- Email: [email protected]
Evaluation of the long-term treatment effects of idursulfase using statistical modelling: Data from the Hunter Outcome Survey (HOS)
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
selectively activate the engineered B cells into long-lived plasma cells that produce a large quantity of IDUA enzyme. Transplantation of this engineered plasma cells into an IDUA deficient mouse model will result in sustainable enzyme secretion into the circulation for systemic cross-correction of IDUA deficiency. This novel strategy will generate long-lived plasma cells that provide sustainable IDUA enzyme for a potential cell-based enzymotherapy for MPS I disorder. This engineering strategy has many potential applications for treating various enzymopathies.
doi:10.1016/j.ymgme.2018.12.258
243 Evaluation of PPS treatment in osteoclast-osteoblast imbalance using in vitro models of Gaucher disease Juan M. Muccia, Constanza Bondara, Andrea Crivaroa, Maximiliano Ormazabala, Edward Schuchmanb, Calogera Simonarob, Paula Rozenfelda, aInstitute of Immunological and Physiopathological Studies, La Plata, Argentina, bIchan School of Medicine at Mount Sinai, New York, NY, United States Gaucher disease (GD) is caused by mutations in the gene encoding for the lysosomal enzyme glucocerebrosidase. Bone alterations are the most disabling condition in Type I GD (GD1) patients and remain a chronic issue in spite of enzyme replacement therapy. Mechanisms leading to bone damage are poorly understood, but previous reports suggest that both osteoblasts and osteoclasts are involved. In the last years, several works have been published in relation to cartilage and bone pathology in mucopolysaccharidoses where inflammation was shown to be a key factor in pathogenesis. A compound called pentosan polysulphate (PPS) was proposed as therapy in MPS models and showed marked improvements in clinical behavior. In the present study we analyzed the effect of PPS treatment on osteoclast differentiation and osteoblast activity using in vitro models of GD. PPS treatment reduced osteoclast differentiation from GD patient PBMCs. Supernatants from two in vitro models of GD osteoblasts (MC3T3) and osteocytes (MLO-Y4) with CBE were obtained in the presence or absence of PPS. When osteoclast precursors were cultured in the presence of these supernatants, the PPS supernatants induced less osteoclast differentiation. Osteoblast activity was also improved by PPS treatment in these in vitro models. In addition, mineral deposition was increased in PPS treated osteoblasts. Our results suggest that PPS should be considered as an alternative treatment for bone implications in GD.
doi:10.1016/j.ymgme.2018.12.259
244 Neurodevelopmental status and adaptive behavior of pediatric patients with Hunter syndrome: A longitudinal observational study a
b
c
Joseph Muenzer , Barbara K. Burton , Paul Harmatz , Hernan Amartinod, Simon A. Jonese, Luis González Gutiérrez-Solanaf, Matilde Ruiz-Garciag, Yuna Wuh, David Alexanderianh, aUniversity of North Carolina Chapel Hill, Chapel Hill, NC, United States, bAnn & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States, cUCSF
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Benioff Children’s Hospital Oakland, Oakland, CA, United States, d Hospital Universitario Austral, Buenos Aires, Argentina, eSt Mary’s Hospital, Manchester, United Kingdom, fInfant Jesus Children’s Hospital, Madrid, Spain, gNational Institute of Pediatrics, Mexico City, Mexico, h Shire, Lexington, MA, United States Two-thirds of patients with mucopolysaccharidosis type II (MPS II Hunter syndrome), a rare lysosomal disease characterized by iduronate-2-sulfatase deficiency, have cognitive impairment. This observational, prospective, longitudinal study (NCT01822184) assessed cognitive status and adaptive behavior in patients aged 2 −b18 years with MPS II patients with a General Conceptual Ability (GCA) score b55 measured by the Differential Abilities Scales-II (DAS-II) were excluded. Patients received IV idursulfase as standardof-care throughout. Cognitive ability (DAS-II) and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II]) assessments were performed at baseline, and 3-month intervals for up to 24 months. Of 55 enrolled patients (mean [SD] age: 5.60 [3.316] years), 32 discontinued (25 to enroll in a phase II/III-treatment study). Mean DAS-II GCA (n=44) and VABS-II Adaptive Behavior Composite (ABC) scores (n=53) at baseline were 78.4 (19.11) and 83.7 (14.22), respectively. Mean changes from baseline at months 12 and 24 were −0.9 (9.39) and −3.8 (12.71), respectively, for DAS-II GCA score (n=27/n=20) and −2.4 (7.64) and −2.0 (8.07) for VABS-II ABC score (n=29/n=21). Changes in GCA scores over time varied widely in individual patients, with some experiencing rapid declines in cognitive ability. Differences in the least-squares mean (LSM) changes from baseline in DAS-II GCA scores between patients with baseline GCA scores of ≤70 (low cognitive function n=18) and N70 (n=26) were −2.4 (p=0.5657) at month 12 and −7.4 (p=0.1461) at month 24. Similarly, for VABS-II ABC scores, differences in LSM changes from baseline between the GCA subgroups (≤70/N70) were −1.9 (p=0.5545) at month 12 and 0.3 (p=0.9484) at month 24. Overall, cognitive ability and adaptive behavior in the pediatric MPS II population who completed this study remained relatively stable over 24 months. However, some patients experienced a rapid decline in cognitive ability, while others retained stable, but impaired, cognitive function. Shire funded this study and medical writing support.
