Taysha Gene Therapies, Inc. · NASDAQ:TSHA
Taysha Gene Therapies — Investor Presentation (April 2021)
103 slides from Taysha Gene Therapies's investor presentation, Apr 14, 2021
Slide 1: Bringing New Cures to Life: Corporate Presentation April 2021
Exhibit 99.1 Bringing New Cures to Life Corporate Presentation April 2021
Slide 2: Legal Disclosure: Forward Looking Statements
Legal Disclosure FORWARD LOOKING STATEMENTS This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operation
Slide 3: Focus on AAV-based gene therapies for CNS disorders
Driven by a relentless focus on discovering, developing, and commercializing novel AAV-based gene therapies for devastating disorders of the central nervous system 3
Slide 4: Taysha Summary Overview
Taysha Summary Overview – First in human clinical data for TSHA-101 in GM2 gangliosidosis in 2H 2021 – Additional clinical data for TSHA-120 in GAN in 2H 2021 Multiple product candidates with anticipated – Open IND for TSHA-118 in CLN1 disease; initiation of Phase 1/2 trial in 2H 2021 near-term cata
Slide 5: Leadership team uniquely positioned to deliver on corporate mission
Leadership team uniquely positioned to deliver on corporate mission Leadership Advisors RA Session II Steven Gray, PhD Founder, President & CEO Chief Scientific Advisor Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Berge Minassian, MD Chief Medical Officer and Head of R&D Chief Medical Advisor Kamran
Slide 6: Scientific Advisory Board
Scientific Advisory Board of preeminent international scientific and clinical thought leaders in gene therapy, CNS diseases and drug discovery and development Scientific Advisory Board University of Utah Registry of Autism and Developmental Deborah Bilder, MD Disabilities (URADD); Utah Regional Educ
Slide 7: Taysha by the numbers
Taysha by the numbers 500,000+ 1 1 4 26 pivotal-stage program programs in US+EU patients IND/CTAs expected differentiated further diversifying development with addressable through strategic partnership to be submitted by portfolio options to acquire an current pipeline with a world class the end of
Slide 8: Diverse pipeline focused exclusively on monogenic disorders of the CNS
Diverse pipeline focused exclusively on monogenic disorders of the central nervous system Neurodevelopmental Neurodegenerative Genetic Disorders Diseases Epilepsies Diseases characterized by the Multi-faceted conditions Disorders characterized by recurrent progressive degeneration of the characteriz
Slide 9: Unparalleled gene therapy pipeline focused on monogenic CNS disorders
Unparalleled gene therapy pipeline focused exclusively on monogenic CNS disorders PROGRAM INDICATION DISCOVERY PRECLINICAL PHASE 1/2 Pivotal GLOBAL COMM. RIGHTS NEURODEGENERATIVE DISEASES TSHA-120 GRT Giant Axonal Neuropathy TSHA-101 GRT GM2 Gangliosidosis Currently open CTA TSHA-118 GRT CLN1 Diseas
Slide 10: Three franchises with potential to address over 500,000 patients
Genetic Epilepsy Our three distinct franchises have the potential to address over 500,000+ patients (US+EU) KCNQ2 37,000 500,000 SLC6A1 Neurodevelopmental 17,000 Additional 2 SLC13A5 Programs 1,900 200,000 Fragile X syndrome 100,000 Angelman Syndrome Neurodegenerative 55,000 Alzheimer’s Prader- ~14M
Slide 11: Strategy focused on rapid clinical and commercial development
Our strategy is focused on rapid clinical and commercial development – We leverage a clinically and commercially proven capsid, manufacturing process, and delivery method – Our strategy is designed to accelerate development timelines and increase the probability of success across our pipeline – Prog
Slide 12: Creating a sustainable business model for gene therapy
Creating a sustainable business model for gene therapy Taysha’s sustainable Traditional chronic dosing One-time dosing gene therapy platform business model business model business model 12
Slide 13: Approach and ability to deliver various payloads
Approach and ability to deliver various payloads Gene Vectorized Regulated Gene Mini-Gene Replacement RNA Replacement Payloads ⎯ Replace gene of interest to treat ⎯ Transgenes designed to ⎯ Regulate expression of a ⎯ Many genes are too large to fit diseases or disorders with express miRNA (small, no
