. Stem cell transplantation has been shown to be an effective treatment. In the five patients published so far, correction of skeletal abnormalities and improvement of neuropsychological capabilities have been observed. We report the first patient who received a T-cell-depleted peripheral blood stem cell transplantation (PBSCT) for alpha-mannosidosis. The diagnosis of alpha-mannosidosis was made at the age of 14 months. At the age of 24 months, he underwent PBSCT with T-cell depletion by CD34-positive selection from his HLA phenotypically identical mother. Conditioning was carried out with busulfan (20 mg/kg), cyclophosphamide (200 mg/kg), OKT3 and methylprednisolone. The patient is alive and well 27 months after PBSCT and has made significant developmental progress. The pattern of urinary oligosaccharides has returned to almost normal. CD34-positive-selected PBSCT is a feasible option to reduce risk for GVHD for these patients.

Recent progress in lysosomal alpha-mannosidase and its deficiency.

Lysosomal alpha-mannosidase (EC 3.2.1.24) is a major exoglycosidase in the glycoprotein degradation pathway. A deficiency of this enzyme causes the lysosomal storage disease, alpha-mannosidosis, which has been described in humans, cattle, domestic cats and guinea pigs. Recently, great progress has been made in studying the enzyme and its deficiency. This includes cloning of the gene encoding the enzyme, characterization of mutations related to the disease, establishment of valuable animal models, and encouraging results from bone marrow transplantation experiments.