Session: Musculo-skeletal Diseases II Hematopoietic Stem Cell Gene Therapy Corrects Neuromuscular Manifestations in Preclinical Study of Pompe Mice Niek van Til, PhD AVROBIO, Cambridge, MA USA May 14, 2020 Exhibit 99.1
Pompe Program Team 3/25/2020 NSG Study What’s Important Now Monthly Report Niek van Til is an employee of AVROBIO.
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Pompe is a lysosomal and glycogen storage disease Rare, progressive, often fatal neuromuscular disorder POMPE DISEASE Mutations in the acid alpha-glucosidase (GAA) gene resulting in deficient enzyme activity Leads to accumulation of glycogen in tissues and organs, predominantly in muscles Manifests as a spectrum of symptoms and rates of progression across patients of different ages Infantile form (<1% GAA activity) Extreme muscle weakness, “floppy” appearance, enlarged heart, typically die before 1 year Late / delayed onset form (2-40% GAA activity) Weakness of leg and hip muscles, become wheelchair-bound and ventilator-dependent, premature death The standard of care is enzyme replacement therapy Lysosome Normal muscle cell Pompe disease (GAA mutation) Affected lysosomes Affected muscle cells Over time Low acid α-glucosidase function Glycogen storage disorder Lysosome & organelle dysfunction Broad inflammation, muscle atrophy Cytoplasmic glycogen Sources: van der Ploeg, Lancet, 2008 Muscle cell Muscle fiber Patient images courtesy of the patients/their families.
Pompe lentiviral gene therapy program advancing Integrated three-part approach GILT: Glycosylation-Independent Lysosomal Targeting Sources: Burton B et al, J Pediatr, 2017; Ausems M et al, Eur J Hum Genet, 1999; Gungor D et al, Orphanet J Rare Dis, 2011; Maga JA et al, J of Bio Chem, 2013; Bartelink, Lancet Haematol, 2016. THE CHALLENGE Pompe requires 20x more ERT than Fabry or Gaucher Requires GAA activity restored to muscle and CNS AVROBIO’s APPROACH Potent transgene promoter GILT uptake tag Bu90-TDM for CNS impact mg Glycogen / g wet tissue 2 4 6 8 10 12 Dose mg/kg 0 5 10 15 20 HEART GILT-rhGAA rhGAA mg Glycogen / g wet tissue 2 4 6 8 10 12 Dose mg/kg 0 5 10 15 20 DIAPHRAGM GILT-rhGAA rhGAA GILT-tagged Recombinant Human (rh)GAA impacts levels of stored glycogen compared to non GILT-tagged Recombinant Human (rh)GAA in a Pompe mouse model
Intravenous injection Lentiviral Vector Containing Gene of Interest Transduced Lin-hematopoietic stem cells HSC gene therapy in Pompe mice Enrichment of Lin- hematopoietic stem cells DONOR MOUSE Femur/Tibia RECIPIENT MOUSE Irradiation or Busulfan conditioning Isolation of bone marrow cells Transduction of hematopoietic stem cells Lin- cell 4 months follow-up Sources: Douillard-Guilloux G et al, J Gene Med, 2009; van Til et al, Blood, 2010; Stok M et al, Mol. Ther. Meth. Clin. Dev, 2020 in press.
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. GAA GILT mutant v1 GILT mutant v2 GILT mutant v3 GILT + tag v1 GILT + tag v2 GILT mutant v4 GFP GILT mutant v1a GILT + tag v1a GILT + tag v2a GILT LTR LTR pr Transgene 2984 2985 2986 2987 2988 3007 2977R 2989 3005 3006 2983 Group number: 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy 7.5Gy Conditioning: 9Gy Busulfan Array of lentiviral vectors tested in vitro and in vivo
High GAA enzyme activity in vitro In vitro Intracellular Secreted HAP1 GAA KO
Urine Hex4: Week 16 Peripheral blood WBCs: Week 16 WT KO 2984 Bu NT NT Bu NS * * 7.5 9Gy * P<0.05 *** P<0.0001 2984 Bu *** * * High GAA enzyme activity and therapeutic response in vivo Therapeutically relevant urine Hex4 biomarker response in treated Pompe mice ** ** ** ***
Vector copy number (<5) optimized for clinical use KO Bu Bu WT GFP groups 2984 7.5 9 Gy Bone marrow cells GAA
GAA enzyme activity Wild type Glycogen KO Bu NT WT NT 2984 Bu 7.5 P<0.0001 9 Gy GAA 2983 2984 Diseased GILT and GILT mutant v1 reduce glycogen by >99% in heart GAA * P<0.01 ** P<0.001
Diaphragm Gastrocnemius ** P<0.01 *** P<0.001 GILT and GILT mutant v1 significantly reduce glycogen in clinically relevant skeletal muscles * ***
11% WT KO 2984 Bu NT NT Bu 7.5 9 Gy NS *** *** Glycogen and GILT and GILT mutant v1 similar to wildtype mice GILT tag is essential for glycogen clearance in CNS and PNS GAA enzyme activity: Cerebrum WT GAA KO 2984 2983 Cerebrum *** P<0.001 Spinal cord <1% GAA 2983 2985 2986 2987 2988 3007 3006 2989 Glycogen
Plasma samples KO Bu NT WT NT 2984 Bu 7.5 9 Gy Blood Glucose (mg/dL) R2 = 0.8409 P <0.0001 GAA Activity (nmols/mL/hr) GILT and GILT mutant v1 do not impact plasma glucose levels GAA protein concentration approximately 300-fold lower than ERT GAA Protein (µg/1.5 mL) GAA protein/mL mouse plasma
Conclusions Clinical development plan is underway 1 2 3 4 Glycogen was significantly cleared in clinically relevant tissues including heart, CNS and skeletal muscles of Pompe mice GILT tag is essential for efficient clearance of glycogen in CNS IND-enabling studies are advancing
Acknowledgements Preclinical Program Team Hannover Medical School Other Collaborators Yildirim Dogan Cecilia Barese Zeenath Unnisa Swaroopa Guda Rena Schindler John Yoon Abhishek Chiyyeadu Bianling Liu Mary Jacobs Claudia Fiorini Vicky Chen Daniel Ivanov Mark DeAndrade Robert Plasschaert Maurine Braun Christine Oborski Daniella Pizzurro Richard Pfeifer Claudia Harper Chris Mason Julie Kerner Betsy Bogard Diana Clarke Cristin O’Rourke Lisamarie Fahy Gabe Cohn Josie Yang Dani Sweeney Jose Gomez Ramesh Arjunji Alayna Tress Fernanda Copeland Mirjam Trame Leslie Jacobsen Manufacturing Robert Kutner Mike Kelly Axel Schambach National Institutes of Health (NIH) Nina Raben BioMarin Jon LeBowitz AVROBIO Pompe Team The research team gratefully acknowledges the contributions and support of the Canadian Pompe community.