AA AAV9. 9. L LAM AMP-2B R 2B Reverses M Metabol olic a and Ph Physiologic Mu Multiorgan Dy Dysfunc uncti tion n in n a Mur urine ne Mo Model el of Da Dano non Di Disease Ana Maria Manso, Emily Gault, Sherin Hashem, Bradley Nelson, Elizza Villarruel, Pavan Battiprolu, Annahita Keravala, Yusu Gu, Nancy Dalton, Kirk Hammond, Kirk Peterson, Eric Adler UC UCSD School ool of of Medicine
Di Disclosur ure Informa mati tion Ana Maria Manso is a consultant for Rocket Pharmaceuticals. • Pavan Battiprolu and Annahita Keravala are employees of Rocket Pharmaceuticals • Eric Adler is a shareholder of Rocket Pharmaceuticals. •
Da Dano non Di Disease: : Clini nical Mani nifestati tions ns • Lethal X-linked disorder caused by mutations in the LAMP-2 ) gene, a Lys ysosomal Asso ssociated Mem embrane Pro rotein 2 ( LA lysosomal pr protein cr criti tical fo for au autophag agy . • Ca Cardi diomyopa path thy, sk skeletal my myopathy, an and in intelle llectual al di disabi bility ty. • Other less prevalent symptoms include retinal disease, hepatic disease, and pulmonary disease. cardiomyopathy that • Patients develop se severe hy hypertrophic ca progresses to heart failure • Mo Most pa pati tients ts di die in in the their 20 20-30 30s wit without he heart tr trans nspl plantati tion • Affected males have the most severe phenotype, some heterozygous females will also show evidence of disease.
Autop Au ophagy gy Danon Di Da Disease LAMP-2 LAMP-2 LAMP-2 LC3 II LC3 II LC3 II LC3 II LC3 II LC3 II LC3 II LC3II LC3 II Impa Impaired ed au autophag agosome-ly lysosome fu fusio ion im impair airs au autophag agy flu flux in in Da Danon di disea ease e
LA LAMP-2 i 2 isof ofor orms Chi et al., 2018 LA LAMP-2B 2B is s the predominant iso soform expresse ssed in ca cardiomyocytesan and has as been postula lated to be cr critical in the pathogenesis of Da Danondi disea ease. e.
Aim: Evaluate the efficacy y of gene therapy y with adeno- as associa iated d vir viral al 9 (AA 9 (AAV9-LA LAMP-2B 2B) v ) vector or i in a a m mou ouse mo mode del of Da Dano non dis diseas ase.
AA AAV9-LA LAMP-2B 2B treatment in in LA LAMP-2 KO KO mice study 12 weeks √ 24 weeks √
Ad Administration on of of AA AAV9. 9.LAM AMP2B 2B showed ed dos ose-de depe pende ndent expr pressio ion n of mR mRNA NA and and human human LAMP-2B 2B pr protein in in in he hear art tis issue ue from m LA LAMP2 KO KO mice together with an improvement in aut autophag phagic ic fl flux (L (LC3 C3 II II level els) 24 24 weeks pos ost-inj injectio ion LAMP-2 LC3 II LC3 II LC3 II LC3 II LC3 II LC3 II LC3II * P <0.05, ** P <0.01, *** P <0.001, **** P <0.001 vs WT # P <0.05, ## P <0.01, ### P <0.001 vs PBS ^ P <0.05, ^^^^ P <0.001 vs 1e13
AA AAV9. 9.LAM AMP-2B 2B administration on was assoc ociated with an improvement in the accumulation on of of aut autophag phagic ic st structures in hearts of LA LAMP-2 2 KO KO mice.
Ca Cardiac con ontractility and relaxation on were also o improved in a dos ose-de depe pende ndent manne manner in in the he AA AAV9. 9.LAM AMP2B 2B trea eated ed LA LAMP2 KO KO mice compared to PBS controls 24 24 weeks pos ost-inj injectio ion Ca Cardiac Co Contractility Ca Cardiac Relaxation ** P <0.01, *** P <0.001, **** P <0.001 vs WT # P <0.05, ## P <0.01, ### P <0.001 vs PBS
Ad Administration on of of AA AAV9. 9.LAM AMP-2B 2B showed dos ose-de depe pende ndent expr pressio ion n of mR mRNA NA and and human human LA LAMP-2B 2B prot otein in liver tissue fr from om LA LAMP-2 2 KO KO mice together with an improvement in aut autophag phagic ic fl flux (L (LC3 C3 II levels) # P <0.05 vs PBS ** P <0.01, vs WT
AA AAV9. 9.LAM AMP2B 2B administration on was assoc ociated ed with an improvem emen ent in the e accumulation on of of aut autophag phagic ic st structures in livers of LA LAMP-2 2 KO KO mice.
AA AAV9. 9.LAM AMP-2B 2B administration on was assoc ociated with an improvement in the serum levels of of AL ALP and AL ALT in LA LAMP-2 2 KO KO mice. Al Alkaline phos osphatase Al Alanine am amin inotran ansferas ase ** P <0.01, **** P <0.001 vs WT # P <0.05, ## P <0.01, #### P <0.0001 vs PBS
Ad Administration on of of AA AAV9. 9.LAM AMP-2B 2B showed dos ose-de depe pende ndent expr pressio ion n of human human LAMP-2B 2B prot otein in sk skeletal musc scle tissu ssue fr from om LA LAMP-2 2 KO KO mice together with an improvement in aut autophag phagic ic fl flux (L (LC3 C3 II levels) * P <0.05 , ** P <0.01 vs WT # P <0.05, ## P <0.01 vs PBS
AA AAV9. 9.LAM AMP-2B 2B administration on was assoc ociated with an improvement in the accumulation on of of aut autophag phagic ic st structures in sk skeletal musc scle of LA LAMP-2 2 KO KO mice.
Su Summary • Administration of AAV9.LAMP-2B showed dose-dependent expression of human LAMP-2B transcript and protein in heart, liver and skeletal muscle. • AAV9.LAMP-2B administration was associated with an improvement in autophagic flux (LC3 II levels) as well as in the accumulation of autophagic structures in all three tissue. • Cardiac function as well as hepatic damage were also improved in the AAV9.LAMP-2B treated LAMP-2 KO mice compared to PBS controls • Concl clusion: Th These da data in indic icate th that AA AAV9.LAM LAMP-2B ge gene tr transfer im improves th the me metabolic an and ph physiologic mu multi tiorgan dysfunct ction in in th the mo mouse mo model of of Da Danon di disease an and de demons nstrate pe persistent tr treatme tment effect cts up up to to 6-mo month ths po post inject ction, in indic icatin ing th the dur durabi bility of of th the th therapy.
Acknowledgments Dr. Eric Adler Emily Gault Elizza Villarruel Yusu Gu Paul Bushway Angel Soto-Hermida Chao Chen Sherin Hashem Bradly Nelson Michela Brambatti Pavan Battiprolu Annahita Keravala Jonathan Schwartz Gaurav Shah H. S. Lopez Family Foundation founded by Czarina and Humberto S. Lopez
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