Lactate Clearance And Mortality In Cardiogenic Shock: A Systematic Review And Meta-Analysis
HFSA ePoster Library. Stone S. 09/10/21; 343440; 209
Samuel Stone
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Abstract
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Background: Danon disease (DD) is an X-linked disorder characterized by severe cardiomyopathy, cognitive impairment and skeletal myopathy. DD is caused by mutations in the gene encoding for lysosome-associated membrane protein 2 (LAMP2), which is essential for autophagy. Treatment options for DD other than cardiac transplantation are limited and median survival for male patients is approximately 19 years of age.
Methods: This open-label Phase 1 study is designed to evaluate the safety of RP-A501 (AAV9.LAMP2B) in male DD patients (Pts). N=12-24 Pts will receive a single IV infusion of RP-A501. Two dose levels have been administered to date: 6.7 x 1013 GC/kg and 1.1 x 1014 GC/kg. There are two age groups: ≥15 years, 8-14 years. Eligibility criteria include a DD diagnosis with a confirmed LAMP2 mutation and evidence of cardiac involvement.
Results: In Cohort 1 (N=3 Pts, ≥15 years, 6.7 x 1013 GC/kg), RP-A501 treatment increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC). The 2 Pts in Cohort 1 who strictly adhered to the post-rx immunosuppressive regimen had high levels of cardiac LAMP2B expression: 68% and 92% vs. normal control by IHC; up to 61% vs. normal control by WB. In these patients, BNP levels were reduced by 59% and 42% from baseline at 9 and 12 months, respectively). CPK-MB either improved or stabilized. Notably, electron microscopic assessment of autophagic vacuoles within myocardium, a hallmark of DD pathology, showed visible decreases in all Cohort 1 patients. Global longitudinal strain (GLS) demonstrated improvement or stabilization in all Cohort 1 patients following therapy.
Evaluation of two patients who received a higher dose (1.1 x 1014 GC/kg) is ongoing.
Side effects from RP-A501 were manageable. Transaminase elevations were observed and returned to baseline within 2 months. One patient who received the higher dose experienced thrombocytopenia and acute kidney injury requiring transient hemodialysis, attributed to complement activation. With enhanced immunosuppression the patient experienced full recovery.
Conclusions: This first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B transgene expression, and is associated with preliminary evidence of improved cardiac parameters.
Further enrollment and safety/efficacy follow-up of all 5 treated patients are ongoing.
RP-A501 gene therapy is a potentially effective gene therapy treatment for patients with DD.
Methods: This open-label Phase 1 study is designed to evaluate the safety of RP-A501 (AAV9.LAMP2B) in male DD patients (Pts). N=12-24 Pts will receive a single IV infusion of RP-A501. Two dose levels have been administered to date: 6.7 x 1013 GC/kg and 1.1 x 1014 GC/kg. There are two age groups: ≥15 years, 8-14 years. Eligibility criteria include a DD diagnosis with a confirmed LAMP2 mutation and evidence of cardiac involvement.
Results: In Cohort 1 (N=3 Pts, ≥15 years, 6.7 x 1013 GC/kg), RP-A501 treatment increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC). The 2 Pts in Cohort 1 who strictly adhered to the post-rx immunosuppressive regimen had high levels of cardiac LAMP2B expression: 68% and 92% vs. normal control by IHC; up to 61% vs. normal control by WB. In these patients, BNP levels were reduced by 59% and 42% from baseline at 9 and 12 months, respectively). CPK-MB either improved or stabilized. Notably, electron microscopic assessment of autophagic vacuoles within myocardium, a hallmark of DD pathology, showed visible decreases in all Cohort 1 patients. Global longitudinal strain (GLS) demonstrated improvement or stabilization in all Cohort 1 patients following therapy.
Evaluation of two patients who received a higher dose (1.1 x 1014 GC/kg) is ongoing.
Side effects from RP-A501 were manageable. Transaminase elevations were observed and returned to baseline within 2 months. One patient who received the higher dose experienced thrombocytopenia and acute kidney injury requiring transient hemodialysis, attributed to complement activation. With enhanced immunosuppression the patient experienced full recovery.
Conclusions: This first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B transgene expression, and is associated with preliminary evidence of improved cardiac parameters.
Further enrollment and safety/efficacy follow-up of all 5 treated patients are ongoing.
