Fabiano de Oliveira Poswar

Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis

Deficiency of adenosine deaminase-2 (DADA2), a monogenic autoinflammatory disorder manifesting with a spectrum of systemic inflammation and vasculitis/vasculopathyrelated symptoms, was recently described [1, 2]. DADA2 is caused by bi-allelic loss-of-function mutations in CECR1 gene. Several patients were identified in populations with founder effects such as Georgian Jewish, Turkish and Pakistani [1, 2]. Here, we report the first molecularly confirmed case of DADA2 in Brazil. A now 25-year-old female, born to non-consanguineous parents fromRio Grande do Sul, Brazil, was referred in 2005 to Hospital de Clinicas de Porto Alegre with a history of progressive weakness and spasticity of the lower limbs. At the age of 6 she presented with acute/subacute spasticity, weakness and vascular manifestations in lower extremities (Fig. 1b). Over the next years, motor function progressively worsened and at age of 12 she developed dysarthria, dysphagia and nasal speech. Neurological examination showed spastic tetraparesis, mild upper-limb ataxia and dysfunction of cranial nerves VII, IX and X. BrainMRI showed nomajor abnormalities. She was investigated for infectious causes of spastic paraplegia, multiple sclerosis and inborn errors of metabolism with no diagnostic conclusion. The patient presented prominent vascular manifestations including Raynaud phenomena and livedo reticularis, and during one of her flare-ups in the year 2006, she had righthand forth finger necrosis that required amputation (Fig. 1c). At this moment, C-reactive protein was 20.4 mg/ L and erythrocyte sedimentation rate was 28 mm/h. Autoantibodies were normal, with the exception of the presence of lupus anticoagulant. She received a presumed diagnosis of antiphospholipid syndrome and started oral anticoagulation. In spite of treatment, patient’s vascular phenomena continued to worsen. After 22 months of anticoagulation, she presented a major intestinal bleeding, leading to warfarin withdrawal. During the follow-up, antiphospholipid antibodies were repeated several times, all with negative results. In 2013, it was noticed that two of her sisters presented with early-onset livedo reticularis (Fig. 1a, d) suggesting an autosomal recessive condition and the family was referred for genetic consultation. Soon after DADA2 description in 2014, we reviewed this family complex phenotype, and DADA2 diagnosis was suspected. CECR1 sequencing revealed compound heterozygous mutations, p.Gly47Arg/p.Tyr453Cys [1–3], in the studied subjects (index case and one sister). Both mutations were previously described as pathogenic [1–3], confirming DADA2 diagnosis. Brain MRI was repeated showing a few FLAIR hyperintensities in the deep frontal white matter, while spine MRI showed no major abnormalities (Fig. 2). Treatment with a TNF-inhibitor, etanercept, was indicated. DADA2 results from loss-of-function mutations in CECR1, which encodes adenosine deaminase 2, an enzyme that plays a role in differentiation of endothelial and & Jonas Alex Morales Saute jsaute@hcpa.edu.br

Phase I and II clinical trials for the mucopolysaccharidoses

ABSTRACT Introduction: The mucopolysaccharidoses are lysosomal diseases characterized by deficient activity of one of the enzymes that degrades glycosaminoglycans. Treatment options are limited; therefore, new treatments are under investigation. Areas covered: We review the medicinal products for the treatment of mucopolysaccharidoses that are currently being investigated in phase I and phase II clinical trials. Expert opinion: The number of alternatives to treat MPS diseases increased dramatically in an attempt to provide therapy options for orphan MPS diseases and to address the unmet needs of the MPS that already have a treatment available. Intravenous enzyme replacement therapy (ERT) with fusion proteins, intrathecal/intracerebroventricular (ICV) ERT and gene therapy are the most promising strategies addressing the CNS manifestations. Stop-codon read-through, although proposed only for patients with nonsense mutations, might be useful in all MPS types. Substrate reduction therapy could also play a role in any MPS type, as anti-inflammatory drugs are also being tested. This new generation of therapies is now in clinical development and should bring new hope to MPS patients. As cost and logistics remain major challenges, especially for low- and middle-income countries, the possibility of having a one-time treatment such as gene therapy is anxiously awaited by affected families and healthcare systems.