Slide 14: Novel platform technology that powers our research engine
Novel platform technology that powers our research engine Novel AAV Dosing Platform Novel Capsid Identification miRARE Platform ⎯ Potential to facilitate redosing via ⎯ Novel miRNA target panel derived from ⎯ Improves targeted delivery through use vagus nerve high-throughput miRNA profiling and of m
Slide 15: Our strategic partnership with UTSW
Our strategic partnership with UTSW We have access to a world-class team of scientists and cutting-edge technology through an exclusive, worldwide royalty-free license to discover, develop, and commercialize gene therapies led by: – Berge Minassian, MD, Division Chief of Child Neurology – Pediatric
Slide 16: Manufacturing strategy allows flexibility and scalability
Manufacturing strategy allows flexibility and scalability to support broad pipeline ⎯ Support the UTSW viral vector core to ⎯ Establish collaborations with leading ⎯ Build internal manufacturing facility to supply early-phase clinical material CDMO to provide additional capacity for support clinical
Slide 17: Neurodegenerative Disease Franchise
Neurodegenerative Disease Franchise 17
Slide 18: TSHA-120 GAN: Rationale for targeting the GAN gene
TSHA-120 GAN Rationale for targeting the GAN gene Normal Healthy Axon GAN Axon ⎯ Mutations affect production of the protein gigaxonin ⎯ Leads to accumulation of neurofilaments in giant axons causing signal interruption and neurodegeneration ⎯ Genetic changes in the GAN gene have been shown to cause
Slide 19: TSHA-120: Giant axonal neuropathy is a rare inherited genetic disorder
TSHA-120 Giant axonal neuropathy (GAN) is a rare inherited genetic disorder GAN that affects both the central and peripheral nervous systems Progressive ⎯ Rare autosomal recessive disease of the central and Tightly Curled Hair Contractures Scoliosis peripheral nervous systems caused by loss-of-funct
Slide 20: GAN natural history and disease progression
TSHA-120 GAN GAN natural history and disease progression Age 0 5 10 15 20 25 30 35 40 45 50 … Early-onset GAN • Delayed early motor development 0-2 yrs • Tightly curled hair • Unsteady gait, foot deformity 3-8 yrs • Progressive motor weakness • Ataxia and dysarthria 7-9 yrs • Nystagmus (cerebellar),
Slide 21: Maximizing patient access and identification
TSHA-120 Maximizing patient access and identification to GAN address the estimated 2,400 patients in US and EU Earlier diagnosis Increased awareness Genotyping • Educate HCPs on GAN • Partner with genetic testing • Establish newborn phenotypes (early vs. late providers (ex. Invitae and screening ons
Slide 22: Primary efficacy endpoint is the Motor Function Measure (MFM32)
TSHA-120 Primary efficacy endpoint is the Motor Function Measure GAN (MFM32) – a validated quantitative scale ⎯ Validated instrument used in multiple regulatory approvals Examples of tasks ⎯ A 32-item scale for motor function measurement developed for neuromuscular diseases No. Domain Starting Posit
Slide 23: GAN natural history study data as comparator
TSHA-120 GAN natural history study data as a dependable GAN comparator for future studies ⎯ 45 GAN patients (2013-present) ages 3-21 years ⎯ Can be accessed for treatment study ⎯ Will be used as comparator for treatment study 8-point decline ⎯ MFM32 8 point decline annually annually ⎯ MFM32 total sc
Slide 24: TSHA-120 program overview and construct
TSHA-120 GAN TSHA-120 program overview and construct ⎯ Construct invented by Dr. Steven Gray (UTSW) ⎯ AAV9 viral vector with engineered transgene AAV9 capsid encoding the human gigaxonin protein Brain tropism & ⎯ Self-complementary AAV capsid (scAAV) for rapid favorable safety profile activation and
Slide 25: Preclinical data supported intrathecal dosing of TSHA-120
TSHA-120 Preclinical data supported intrathecal GAN dosing of TSHA-120 Comprehensive preclinical results demonstrated: ⎯ Function of gigaxonin demonstrated in vitro and in vivo ⎯ Phenotypic rescue in GAN mice after intrathecal injection, improving motor function and nerve pathology ⎯ No toxicities i
