Disclosures. Learning Objectives. Inheritance patterns. Lysosomal function. Mucopolysaccharidoses (MPS): Keys to Early Recognition and Intervention

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1 39 th National Conference on Pediatric Health Care March 19-22, 2018 CHICAGO Disclosures Mucopolysaccharidoses (MPS): Keys to Early Recognition and Intervention Lindsay Torrice, MSN, CPNP PC Clinical Instructor Division of Genetics and Metabolism Department of Pediatrics University of North Carolina at Chapel Hill No financial disclosures No discussion of off label use I am a sub investigator in a Phase I/II and Phase II/III clinical trial investigating intrathecal enzyme replacement therapy for MPS II and in a Phase I clinical trial investigating gene editing therapy for MPS II. Learning Objectives Discuss the inheritance patterns and pathophysiology of MPS disorders. Describe clinical presentation of the MPS disorders, including pertinent findings on physical exam. Identify current treatments and investigational therapies for the MPS disorders. Overview of Mucopolysaccharidosis (MPS) Rare genetic Lysosomal storage disorder Approximate incidence 1:25,000 across all types Deficiency of specific lysosomal enzymes leads to accumulation of glycosaminoglycans (GAG) within the lysosomes Eleven known enzyme deficiencies cause 7 clinical types Progressive and debilitating disorder involving multiple organ systems Wide spectrum of clinical manifestations within each disorder and across disorders Inheritance patterns Lysosomal function Breakdown/recycling of macromolecules and organelles into precursors Deficient/absent activity of a specific lysosomal enzyme results in either non degraded or partially degraded material Results in expansion of the size and number of the lysosomes 1

2 Enzyme function Glycosaminoglycans (GAG) Present in cells throughout the body Carbohydrate chains that are part of proteoglycans in extracellular space Broken down by lysosomal enzymes Primary Dermatan sulfate occur primarily in connective tissue Heparan sulfate occurs primarily in neurological Keratan sulfate occurs primarily bone Glycosaminoglycan accumulation Progressive Storage causes cellular injury and dysfunction Irreversible cell and organ damage Lysosome images Mucopolysaccharidoses # Name Enzyme Defect GAG I H Hurler Alpha L iduronidase DS, HS I H/S Hurler/Scheie Alpha L iduronidase DS, HS I S Scheie Alpha L iduronidase DS, HS II Hunter severe Iduronate 2 sulfatase DS, HS II Hunter attenuated Iduronate 2 sulfatase DS, HS III A Sanfilippo A Heparan N sulfatase HS III B Sanfilippo B N acetylglucosaminidase HS III C Sanfilippo C Acetyl CoA:a glucosamine N acetyltransferase HS III D Sanfilippo D N acetyl a glucosamine 6 sulfatase HS DS = dermatan sulfate KS = keratin sulfate HS = heparin sulfate Mucopolysaccharidoses # Name Enzyme Defect GAG IV A Morquio A N acetylgalactosamine 6 sulfatase KS IV B Morquio B beta galactosidase KS V No longer used VI Maroteaux Lamy N acetylgalactosamine 4 sulfatase (arylsulfatase B) DS VII Sly beta glucaronidase DS,HS VIII No longer used IX Hyaluronidase Hyaluronan DS = dermatan sulfate KS = keratin sulfate HS = heparin sulfate 2

3 Common clinical manifestations Cognitive impairment Seen in MPS I, II, III, VII Communicating hydrocephalus Spinal cord compression Carpal tunnel syndrome Hearing loss Coarse facial features Obstructive sleep apnea Tracheomalacia Hepatomegaly Splenomegaly Umbilical or inguinal hernia Cardiac valve disease Dysostosis multiplex Short stature Restricted JROM Hip dysplasia Patient images Dysostosis multiplex Skeletal manifestations characteristic of MPS Hypoplastic and abnormally shaped vertebral bodies Thoracolumbar kyphosis Genu valgum Hip dysplasia May lead to dislocation/subluxation of femoral head Bullet shaped metacarpals and phalanges Enlarged/thickened skull Broad, oar shaped ribs Broad clavicles MPS I Deficiency of alpha L iduronidase Accumulation of dermatan sulfate and heparan sulfate Somatic and neurological manifestations Rare (1:100,000) Autosomal recessive inheritance Spectrum of severity MPS I MPS I Hurler MPS IH Hurler Scheie MPS IH/S Scheie MPS IS Hurler Hurler Scheie Scheie More progressive Onset of symptoms before 6 months old Severe cognitive impairment Severe airway and respiratory disease Death by 10 years old Minimal to no cognitive impairment Respiratory and cardiac disease Obstructive airway disease Restricted JROM Skeletal abnormalities Cognitively intact Joint stiffness Corneal clouding Cardiac valve disease Less progressive physical symptoms May live in to later decades Images courtesy of J. Muenzer,