doi:10.1016/j.ymgme.2018.12.260
245 Evaluation of the long-term treatment effects of idursulfase using statistical modelling: Data from the Hunter Outcome Survey (HOS) Joseph Muenzera, Barbara K. Burtonb, Paul Harmatzc, Jaco Bothad, Christoph Kampmanne, aUniversity of North Carolina Chapel Hill, Chapel Hill, NC, United States, bAnn & Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, United States, cUCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States, dShire, Zug, Switzerland, e Johannes-Gutenberg University, Mainz, Germany Treatment for mucopolysaccharidosis type II (MPS II Hunter syndrome) is available in the form of intravenous enzyme replacement therapy (ERT) with idursulfase (Shire, Lexington, MA, USA). This analysis used statistical modelling to evaluate the long-term treatment effects of idursulfase on selected clinical parameters based on data from HOS, a global, observational registry (Shire, Lexington, MA, USA). Mixed modelling was used to analyse data from male
S104
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
patients followed prospectively in HOS who had received idursulfase for 5-8 years and information available for two or more timepoints, of which one was pre-ERT. Data were excluded from patients with only pre-ERT information available, who had received a bone marrow transplant or had enrolled in an idursulfase clinical trial. Age at and time since ERT start were included as covariates and results were modelled for up to 8 years of treatment. For the prediction of percent-predicted forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and the 6-minute walk test (6MWT), only data from patients aged ≥5 years and without cognitive impairment were used. A sensitivity analysis assessed robustness of the model using information from patients with data for five or more timepoints. The main model indicated a decrease over time in urinary glycosaminoglycan levels and palpable liver size. Left ventricular mass index was stable for up to 8 years of treatment while there was a slight decrease in percent-predicted FVC and FEV1 and a gradual increase in distance walked in the 6MWT. Similar results were observed in the sensitivity analysis, indicating that this model provides reliable estimates. The nature of this analysis means that these findings are descriptive only. However, our results support those of previous studies and indicate that idursulfase has a positive effect on somatic manifestations of MPS II. Shire sponsors HOS and funds medical writing support.