Slide 26: TSHA-120 normalized performance of 18-month-old GAN rodent model
TSHA-120 TSHA-120 normalized performance of 18-month-old GAN GAN rodent knockout model ⎯ Untreated GAN rodents performed significantly worse than heterozygous controls Rotarod Performance ⎯ GAN rodents treated at 16 months old performed significantly better than untreated GAN rodents at Control n=14
Slide 27: TSHA-120 improved pathology of the DRG in GAN KO mice
TSHA-120 TSHA-120 improved pathology of the DRG GAN in the GAN KO mice Normal control GAN KO – vehicle injected GAN KO – AAV9-GAN 27 Bailey, R. et al, 2018, MTMCD
Slide 28: TSHA-120 reduced neuronal inclusions in GAN KO mice
TSHA-120 TSHA-120 improved pathology of the DRG GAN in the GAN KO mice Significant reduction in % neuronal inclusions 28 Bailey, R. et al, 2018, MTMCD
Slide 29: Historic dose escalation clinical trial: first intrathecally-dosed gene therapy
Groundbreaking, historic dose escalation clinical trial – First intrathecally-dosed gene therapy Goals Target Recruitment Target Areas to Transduce • Primary – Safety: clinical and laboratory assessments • 14 subjects injected • Secondary – Efficacy: pathologic, physiologic, • > 5 years old function
Slide 30: TSHA-120 achieved sustained improvement in primary efficacy endpoint
TSHA-120 TSHA-120 achieved sustained improvement in primary GAN efficacy endpoint and was well tolerated at multiple doses ⎯ First successful in-human intrathecal gene transfer ⎯ 14 patients dosed ⎯ Positive efficacy results support a dose-response relationship with TSHA-120 14 14 ⎯ 1.8x10 total vg
Slide 31: Clear arrest of disease progression at therapeutic doses
TSHA-120 Treatment with TSHA-120 resulted in a clear arrest of disease GAN progression at therapeutic doses and long-term durability 14 14 1.8 x 10 total vg 1.2 x 10 total vg ⎯ Arrest of disease progression at therapeutic doses⎯ 6 patients treated for 3+ years supporting long-term durability ⎯ TSHA-
Slide 32: Bayesian analysis confirmed arrest of disease progression
TSHA-120 Additional analysis using Bayesian methodology GAN confirmed arrest of disease progression ⎯ Bayesian analysis ⎯ Enables direct probability statements about any unknown quantity of interest 14 1.8 x 10 total vg ⎯ Enables immediate incorporation of data gathered as the 14 1.2 x 10 total vg t
Slide 33: TSHA-120 halted pre-treatment rate of decline
TSHA-120 TSHA-120 halted patient pre-treatment rate of GAN 14 decline at 1.8x10 total vg dose Bayesian Efficacy Analysis Compared to individual historical data 14 14 Posterior distribution of ���� (1.8 x 10 total vg dose, noninformative prior) Posterior distribution of ���� (1.2 x 10 total vg dose,
Slide 34: Probability of clinically meaningful slowing of disease vs natural history
TSHA-120 Further analyses confirmed nearly 100% probability of clinically GAN meaningful slowing of disease compared to natural history 14 Posterior distribution of ���� (1.8 x 10 total vg dose, flat prior) 2 14 ⎯ Further analyses were conducted to assess the probability of 1.8 x 10 total vg clinica
Slide 35: Anticipated next steps for TSHA-120 by end of 2021
TSHA-120 GAN Anticipated next steps for TSHA-120 by the end of 2021 Complete transfer data from the NIH Request regulatory guidance from EMA and PMDA Initiate manufacturing of commercial-grade GMP material Initiate new clinical sites in US and EU Request an end-of-Phase meeting; Update on regulatory
Slide 36: TSHA-101: GM2 gangliosidosis is a severe neurodegenerative disease
TSHA-101 GM2 gangliosidosis is a severe GM2 gangliosidosis neurodegenerative disease ⎯ GM2 gangliosidosis results from a deficiency in the β- hexosaminidase A (Hex A) enzyme ⎯ Hex A is comprised of 2 subunits encoded by the alpha-subunit, HEXA, coded for by the HEXA gene, and the beta-subunit, HEXB,
Slide 37: Residual Hex A activity determines severity of GM2
TSHA-101 Residual Hex A activity determines GM2 gangliosidosis the severity of GM2 Normal life span ⎯ Small increases in Hex A activity may lead to significant improvements in clinical outcomes and quality of life ⎯ Infantile onset is the most severe form of GM2 ⎯ Infantile forms may die within the
