Sio Gene Therapies Inc (fka SIOX)

[georgejjl]

Phase 1/2 Open-label Dose Evaluation Study of AXO-Lenti-PD Gene Therapy for Parkinson's Disease: Efficacy, Safety, and Tolerability Data up to 24 Months

G Corcoran1 A Karunakara1 E Dumayas1 D Valencia1 E De Boever1 T Foltynie2 R A Barker3 S Palfi4

1: Sio Gene Therapies 2: UCL Institute of Neurology 3: Addenbrooke's Hospital 4: Groupe Hospitalier Henri-Mondor

AXO-Lenti-PD uses a lentiviral vector that includes the three genes required for endogenous dopamine synthesis (TH, CH1 and AADC) and is delivered via one-time direct bilateral infusions into each putamen. Six subjects have been enrolled in 2 cohorts in the Phase 1/2 SUNRISE-PD study (NCT03720418): low-dose (4.2E+6 TU), n?=?2, follow-up 24-months; mid-dose (1.4E+7 TU), n?=?4, follow-up 12-months. AXO-Lenti-PD was generally well-tolerated with no hypersensitivity, immune response or endotoxicity related adverse events. Two subjects experienced 5 serious adverse events, all unrelated to AXO-Lenti-PD. Subjects continued to show improvements from baseline in UPDRS Part III (Motor) OFF: 14-27 points in low-dose subjects at 24-months and 5-23 points in two UPDRS-evaluable mid-dose subjects at 12-months. Changes from baseline in UPDRS Part II (Activities of Daily Living) OFF of 8-19 points in low-dose subjects at 24-months and 0-8 points in two UPDRS-evaluable mid-dose subjects at 12-months were reported. One low-dose subject completed the Hauser diary at 24-months and had an increase from baseline in good ON time (ON without dyskinesia plus ON with non-troublesome dyskinesia) of 2.0 hours and a mean decrease from baseline in OFF time of 0.5 hours. Mid-dose subjects at 12-months reported a mean increase from baseline in good ON time of 1.8 hours and a mean decrease from baseline in OFF time of 2.1 hours. Further evaluation of AXO-Lenti-PD is planned using a higher dose/volume open label cohort followed by a sham-controlled study.


Phase 1/2 Trial of AXO-AAV-GM1 Gene Therapy for the Treatment of Infantile- and Juvenile-onset GM1 Gangliosidosis

C Tifft12 P D'Souza12 J M Johnston12 M T Acosta12 E R Nicoli12 C Rothermel12 A Thurm13 A Karunakara4 B Thorp4 P Ross4 J Jameson4 M Sheehan4 T Vaughn4 D Valencia4 E De Boever4 G Corcoran4

1: National Institutes of Health 2: National Human Genome Research Institute 3: National Institute of Mental Health 4: Sio Gene Therapies Inc.

Data is presented from an ongoing open-label, single-arm, dose-ranging Phase 1/2 trial (NCT03952637) of an investigational gene therapy AXO-AAV-GM1 (AAV9-GLB1) for treatment of GM1 gangliosidosis which is a rare, fatal, neurodegenerative lysosomal storage disorder. Subjects are administered AXO-AAV-GM1 intravenously following immune modulation with rituximab, sirolimus and glucocorticoids. Seven subjects have been enrolled in 2 cohorts: low-dose (1.5x1013 vg/kg), n?=?4 late-infantile-onset and n?=?1 juvenile-onset, follow-up 12-months; high-dose (4.5x1013 vg/kg), n?=?2 juvenile-onset, follow-up 6-months. AXO-AAV-GM1 was generally safe and well-tolerated. There were two serious adverse events unrelated to AXO-AAV-GM1. Six subjects had adverse events of AST or ALT elevations (≤5X above baseline) that did not require clinical intervention or have associated clinical sequelae and no adverse events of elevations in GGT or bilirubin were reported. At 6-months, CSF GM1 ganglioside was reduced to published normal levels and serum ß-gal enzyme activity increased above the lower limit of normal reference levels in the high-dose subjects. At 12-months, the CSF GM1 ganglioside remained below baseline levels in all low-dose subjects and serum ß-gal activity remained above baseline levels in two of five subjects. Volumetric MRI data in low-dose subjects showed maintenance of brain volume in four of five subjects at 12-months. There was no clinical evidence of disease progression in four of five low-dose subjects at 12-months or in the high-dose cohort at 6-months post-treatment as assessed by Vineland-3, Upright/Floor Mobility Score, Clinical Global Impression, and neurological examination. Further evaluation of these subjects is ongoing.


Bicistronic AAV gene therapy for Tay-Sachs and Sandhoff diseases in a sheep model

T Taghian D Fernau K Mercado L Ellis E Diffie A Gross A Maguire A Batista S Bertrand M Otero R Prestigiacomo R Gately J Gallagher H Lahey A Taylor J Koehler D Martin M Sena-Esteves1 H Gray-Edwards

1: University of Massachusetts Medical School 2: Auburn University 3: Tufts Cummings School of Veterinary Medicine

Tay-Sachs and Sandhoff diseases (TSD, SD) are fatal neurodegenerative disorders, caused by mutations in alpha or beta subunit of enzyme Hexosaminidase (Hex), respectively, and result in GM2 ganglioside storage and neuronal death. Here we describe therapeutic efficacy of a bicistronic AAV9 vector construct in naturally occurring sheep model of TSD. TSD sheep were injected with 1E14 vg total intravenously (IV, n?=?5) or via cerebrospinal fluid (CSF, n?=?9). Sheep treated IV survived to 18?±?5 months and CSF treated sheep are ongoing with the oldest now more than 3 years old. Untreated TSD sheep reach humane endpoint at ~9 months. GM2 levels in CSF of sheep treated by CSF administration were normalized starting at 1 month after treatment and remained in normal range up to 2 years, however, GM2 levels in IV cohort remained above normal. CSF treatment resulted in HexA activity at above normal levels in central nervous system (CNS), however, for IV cohort only lumbar spinal cord reached normal level. HexA expression in peripheral nervous system (PNS) was similar for both cohorts. GM2 levels in CNS and PNS were in line with HexA levels. Vector genome content in CNS was consistent with HexA levels, however, IV treatment except for optic nerve resulted in higher number of virus particles in PNS. Magnetic resonance spectroscopy of treated sheep thalamus showed normalization of neuronal health markers, myelination and metabolism in CSF cohort and slight improvements in IV cohort. Both cohorts exhibited marked attenuation of neurologic disease and normal cognition in neurological examination.


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