doi:10.1016/j.ymgme.2018.12.261
246 Characteristics of patients with mucopolysaccharidosis type II who have received a bone marrow transplant: Data from the Hunter Outcome Survey Joseph Muenzera, Barbara K. Burtonb, Christoph Kampmannc, Jaco Bothad, Simon A. Jonese, aUniversity of North Carolina Chapel Hill, Chapel Hill, NC, United States, bAnn & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States, cJohannes-Gutenberg University, Mainz, Germany, dShire, Zug, Switzerland, eSt Mary's Hospital, Manchester University NHS Foundation Trust, University of Manchester, Manchester, United Kingdom Mucopolysaccharidosis type II (MPS II Hunter syndrome) is a rare, life-limiting, X-linked lysosomal storage disease. The Hunter Outcome Survey (HOS) is a Shire-sponsored, global, observational registry initiated in 2005 that collects real-world data on the natural history of MPS II and long-term treatment with enzyme replacement therapy (ERT) with idursulfase. Patients receiving other forms of pharmacological ERT are excluded from HOS but individuals who have received a bone marrow transplant (BMT) may be enrolled. This analysis examined the characteristics of 36 male patients in HOS from Europe and North America who had received a BMT (March 2018 data). In total, 22 patients (61.1%) were European and 14 (38.9%) were North American. Twenty-seven patients (75%) were followed prospectively in HOS 9 (25%) were enrolled after their death (followed retrospectively). Median (10th percentile, 90th percentile) ages at symptom onset, diagnosis and last visit were 0.8 (0.1, 3.0) years (n=26), 2.5 (0.8, 5.0) years (n=35) and 15.2 (4.9, 28.4) years (n=27), respectively patients were aged 2.6 (0.7, 4.5) years at BMT (n=10). Fourteen patients (38.9%) had received at least one idursulfase infusion, 16 (44.4%) had not received idursulfase idursulfase treatment status was unknown for six patients (16.7%). Of seven patients with data available on the relative timing of idursulfase treatment and BMT, six started idursulfase before BMT
and one started idursulfase after BMT. Median time between idursulfase start and BMT was 3.5 (−173.5, 24.3) months (n=7). Cognitive impairment at any time was reported for 21 patients (58.3% n=36). In total, 13/36 patients died median age at death was 8.8 (3.4, 17.6) years. The most common cause of death was graft versus host disease/transplant complications (n=4) followed by respiratory failure (n=3). These long-term data from HOS provide valuable information on patients with MPS II undergoing BMT. Shire sponsors HOS and funds medical writing support. doi:10.1016/j.ymgme.2018.12.262
247 CHAMPIONS: A phase 1/2 clinical trial with dose escalation of SB913 ZFN-mediated in vivo human genome editing for treatment of MPS II (Hunter syndrome) Joseph Muenzera, Carlos E. Pradab, Barbara Burtonc, Heather A. Laud, Can Ficicioglue, Cheryl Wong Po Foof, Sagar A. Vaidyaf, Chester B. Whitleyg, Paul Harmatzh, aUniversity of North Carolina, Chapel Hill, Chapel Hill, NC, United States, bCincinnati Children’s Hospital Medical Center, Cinncinati, OH, United States, cLurie Children’s Hospital, Chicago, IL, United States, dNYU Langone Medical Center, New York, NY, United States, eChildren’s Hospital of Philadelphia, Philadelphia, PA, United States, fSangamo Therapeutics, Richmond, CA, United States, gUniversity of Minnesota, Minneapolis, MN, United States, hUCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States. Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, progressive, X-linked genetic disorder that is caused by mutations in the human IDS gene and is characterized by deficient activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). Without functional IDS activity, the glycosaminoglycans (GAG), dermatan sulfate and heparan sulfate, accumulate in the body and lead to widespread tissue and organ damage. Patients with MPS II develop progressive respiratory and cardiac disease, skeletal abnormalities and in the severe form, cognitive decline and early death, despite treatment with enzyme replacement therapy. SB-913 is a new type of investigational treatment for MPS II. SB-913 uses zinc finger nuclease (ZFN)-mediated in vivo genome editing to insert a normal copy of the IDS transgene into liver cells, delivered via AAV2/ 6 vectors. The precision and specificity of SB-913 allows for integration at a targeted genomic location and is intended to reduce GAG accumulation with lifelong continuous endogenous production of IDS. CHAMPIONS is an ongoing Phase 1/2 clinical trial to determine if dose escalation of SB-913 is safe and tolerable in patients with MPS II, and is the first trial to attempt in vivo genome editing in humans. CHAMPIONS is a multicenter, open-label, dose escalation study with one-time peripheral intravenous infusion of SB-913, followed by three years of observation. Six adult subjects with attenuated MPS II have received SB-913, with two subjects in each of three dose cohorts (5e12 vg/kg, 1e13 vg/kg, and 5e13 vg/kg). The infusions were generally well-tolerated and no serious adverse events related to the study drug were reported at any dose with up to 10 months of exposure. No persistent transaminitis was observed. Additional analysis of the trial data is ongoing and will be presented as available. These results support further development of SB-913 for the treatment of MPS II. doi:10.1016/j.ymgme.2018.12.263
selectively activate the engineered B cells into long-lived plasma cells that produce a large quantity of IDUA enzyme. Transplantation of this engineered plasma cells into an IDUA deficient mouse model will result in sustainable enzyme secretion into the circulation for systemic cross-correction of IDUA deficiency. This novel strategy will generate long-lived plasma cells that provide sustainable IDUA enzyme for a potential cell-based enzymotherapy for MPS I disorder. This engineering strategy has many potential applications for treating various enzymopathies.
