Treatment of mucopolysaccharidosis II with recombinant human iduronate-2-sulfatase (IDS)
Inventors
Pakola, Stephen Joseph • Falabella, Paulo • NEVORET, Marie-Laure
Assignees
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Publication Number
US-11986515-B2
Publication Date
2024-05-21
Expiration Date
Abstract
Compositions and methods are described for the delivery of recombinant human iduronate-2-sulfatase (IDS) produced by human neuronal or glial cells to the cerebrospinal fluid of the central nervous system (CNS) of a human subject diagnosed with mucopolysaccharidosis II (MPS II).
Core Innovation
The patent describes treating mucopolysaccharidosis II (MPS II) in a human subject by delivering an effective amount of an active human iduronate-2-sulfatase (hIDS) to the central nervous system (CNS). It uses the biomarker D2S6 measured in a biological sample to diagnose MPS II and to assess treatment response after CNS delivery. The method includes calculating a ratio of D2S6 to total heparan sulfate disaccharides (HS), where the total HS comprises disaccharides D2S6, D0A0, D0S0, and D0A6.
The patent further relates monitoring to biomarker trends and includes measuring D2S6 and heparan sulfate (HS) disaccharides in biological samples such as CSF/serum/urine, along with I2S enzyme activity and anti-AAV and anti-IDS antibodies. The monitoring is used in conjunction with response criteria framed by D2S6 levels and D2S6-to-total-HS ratio calculations to indicate diagnostic status and treatment response, including guidance related to discontinuation of ERT and longer-term monitoring.
Claims Coverage
The independent claims cover three inventive aspects: (i) a diagnostic-and-treatment method using D2S6 and a D2S6/total HS ratio to decide diagnosis and guide CNS hIDS delivery; (ii) a treatment method measuring D2S6 after delivering active hIDS; and (iii) a treatment method comparing pre- and post-delivery CSF D2S6 in the same subject. Across these independent claims, the primary inventive feature is CNS delivery of active hIDS combined with D2S6 measurement frameworks for diagnosing and/or assessing response.
D2S6-based diagnosis and CNS hIDS delivery with a D2S6/total HS ratio
Measuring the level of D2S6 present in a biological sample, diagnosing MPS II when the level of D2S6 is higher than a reference, and delivering an effective amount of an active human iduronate-2-sulfatase (hIDS) to the CNS, further comprising calculating a ratio of D2S6 to total heparan sulfate disaccharides (total HS) in the biological sample, wherein the total HS comprises disaccharides D2S6, D0A0, D0S0, and D0A6.
Post-delivery D2S6 measurement after CNS hIDS delivery
Delivering an effective amount of an active human iduronate-2-sulfatase (hIDS) to the CNS of the human subject diagnosed with MPS II and measuring the level of D2S6 present in a biological sample obtained from the human subject after the active hIDS has been delivered to the CNS.
Pre- and post-delivery CSF D2S6 comparison for CNS hIDS treatment
Delivering an effective amount of an active human iduronate-2-sulfatase (hIDS) to the CNS of the human subject diagnosed with MPS II and measuring the level of D2S6 in a biological sample obtained from the human subject, wherein the method comprises measuring the level of D2S6 present in a first biological sample obtained from the human subject before delivering the active hIDS and measuring the level of D2S6 present in a second biological sample obtained from the human subject after delivering the active hIDS, and wherein the first and second biological samples are obtained from the cerebrospinal fluid (CSF) of the human subject.
Overall, the independent claims require CNS delivery of active hIDS in MPS II and integrate D2S6-based measurement frameworks, including a D2S6-to-total-HS ratio (with D0A0, D0S0, and D0A6 defining total HS) and/or paired pre- and post-delivery measurement of CSF D2S6 to support diagnosis and assessment of response.
Stated Advantages
Provides criteria for diagnosing MPS II based on whether the level of D2S6 is higher than a reference.
Supports treatment evaluation by measuring D2S6 after delivering active hIDS to the CNS.
Allows response assessment using paired pre-delivery and post-delivery D2S6 measurements from cerebrospinal fluid (CSF).
Documented Applications
Treating mucopolysaccharidosis II (MPS II) in a human subject by delivering an effective amount of active hIDS to the CNS and using D2S6 measurement in biological samples, including CSF, for diagnosis and post-delivery monitoring.
Clinical trial and nonclinical supporting data described for an AAV9-based gene therapy construct (Construct 1 (AAV9.CB7.hIDS)) in mucopolysaccharidosis II (MPS II), including safety monitoring and pharmacodynamic efficacy assessments using D2S6 and related biomarkers in CSF/plasma/urine, plus neurocognitive/auditory outcomes and exploratory immunogenicity measures.
Clinical management framework for switching from enzyme replacement therapy (ERT) to recombinant vector therapy, using biomarker and hepatosplenomegaly trends and antibody criteria, with post-discontinuation monitoring and possible re-initiation of ERT if biomarkers/hepatosplenomegaly worsen.
Monitoring and evaluation using D2S6 activity in cerebrospinal fluid (CSF) and additional endpoints including neurocognitive/neurodegeneration assessments (e.g., BSID-III, IQ/DQ subtests), sleep/breathing measures, maladaptive behavior/toileting, and physical changes.
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