Neurological manifestations of lysosomal disorders and emerging therapies targeting the CNS

Lysosomal disorders have been an area of interest since intravenous enzyme replacement therapy was successfully introduced for the treatment of Gauchers disease in the early 1990s. This treatment approach has also been developed for several other lysosomal disorders, including Fabrys disease, Pompes disease, lysosomal acid lipase deficiency, and five types of mucopolysaccharidosis. Despite the benefits of enzyme replacement therapy, it has limitations-most importantly, its ineffectiveness in treating the neurological components of lysosomal disorders, as only a small proportion of recombinant enzymes can cross the blood-brain barrier. Development of strategies to improve drug delivery to the CNS is now the primary focus in lysosomal disorder research. This Review discusses the neurological manifestations and emerging therapies for the CNS component of these diseases. The therapies in development (which are now in phase 1 or phase 2 clinical trials) might be for specific lysosomal disorders (enzyme replacement therapy via intrathecal or intracerebroventricular routes or with fusion proteins, or gene therapy) or applicable to more than one lysosomal disorder (haemopoietic stem cell transplantation, pharmacological chaperones, substrate reduction therapy, or stop codon readthrough). The combination of early diagnosis with effective therapies should change the outlook for patients with lysosomal disorders with neurological involvement in the next 5-10 years.

Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial

BackgroundMucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline.ResultsDrug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion.ConclusionClinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI.Trial registrationClinical Trials.Gov, NCT03053089. Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341. Registered 6 March, 2017.

Aortic root dilatation in patients with mucopolysaccharidoses and the impact of enzyme replacement therapy

Mucopolysaccharidoses (MPS) are disorders characterized by impaired glycosaminoglycan (GAG) catabolism as a consequence of a deficiency or the absence of lysosomal enzymes directly involved in their degradation. Multiple organ systems are involved in MPS, including the cardiovascular system. Recently, aortic root dilatation (ARD) has been described in these patients. Thus, we reviewed aortic root diameter measurements in 69 MPS patients from a single center from 2000 to 2016. Aortic root diameter z scores were calculated based on data published by Colan et al. according to the body surface area (BSA) determined using the Haycock formula. The overall incidence of ARD in MPS patients was 39.1%. Higher mean z scores were present in patients with MPS IVA and VI when compared to MPS I and II. Aortic root z scores were higher in older MPS IVA patients, which may suggest a progressive ARD change in this MPS type. No significant differences were found before and after enzyme replacement therapy (ERT) in 11 patients with available data (2 with MPS I; 4 with MPS II; 2 with MPS IVA, and 3 with MPS VI). This work provides further evidence that ARD is common in different types of MPS, being especially evident in MPS IVA, but with a significant occurrence also in MPS VI.

Intrathecal/Intracerebroventricular enzyme replacement therapy for the mucopolysaccharidoses: efficacy, safety, and prospects

ABSTRACT Introduction: The mucopolysaccharidoses (MPS) are lysosomal storage diseases (LSDs) caused by the deficiency of an enzyme involved in the breakdown of glycosaminoglycans (GAGs), which leads to GAG storage and results in multisystemic manifestations. In some of the 11 MPS types, patients could have cognitive involvement and/or secondary neurologic manifestations. Intravenous enzyme replacement therapy (ERT), already approved for several MPS types, is not able to cross the blood–brain barrier and does not address the neurologic manifestations present in most MPS types. Intrathecal (IT) or intracerebroventricular (ICV) administration of the enzyme directly into the cerebrospinal fluid (CSF) has been proposed and experienced in clinical trials and in single cases. Areas covered: This paper briefly summarizes the development of ERT to treat LSDs, particularly MPS, the technical aspects related to its CSF administration, the experience obtained so far with the IT and ICV use in several MPS types and provides an expert opinion on this subject. Expert opinion: Treatment of neuropathic MPS remains a challenge. The results of ongoing trials may bring IT and ICV administration of ERT to clinical use in the coming years, making it a therapeutic option for the treatment of neuronopathic patients in several MPS types.

Enzyme Replacement Therapy With Elosulfase Alfa Decreases Storage of Glycosaminoglycan in White Blood Cells of Patients With Morquio A Syndrome

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by a deficient N-acetylgalactosamine-6-sulfate sulfatase activity, leading to cellular storage of undegraded keratan sulfate. Recently enzyme replacement therapy (ERT) was approved for MPS IVA, but some of ERT effects are still unknown. In the present study, we aimed to evaluate the efficacy of elosulfase alfa upon glycosaminoglycan (GAG) storage in peripheral blood white blood cells of patients with MPS IVA treated for 6 months, comparing samples from patients who received weekly infusions of enzyme (ERT-W) versus infusions every other week (ERT-EOW) versus placebo. A significant reduction in GAG storage was observed in both ERT-treated groups, with weekly ERT showing slightly better performance than ERT-EOW.