doi:10.1016/j.ymgme.2018.12.258
243 Evaluation of PPS treatment in osteoclast-osteoblast imbalance using in vitro models of Gaucher disease Juan M. Muccia, Constanza Bondara, Andrea Crivaroa, Maximiliano Ormazabala, Edward Schuchmanb, Calogera Simonarob, Paula Rozenfelda, aInstitute of Immunological and Physiopathological Studies, La Plata, Argentina, bIchan School of Medicine at Mount Sinai, New York, NY, United States Gaucher disease (GD) is caused by mutations in the gene encoding for the lysosomal enzyme glucocerebrosidase. Bone alterations are the most disabling condition in Type I GD (GD1) patients and remain a chronic issue in spite of enzyme replacement therapy. Mechanisms leading to bone damage are poorly understood, but previous reports suggest that both osteoblasts and osteoclasts are involved. In the last years, several works have been published in relation to cartilage and bone pathology in mucopolysaccharidoses where inflammation was shown to be a key factor in pathogenesis. A compound called pentosan polysulphate (PPS) was proposed as therapy in MPS models and showed marked improvements in clinical behavior. In the present study we analyzed the effect of PPS treatment on osteoclast differentiation and osteoblast activity using in vitro models of GD. PPS treatment reduced osteoclast differentiation from GD patient PBMCs. Supernatants from two in vitro models of GD osteoblasts (MC3T3) and osteocytes (MLO-Y4) with CBE were obtained in the presence or absence of PPS. When osteoclast precursors were cultured in the presence of these supernatants, the PPS supernatants induced less osteoclast differentiation. Osteoblast activity was also improved by PPS treatment in these in vitro models. In addition, mineral deposition was increased in PPS treated osteoblasts. Our results suggest that PPS should be considered as an alternative treatment for bone implications in GD.
doi:10.1016/j.ymgme.2018.12.259
244 Neurodevelopmental status and adaptive behavior of pediatric patients with Hunter syndrome: A longitudinal observational study a
b
c
Joseph Muenzer , Barbara K. Burton , Paul Harmatz , Hernan Amartinod, Simon A. Jonese, Luis González Gutiérrez-Solanaf, Matilde Ruiz-Garciag, Yuna Wuh, David Alexanderianh, aUniversity of North Carolina Chapel Hill, Chapel Hill, NC, United States, bAnn & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States, cUCSF
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Benioff Children’s Hospital Oakland, Oakland, CA, United States, d Hospital Universitario Austral, Buenos Aires, Argentina, eSt Mary’s Hospital, Manchester, United Kingdom, fInfant Jesus Children’s Hospital, Madrid, Spain, gNational Institute of Pediatrics, Mexico City, Mexico, h Shire, Lexington, MA, United States Two-thirds of patients with mucopolysaccharidosis type II (MPS II Hunter syndrome), a rare lysosomal disease characterized by iduronate-2-sulfatase deficiency, have cognitive impairment. This observational, prospective, longitudinal study (NCT01822184) assessed cognitive status and adaptive behavior in patients aged 2 −b18 years with MPS II patients with a General Conceptual Ability (GCA) score b55 measured by the Differential Abilities Scales-II (DAS-II) were excluded. Patients received IV idursulfase as standardof-care throughout. Cognitive ability (DAS-II) and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II]) assessments were performed at baseline, and 3-month intervals for up to 24 months. Of 55 enrolled patients (mean [SD] age: 5.60 [3.316] years), 32 discontinued (25 to enroll in a phase II/III-treatment study). Mean DAS-II GCA (n=44) and VABS-II Adaptive Behavior Composite (ABC) scores (n=53) at baseline were 78.4 (19.11) and 83.7 (14.22), respectively. Mean changes from baseline at months 12 and 24 were −0.9 (9.39) and −3.8 (12.71), respectively, for DAS-II GCA score (n=27/n=20) and −2.4 (7.64) and −2.0 (8.07) for VABS-II ABC score (n=29/n=21). Changes in GCA scores over time varied widely in individual patients, with some experiencing rapid declines in cognitive ability. Differences in the least-squares mean (LSM) changes from baseline in DAS-II GCA scores between patients with baseline GCA scores of ≤70 (low cognitive function n=18) and N70 (n=26) were −2.4 (p=0.5657) at month 12 and −7.4 (p=0.1461) at month 24. Similarly, for VABS-II ABC scores, differences in LSM changes from baseline between the GCA subgroups (≤70/N70) were −1.9 (p=0.5545) at month 12 and 0.3 (p=0.9484) at month 24. Overall, cognitive ability and adaptive behavior in the pediatric MPS II population who completed this study remained relatively stable over 24 months. However, some patients experienced a rapid decline in cognitive ability, while others retained stable, but impaired, cognitive function. Shire funded this study and medical writing support.