4 MPS II Hunter syndrome MPS III (A D) Sanfilippo syndrome Deficiency of iduronate 2 sulfatase Approximately 1:100,000 X linked inheritance Onset of symptoms 1 3yo Severe form Cognitive impairment Death in teenage years Attenuated (mild) form Cognitively intact May live to later decades Obstructive airway disease Cardiac valve disease Visual impairment Loss of peripheral vision Night blindness Deficiency of one of four distinct enzymes causes each subtype Leads to accumulation of heparan sulfate Subtypes are clinically indistinguishable Progressive and debilitating neurological disease Minimal physical involvement Developmental delay, behavioral challenges, hyperactivity, aggression, sleep disturbances Behavior issues decline as neurological impairment progresses May persist in vegetative state for years Death usually due to overwhelming neurological compromise MPS IV (A and B) Morquio syndrome Morquio A Joint hypermobility* Deficiency of N Short stature acetylgalactosamine 6 sulfatase Odontoid hypoplasia Accumulation of keratan sulfate Atlanto axial instability Rare (1:250,000) Most require cervical fusion in Skeletal dysplasia childhood Vertebral platyspondyly Corneal clouding Hip dysplasia No cognitive impairment Genu valgum Genu valgum Progressive Likely requires surgical intervention Correction of genu valgum may be more beneficial than correction of hip dysplasia for maintaining mobility Adapted from SIMDNAMA 2017 MPS VI Maroteaux Lamy syndrome Deficiency of N acetylgalactosamine 6 sulfatase Accumulation of dermatan sulfate Primarily somatic involvement Resembles MPS I physical manifestations More severe physical impairment due to longer lifespan No cognitive impairment Can have increased intracranial pressure Rare (est. incidence 1:340,000) In severe, rapidly progressing form, death in 1 st or 2 nd decade due to cardiac/respiratory disease Slower progressing form generally has later onset of symptoms and can survive to adulthood MPS VII Sly syndrome Deficiency of beta glucuronidase Autosomal recessive inheritance Very rare Common clinical presentation of non immune hydrops fetalis Somatic/CNS involvement Similar to MPS I presentation 4

5 Clinical Suspicion Developmental delay Hepatosplenomegaly Inguinal/umbilical hernias Frequent, recurrent ear infections Coarse facial features Corneal clouding Restricted joint range of motion Kyphosis Diagnosis Measurement of urine GAG Negative urine GAG by older testing methods does not rule out an MPS disorder Specific enzyme assay Serum, leukocytes or skin fibroblasts DNA analysis Very difficult to predict disease severity!! ERT Enzyme replacement therapy Current therapies HSCT Hematopoietic stem cell transplantation Current therapies HSCT ERT Somatic disease CNS disease MPS I Yes Yes Yes MPS II Yes No Yes MPS IIIA No No MPS IIIB No No MPS IVA No No Yes MPS VI Yes No Yes MPS VII?? Yes Enzyme Replacement Therapy (ERT) HSCT for MPS I Recombinant enzyme administered weekly/bi weekly via intravenous infusion Reduces GAG excretion in urine Reduces hepatomegaly and splenomegaly Can improve endurance (6MWT), pulmonary function (PFT), JROM, energy level Prevents progression of disease rather than reversing existing damage For optimal benefit, start ERT as early as possible Need suitable donor Easier with cord blood Start ERT while awaiting transplant Earlier treatment is key Difficult to predict disease severity/progression Does not reverse existing brain disease Recommended for patients with no to moderate cognitive impairment Orphanet J Rare Dis. 2011; 6: 55. Published online 2011 Aug 10. doi: /