RP-A501 gene therapy is a potentially effective gene therapy treatment for patients with DD.
Background: Danon disease (DD) is an X-linked disorder characterized by severe cardiomyopathy, cognitive impairment and skeletal myopathy. DD is caused by mutations in the gene encoding for lysosome-associated membrane protein 2 (LAMP2), which is essential for autophagy. Treatment options for DD other than cardiac transplantation are limited and median survival for male patients is approximately 19 years of age.
Methods: This open-label Phase 1 study is designed to evaluate the safety of RP-A501 (AAV9.LAMP2B) in male DD patients (Pts). N=12-24 Pts will receive a single IV infusion of RP-A501. Two dose levels have been administered to date: 6.7 x 1013 GC/kg and 1.1 x 1014 GC/kg. There are two age groups: ≥15 years, 8-14 years. Eligibility criteria include a DD diagnosis with a confirmed LAMP2 mutation and evidence of cardiac involvement.
Results: In Cohort 1 (N=3 Pts, ≥15 years, 6.7 x 1013 GC/kg), RP-A501 treatment increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC). The 2 Pts in Cohort 1 who strictly adhered to the post-rx immunosuppressive regimen had high levels of cardiac LAMP2B expression: 68% and 92% vs. normal control by IHC; up to 61% vs. normal control by WB. In these patients, BNP levels were reduced by 59% and 42% from baseline at 9 and 12 months, respectively). CPK-MB either improved or stabilized. Notably, electron microscopic assessment of autophagic vacuoles within myocardium, a hallmark of DD pathology, showed visible decreases in all Cohort 1 patients. Global longitudinal strain (GLS) demonstrated improvement or stabilization in all Cohort 1 patients following therapy.
Evaluation of two patients who received a higher dose (1.1 x 1014 GC/kg) is ongoing.
Side effects from RP-A501 were manageable. Transaminase elevations were observed and returned to baseline within 2 months. One patient who received the higher dose experienced thrombocytopenia and acute kidney injury requiring transient hemodialysis, attributed to complement activation. With enhanced immunosuppression the patient experienced full recovery.
Conclusions: This first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B transgene expression, and is associated with preliminary evidence of improved cardiac parameters.
Further enrollment and safety/efficacy follow-up of all 5 treated patients are ongoing.
RP-A501 gene therapy is a potentially effective gene therapy treatment for patients with DD.
Methods: This open-label Phase 1 study is designed to evaluate the safety of RP-A501 (AAV9.LAMP2B) in male DD patients (Pts). N=12-24 Pts will receive a single IV infusion of RP-A501. Two dose levels have been administered to date: 6.7 x 1013 GC/kg and 1.1 x 1014 GC/kg. There are two age groups: ≥15 years, 8-14 years. Eligibility criteria include a DD diagnosis with a confirmed LAMP2 mutation and evidence of cardiac involvement.
Results: In Cohort 1 (N=3 Pts, ≥15 years, 6.7 x 1013 GC/kg), RP-A501 treatment increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC). The 2 Pts in Cohort 1 who strictly adhered to the post-rx immunosuppressive regimen had high levels of cardiac LAMP2B expression: 68% and 92% vs. normal control by IHC; up to 61% vs. normal control by WB. In these patients, BNP levels were reduced by 59% and 42% from baseline at 9 and 12 months, respectively). CPK-MB either improved or stabilized. Notably, electron microscopic assessment of autophagic vacuoles within myocardium, a hallmark of DD pathology, showed visible decreases in all Cohort 1 patients. Global longitudinal strain (GLS) demonstrated improvement or stabilization in all Cohort 1 patients following therapy.
Evaluation of two patients who received a higher dose (1.1 x 1014 GC/kg) is ongoing.
Side effects from RP-A501 were manageable. Transaminase elevations were observed and returned to baseline within 2 months. One patient who received the higher dose experienced thrombocytopenia and acute kidney injury requiring transient hemodialysis, attributed to complement activation. With enhanced immunosuppression the patient experienced full recovery.
Conclusions: This first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B transgene expression, and is associated with preliminary evidence of improved cardiac parameters.
Further enrollment and safety/efficacy follow-up of all 5 treated patients are ongoing.
RP-A501 gene therapy is a potentially effective gene therapy treatment for patients with DD.
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