doi:10.1016/j.ymgme.2018.12.260
245 Evaluation of the long-term treatment effects of idursulfase using statistical modelling: Data from the Hunter Outcome Survey (HOS) Joseph Muenzera, Barbara K. Burtonb, Paul Harmatzc, Jaco Bothad, Christoph Kampmanne, aUniversity of North Carolina Chapel Hill, Chapel Hill, NC, United States, bAnn & Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, United States, cUCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States, dShire, Zug, Switzerland, e Johannes-Gutenberg University, Mainz, Germany Treatment for mucopolysaccharidosis type II (MPS II Hunter syndrome) is available in the form of intravenous enzyme replacement therapy (ERT) with idursulfase (Shire, Lexington, MA, USA). This analysis used statistical modelling to evaluate the long-term treatment effects of idursulfase on selected clinical parameters based on data from HOS, a global, observational registry (Shire, Lexington, MA, USA). Mixed modelling was used to analyse data from male
S104
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
patients followed prospectively in HOS who had received idursulfase for 5-8 years and information available for two or more timepoints, of which one was pre-ERT. Data were excluded from patients with only pre-ERT information available, who had received a bone marrow transplant or had enrolled in an idursulfase clinical trial. Age at and time since ERT start were included as covariates and results were modelled for up to 8 years of treatment. For the prediction of percent-predicted forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and the 6-minute walk test (6MWT), only data from patients aged ≥5 years and without cognitive impairment were used. A sensitivity analysis assessed robustness of the model using information from patients with data for five or more timepoints. The main model indicated a decrease over time in urinary glycosaminoglycan levels and palpable liver size. Left ventricular mass index was stable for up to 8 years of treatment while there was a slight decrease in percent-predicted FVC and FEV1 and a gradual increase in distance walked in the 6MWT. Similar results were observed in the sensitivity analysis, indicating that this model provides reliable estimates. The nature of this analysis means that these findings are descriptive only. However, our results support those of previous studies and indicate that idursulfase has a positive effect on somatic manifestations of MPS II. Shire sponsors HOS and funds medical writing support.