Slide 38: Novel bicistronic vector design for HEXA and HEXB
TSHA-101 Novel bicistronic vector design allows GM2 gangliosidosis consistent expression of HEXA and HEXB genes ⎯ HEXA and HEXB genes are required to produce the subunits of the beta-hexosaminidase A enzyme AAV9 capsid Brain tropism & ⎯ The novel bicistronic vector design enables 1:1 favorable safet
Slide 39: Dose-dependent improvement in survival in mice treated with TSHA-101
TSHA-101 Significant, dose-dependent improvement in GM2 gangliosidosis survival observed in mice treated with TSHA-101 100 Heterozygote/Vehicle (n=6) Knockout/TSHA-101 low dose(n=6) Knockout/TSHA-101 medium dose (n=6) ** * ** **** Knockout/TSHA-101 high dose (n=11) 50 Knockout/Vehicle (n=6) * p-valu
Slide 40: Dose-dependent improvements in rotarod assessments
TSHA-101 Dose-dependent improvements observed in GM2 gangliosidosis rotarod assessments in mice treated with TSHA-101 Heterozygote/Vehicle Knockout/TSHA-101 low dose Knockout/Vehicle Knockout/TSHA-101 medium dose Knockout/TSHA-101 high dose 40
Slide 41: GM2 accumulation significantly reduced after TSHA-101
TSHA-101 GM2 accumulation was significantly reduced in the mid-section GM2 gangliosidosis of the brain following treatment with TSHA-101 after 16 weeks Heterozygote/Vehicle (n=6) Knockout/TSHA-101 low dose (n=6) Knockout/TSHA-101 medium dose (n=6) Knockout/TSHA-101 high dose (n=11) Knockout/Vehicle
Slide 42: Phase 1/2 adaptive trial for TSHA-101 in GM2 gangliosidosis
TSHA-101 Phase 1/2 adaptive trial for TSHA-101 GM2 gangliosidosis in GM2 gangliosidosis • Open-label, single center, Phase 1/2 trial Study design and duration • Patients evaluated for one year, followed by longer-term extension • Age younger than 1 year Patient cohort (n=4) • Pathogenic confirmation
Slide 43: TSHA-118: CLN1 disease is a severe neurodegenerative lysosomal storage disease
TSHA-118 CLN1 disease is a severe neurodegenerative CLN1 disease lysosomal storage disease ⎯ Severe, progressive, neurodegenerative lysosomal storage disease, with no approved treatment AAV9 capsid Brain tropism & ⎯ Caused by mutations in the CLN1 gene, encoding the favorable safety profile soluble
Slide 44: TSHA-118-treated CLN1 KO mice had improved survival
TSHA-118 TSHA-118-treated CLN1 KO mice CLN1 disease had improved survival rates 100 Untreated Het 75 Untreated KO 50 4 week IT TSHA-118 12 week IT TSHA-118 25 0 0 3 6 9 12 15 18 21 24 Age (Months) IT administration of TSHA-118 significantly extended survival of PPT1 KO mice for all ages and at all d
Slide 45: Increased and sustained plasma PPT1 activity
TSHA-118 TSHA-118-treated CLN1 mice had increased CLN1 disease and sustained plasma PPT1 activity WT-Untreated Het-Untreated KO-Untreated TSHA-118 • Supraphysiological levels of active PPT1 were observed in all TSHA-118 treated mice and persisted through the study endpoint • Persistence of effect af
Slide 46: Phase 1/2 adaptive trial for TSHA-118 in CLN1 disease
TSHA-118 Phase 1/2 adaptive trial for CLN1 disease TSHA-118 in CLN1 disease • Open-label, dose finding, adaptive design trial Study design and duration • Patients evaluated for one year, followed by longer-term extension • Infantile and juvenile patients Patient cohort (n=18) • Pathogenic confirmati
Slide 47: TSHA-104: SURF1 deficiency is the most common cause of Leigh syndrome
TSHA-104 SURF1 deficiency is the most SURF1 deficiency common cause of Leigh syndrome – A monogenic mitochondrial disorder – Most common cause of cytochrome c oxidase deficient Leigh syndrome – Leigh syndrome – severe neurological disorder that presents in the first year of life – Initially often pr
Slide 48: TSHA-104 IND or CTA filing expected in 2H 2021
TSHA-104 TSHA-104 IND or CTA filing SURF1 deficiency expected in 2H 2021 – Recombinant AAV9 viral vector with engineered transgene encoding the human SURF1 protein AAV9 capsid Brain tropism & – Designed to deliver a functional copy of the SURF1 gene favorable safety profile – Received orphan drug an
