The Virtual Conference on

Lysosomal Diseases

Recurrent infections of the airways and ears, inguinal and/or umbilical hernia in combination with joint stiffness and contractures as well as other skeletal abnormalities may lead to the diagnosis of a rare, inherited disease: mucopolysaccharidosis.

The mucopolysaccharidoses (MPS) are one group of lysosomal storage disorders caused by a deficiency of lysosomal enzymes, that are responsible for the degradation of glycosaminoglycans (GAGs), important components of the connective tissues. This is accomplished by complex pathophysiological cascades and results in a storage of GAGs in the cells. Almost all organs and organ systems are affected.

The accumulation of undegraded GAGs leads to a progressive variety of somatic and neurological symptoms, including skeletal, musculoskeletal and cardiorespiratory complications. Some MPS types show also a mental development decline. Early diagnosis, appropriate management and – in some MPS types available- therapies affect the quality of life of patients and can lead to a slowdown or a prevention of irreversible complications.

Since there is not a typical “MPS-symptom”, but only the sum of many nonspecific and variable symptoms may lead to the diagnosis, in particular in attenuated / milder MPS types, they are often diagnosed late and mistaken for an (uncharacteristically running) rheumatologic or skeletal disease.

Gaucher disease is an autosomal recessive disorder that is caused by mutations in the GBA1 gene leading to insufficient activity of the hydrolase acid beta-glucosidase (glucocerebrosidase). Patients are classified into three phenotypes depending on whether the central nervous system (CNS) is involved and on the age of onset of clinical manifestations. Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form—Gaucher type 2—from the subacute or chronic form—Gaucher type 3. We recently positively defined the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. We discuss the features that suggest nGD and what clinical features differentiate between Gaucher type 2 and type 3.  This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming research studies. Enzyme replacement therapy is the standard medical treatment for nGD. Substrate reduction therapy with venglustat is in clinical trial and gene therapy trials will likely start very soon.

Manisha Balwani¹; William Balistreri²; Lorenzo D’Antiga³; Shona Fang⁴; Simon A. Jones⁵; Emilio Ros⁶; Florian Abel⁴; Don P. Wilson⁷

 ¹Icahn School of Medicine at Mount Sinai Hospital, New York, New York; ²Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; ³Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; ⁴Alexion Pharmaceuticals, Inc., Boston, Massachusetts; ⁵Manchester University Hospital NHS Trust, Manchester, UK; ⁶Hospital Clinic de Barcelona, Barcelona, Spain; ⁷Cook Children’s Medical Center, Fort Worth, Texas

An international registry (NCT01633489; Alexion Pharmaceuticals, Inc.; 2013–ongoing) was established to better understand the natural history of lysosomal acid lipase deficiency (LAL-D) and to evaluate long-term treatment outcomes. Baseline findings for patients enrolled through July 1, 2019 are presented. Of 190 patients enrolled, 35 were excluded from this analysis (LIPA carrier, deceased at enrollment, unconfirmed LAL-D diagnosis); 155 patients with confirmed LAL-D diagnosis were included (12 infants, 143 children/adults). LAL enzyme activity analysis was performed for 145/154 patients (94%) and genetic testing for 128/154 patients (83%). Of 105 children/adults with reported LIPA mutations, 39 were homozygous and 34 were compound heterozygous for the common LIPA mutation E8SJM (c.894G>A); 6 infants with reported LIPA mutations were homozygotes and 2 were compound heterozygotes. Of the 155 patients, 62% were <18 years, 52% were male, and 85% were white. Median (range) age at clinical onset was 0.2 years (0.0–0.7) among infants and 6.0 years (0.0–41.3) among 133 children/adults with data; median (range) age at diagnosis was 0.2 years (−0.1 to 1.2) among infants and 10.8 years (0.2–53.6) among 135 children/adults with data. Manifestations that raised suspicion of LAL-D were reported in 149/155 patients. Infants (12 with data) presented predominantly with hepatomegaly (75%), splenomegaly (58%), nausea/vomiting (58%), and diarrhea (50%), and 50% had a known family history of LAL-D. Children/adults (n=143) presented predominantly with elevated alanine aminotransferase levels (67%), hepatomegaly (66%), and elevated aspartate aminotransferase levels (65%). Of 74 children/adults with baseline liver biopsy, 58% had microvesicular steatosis, 16% had micro- and macrovesicular steatosis, and 32% had lobular inflammation. Of the 155 patients, 6% had a medical history of cirrhosis. Analyses exploring the genotype-phenotype relationship will be presented. Registry data of >150 LAL-D patients demonstrate early symptom onset, variable clinical manifestations, and a significant diagnostic delay in children/adults.

Disclosures:  

Balwani: Alexion Pharmaceuticals, Inc., honorarium, advisory board; Lysosomal Acid Lipase Deficiency Registry, scientific advisory board.

Balistreri: Otsuka, Alexion Pharmaceuticals, Inc., consultant; Gilead, AbbVie, Merck, research grants.

D’Antiga: Alexion Pharmaceuticals, Inc., advisory board, honorarium, grants, speaker; Lysosomal Acid Lipase Deficiency Registry, scientific advisory board.

Fang and F. Abel: Alexion Pharmaceuticals, Inc., employment.

S.A. Jones: Alexion Pharmaceuticals, Inc., honorarium, grants, speaker.

Ros: Alexion Pharmaceuticals, Inc., honorarium, grants, speaker; Lysosomal Acid Lipase Deficiency Registry, scientific advisory board.

D.P. Wilson: Osler Institute, National Lipid Association, Insulet Corp., Alexion Pharmaceuticals, Inc., speaker; Aegerion, Alexion Pharmaceuticals, Inc., Merck Sharp & Dohme, Novo Nordisk, advisory board; Merck Sharp & Dohme, Novo Nordisk, research funding.

AVROBIO, a clinical-stage gene therapy company with a mission to free people from a lifetime of genetic disease, aims to develop potential one-time lentiviral-based gene therapies to treat patients with LDs caused by the mutation of a single gene. Our gene therapies employ patient-derived hematopoietic stem cells modified with a lentiviral vector to insert a therapeutic copy of the mutated gene. Our clinical stage programs include Fabry disease (AVR-RD-01), cystinosis (AVR-RD-04) and Gaucher disease (AVR-RD-02).

AVR-RD-01 is being evaluated in an investigator-sponsored Ph1 trial and AVROBIO-sponsored Ph2 trial. Nine classic male Fabry patients have been dosed to date. Initial data suggest durable effect, including up to 32 months in one patient, as demonstrated by VCN, AGA enzyme activity in leukocytes and plasma and associated reductions in plasma lyso-Gb3. An 87% reduction in average number of kidney peritubular cell Gb3 substrate deposits was reported in the first treatment naïve patient at 48 weeks. Per the last safety data cut-off date, there have been no SAEs associated with AVR-RD-01 and the safety profile reported is consistent with conditioning and underlying disease.

AVR-RD-04 is being studied by UCSD collaborators in a Ph1/2 investigator-sponsored trial to treat cystinosis. Three-month data from the first dosed patient demonstrated a reduction in granulocyte cystine levels and positive trends across multiple clinical measures. Per the last safety data cut-off date, no SAEs were reported and AEs were consistent with conditioning and underlying disease.

The Ph1/2 trial in Gaucher disease Type 1 investigating AVR-RD-02 has enrolled the first patient.