doi:10.1016/j.ymgme.2018.12.261
246 Characteristics of patients with mucopolysaccharidosis type II who have received a bone marrow transplant: Data from the Hunter Outcome Survey Joseph Muenzera, Barbara K. Burtonb, Christoph Kampmannc, Jaco Bothad, Simon A. Jonese, aUniversity of North Carolina Chapel Hill, Chapel Hill, NC, United States, bAnn & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States, cJohannes-Gutenberg University, Mainz, Germany, dShire, Zug, Switzerland, eSt Mary's Hospital, Manchester University NHS Foundation Trust, University of Manchester, Manchester, United Kingdom Mucopolysaccharidosis type II (MPS II Hunter syndrome) is a rare, life-limiting, X-linked lysosomal storage disease. The Hunter Outcome Survey (HOS) is a Shire-sponsored, global, observational registry initiated in 2005 that collects real-world data on the natural history of MPS II and long-term treatment with enzyme replacement therapy (ERT) with idursulfase. Patients receiving other forms of pharmacological ERT are excluded from HOS but individuals who have received a bone marrow transplant (BMT) may be enrolled. This analysis examined the characteristics of 36 male patients in HOS from Europe and North America who had received a BMT (March 2018 data). In total, 22 patients (61.1%) were European and 14 (38.9%) were North American. Twenty-seven patients (75%) were followed prospectively in HOS 9 (25%) were enrolled after their death (followed retrospectively). Median (10th percentile, 90th percentile) ages at symptom onset, diagnosis and last visit were 0.8 (0.1, 3.0) years (n=26), 2.5 (0.8, 5.0) years (n=35) and 15.2 (4.9, 28.4) years (n=27), respectively patients were aged 2.6 (0.7, 4.5) years at BMT (n=10). Fourteen patients (38.9%) had received at least one idursulfase infusion, 16 (44.4%) had not received idursulfase idursulfase treatment status was unknown for six patients (16.7%). Of seven patients with data available on the relative timing of idursulfase treatment and BMT, six started idursulfase before BMT
and one started idursulfase after BMT. Median time between idursulfase start and BMT was 3.5 (−173.5, 24.3) months (n=7). Cognitive impairment at any time was reported for 21 patients (58.3% n=36). In total, 13/36 patients died median age at death was 8.8 (3.4, 17.6) years. The most common cause of death was graft versus host disease/transplant complications (n=4) followed by respiratory failure (n=3). These long-term data from HOS provide valuable information on patients with MPS II undergoing BMT. Shire sponsors HOS and funds medical writing support. doi:10.1016/j.ymgme.2018.12.262
247 CHAMPIONS: A phase 1/2 clinical trial with dose escalation of SB913 ZFN-mediated in vivo human genome editing for treatment of MPS II (Hunter syndrome) Joseph Muenzera, Carlos E. Pradab, Barbara Burtonc, Heather A. Laud, Can Ficicioglue, Cheryl Wong Po Foof, Sagar A. Vaidyaf, Chester B. Whitleyg, Paul Harmatzh, aUniversity of North Carolina, Chapel Hill, Chapel Hill, NC, United States, bCincinnati Children’s Hospital Medical Center, Cinncinati, OH, United States, cLurie Children’s Hospital, Chicago, IL, United States, dNYU Langone Medical Center, New York, NY, United States, eChildren’s Hospital of Philadelphia, Philadelphia, PA, United States, fSangamo Therapeutics, Richmond, CA, United States, gUniversity of Minnesota, Minneapolis, MN, United States, hUCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States. Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, progressive, X-linked genetic disorder that is caused by mutations in the human IDS gene and is characterized by deficient activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). Without functional IDS activity, the glycosaminoglycans (GAG), dermatan sulfate and heparan sulfate, accumulate in the body and lead to widespread tissue and organ damage. Patients with MPS II develop progressive respiratory and cardiac disease, skeletal abnormalities and in the severe form, cognitive decline and early death, despite treatment with enzyme replacement therapy. SB-913 is a new type of investigational treatment for MPS II. SB-913 uses zinc finger nuclease (ZFN)-mediated in vivo genome editing to insert a normal copy of the IDS transgene into liver cells, delivered via AAV2/ 6 vectors. The precision and specificity of SB-913 allows for integration at a targeted genomic location and is intended to reduce GAG accumulation with lifelong continuous endogenous production of IDS. CHAMPIONS is an ongoing Phase 1/2 clinical trial to determine if dose escalation of SB-913 is safe and tolerable in patients with MPS II, and is the first trial to attempt in vivo genome editing in humans. CHAMPIONS is a multicenter, open-label, dose escalation study with one-time peripheral intravenous infusion of SB-913, followed by three years of observation. Six adult subjects with attenuated MPS II have received SB-913, with two subjects in each of three dose cohorts (5e12 vg/kg, 1e13 vg/kg, and 5e13 vg/kg). The infusions were generally well-tolerated and no serious adverse events related to the study drug were reported at any dose with up to 10 months of exposure. No persistent transaminitis was observed. Additional analysis of the trial data is ongoing and will be presented as available. These results support further development of SB-913 for the treatment of MPS II. doi:10.1016/j.ymgme.2018.12.263