6 Therapeutic challenges Symptom management No effective treatments for some types of MPS No treatment for MPS III ERT for MPS VII was only recently approved (2017) HSCT carries significant risk Most effective when performed before cognitive impairment occurs Limited impact on eye and bone disease Not typically recommended to treat brain disease in MPS II and MPS III ERT requires weekly infusions over 3 4 hours Initially performed in clinic/hospital setting May transition to home infusion therapy Risk of infusion reaction Limited impact on eye and bone disease Current enzyme replacement therapy does not cross the blood brain barrier No current commercial therapy to treat brain disease in MPS II and MPS III Physical therapy Occupational therapy Hearing aids Respiratory support CPAP during sleep Tracheostomy Surgery Carpal tunnel syndrome Hip dysplasia Genu valgum Spinal cord compression Atlanto axial instability Interdisciplinary Care Specialties that may be involved in the care of MPS patients include Primary care Genetics Pulmonology Cardiology ENT Audiology Neurology Anesthesiology Dental Physical therapy Occupational therapy Ophthalmology Orthopedics Infusion nurses What is the future of MPS diagnosis and treatment? Newborn Screening Dried blood spot Measurement of enzyme activity Different methods available to measure activity Currently recommended for MPS I Newborn Screening for MPS As of 2017, only 6 states are universally screening for MPS I Added February screening status all disorders 6

7 Emerging therapies Current and future clinical trials Intravenous enzyme replacement Intrathecal enzyme replacement Gene therapy Intravenous enzyme replacement Designed to prevent accumulation of storage material within the lysosome by delivering intact enzyme Current therapies are effective in treating aspects of somatic disease Investigational therapies aim to modify enzyme such that the deficient enzyme will cross the blood brain barrier to provide treatment for brain disease Intravenous enzyme replacement Some therapies under investigation: ArmaGen have produced modified recombinant enzymes designed to cross the blood brain barrier for MPS I (AGT 181) and MPS II (AGT 182) Current Phase I clinical trial in adult and pediatric patients JCR Pharmaceuticals (Japan) has developed an IV administered antibody enzyme comples which recognizes the transferrin receptor to allow iduronate 2 sulfatase to cross the blood brain barrier. Phase I/II clinical trial Sobi (Swedish Orphan Biobitrum) has developed a glycan modified sulfamidase (SOB1003) to treat the CNS disease in MPS IIIA. Modified enzyme to cross blood brain barrier Entering Phase I clinical trial in 2018 Intrathecal Enzyme Replacement Shire developed idursulfase IT, a formulation of idursulfase that may be delivered directly to the CSF via an intrathecal drug delivery device or lumbar puncture Intended to treat brain disease Administered concurrently with IV ERT Currently in Phase II/III trial 1 year data released December 2017 Unfortunately did not meet primary endpoints (comparison of GCA score in control and intervention groups) Study continues as additional data (extension study, sub study) is reviewed Intrathecal Enzyme Replacement BioMarin has developed a human recombinant NAGLU enzyme fused to a peptide derived from insulin like growth factor II. For treatment of brain disease in MPS IIIB Given directly into CSF via ICV reservoir (Ommaya) Phase II/III clinical trial Gene therapy Introduction of genetic material into a human cell correct genetic error introduce new function to the cell Two general clinical approaches Introduce vector directly into the bloodstream (in vivo) Vector is typically a modified virus Remove cells, transfect in culture and reintroduce genetically modified cells (ex vivo) One and done Develop antibodies to the vector 7

8 In vivo Gene therapy Ex vivo Gene Therapy Lysogene MPS IIIA Twelve direct intracerebral injections Phase I trial completed in Europe Preparing phase II/III clinical trial Abeona MPS IIIB Intravenous administration using AAV vector Phase I/II trial MPS IIIA Intravenous administration using AAV vector Phase I/II trial dose escalation study Fondazione Telethon/MeuSix Consortium MPS VI Intravenous administration using AAV vector Phase I/II clinical trial RegenxBio Intrathecal administration using AAV vector MPS I and MPS II Sangamo Intravenous administration using AAV vector ZFN mediated insertion of gene into albumin locus to promote production of endogenous enzyme by the hepatocytes MPS I Insertion of IDUA gene Phase I/II to start in 2018 MPS II Insertion of IDS gene Phase I/II dose escalation trial Two patients have been dosed Orchard Therapeutics MPS IIIA and IIIB Autologous ex vivo lentiviral hematopoietic stem cell gene therapy Pre clinical data suggests normalization of HS levels in the brain and peripheral organs, as well as correction of neurological disease tx.com/2017/11/license mps iiib/ Patient/family/provider resources Final Thoughts National MPS Society Clinical trials information NIH Genetics home reference MPS is a progressive and debilitating disorder Currently available therapies are more effective at preventing progression than reversing existing disease/damage Clinical suspicion is key to early recognition and referral for treatment! 8