Slide 49: TSHA-104 increased COX1 activity in SURF1 KO mice
TSHA-104 TSHA-104 increased COX1 activity in brain and muscle and restored elevation of SURF1 deficiency blood lactate on exhaustive exercise in dose-dependent manner in SURF1 KO mice 2 2 Change of blood lactate after exhaustive Change in relative COX1 activity running 9∆ lactate 10 months 1.5 1.5 M
Slide 50: TSHA-104 MR spectroscopy analysis
TSHA-104 TSHA-104 MR spectroscopy analysis – Reduction in SURF1 deficiency choline levels reflective of reduction in brain inflammation CHO/CR+pCR Amplitude 5 4 3 2 1 0 WT KO+Vehicle KO+Low KO+High 50
Slide 51: Phase 1/2 trial for TSHA-104 in SURF1 deficiency
TSHA-104 SURF1 deficiency Phase 1/2 trial for TSHA-104 in SURF1 deficiency • Open-label, single center, Phase 1/2 trial Study design and duration • Patients evaluated for one year, followed by longer-term extension • Pathogenic confirmation of mutation in SURF1 gene Patient cohort (n=4) • Patients n
Slide 52: Lafora disease is a progressive and fatal neurodegenerative disorder
Lafora disease is a progressive and fatal TSHA-111 Lafora disease neurodegenerative disorder – Inherited, severe form of progressive myoclonus epilepsy – Caused by loss of function mutations in the EPM2A (laforin) or EPM2B (malin) genes responsible for glycogen metabolism – Absence of laforin or mal
Slide 53: TSHA-111 Lafora disease miRNA approaches
TSHA-111-LAFORIN and TSHA-111-MALIN, TSHA-111 Lafora disease miRNA approaches – Recombinant AAV9 viral vector designed for AAV9 capsid Brain tropism & miRNA-mediated knockdown of the GYS1 gene favorable safety profile – GYS1 knockdown designed to reduce Lafora bodies and improve clinical condition –
Slide 54: TSHA-111 reduced GYS1 expression in KO models
TSHA-111-LAFORIN and TSHA-111-MALIN reduced TSHA-111 Lafora disease GYS1 expression in the laforin and malin KO models laforin knock out model laforin ✱✱✱✱ PBS miRNA 1.0 0.8 GYS1 0.6 GFP 0.4 0.2 SatinFree 0.0 PBS miRNA PBS miRNA malin malin knock out model ✱✱✱ PBS miRNA 1.0 0.8 GYS1 0.6 GFP 0.4 0.2
Slide 55: TSHA-111 decreased Lafora body formation in mice brain
TSHA-111-LAFORIN and TSHA-111-MALIN decreased TSHA-111 Lafora disease Lafora body formation in mice brain Knockdown of GYS1 decreased lafora bodies 8 8 laforin malin *** * 6 6 4 4 2 2 0 0 miRNA PBS miRNA PBS 55 L B % in H i p p o c a m p u s LB % in Hippocampus L B in i p p o c a m p u s LB % in Hip
Slide 56: TSHA-112: Adult polyglucosan body disease (APBD)
TSHA-112 APBD Adult polyglycosan body disease (APBD) ⎯ Caused by a mutation in the GBE1 gene, responsible for the creation of branches during glycogen synthesis ⎯ Reduction in glycogen synthesis yields elongated glycogen changes that form poorly Histopathology soluble aggregates in the liver, muscle
Slide 57: TSHA-112 expected to advance in IND/CTA-enabling studies in 2021
TSHA-112 expected to advance in TSHA-112 APBD IND/CTA-enabling studies in 2021 – Recombinant AAV9 viral vector designed for AAV9 capsid miRNA-mediated knockdown of the GYS1 gene Brain tropism & to treat APBD favorable safety profile – Self-complementary AAV capsid (scAAV) for rapid activation and st
Slide 58: TSHA-112 reduced GYS1 expression in APBD KO model
TSHA-112 reduced GYS1 expression in the TSHA-112 APBD APBD KO model * PBS miRNA 1.0 0.8 GYS1 0.6 GFP 0.4 0.2 SatinFree 0.0 PBS miRNA PBS miRNA Gumusgoz, E. 2020 58 Relative Expression of GYS1
Slide 59: TSHA-112 decreased polyglucosan body formation
TSHA-112 decreased polyglucosan body TSHA-112 APBD formation in mice hippocampus ** 8 6 4 2 0 miRNA PBS TSHA-112 decreased polyglucosan body formation in the hippocampus 59 PB% in Hippocampus PB%inHippocampus
Slide 60: TSHA-119: GM2 gangliosidosis, AB variant
TSHA-119 GM2 AB Variant GM2 gangliosidosis, AB variant – Characterized by a mutation in the GM2A Hex A gene, leading to a deficiency of the GM2- HexA activator protein (GM2AP), a required co- factor for the breakdown of GM2- gangliosides by the protein Hex A HexB – Loss-of-function mutations result
Slide 61: TSHA-119 in preclinical development
TSHA-119 GM2 AB Variant TSHA-119 in preclinical development – Self-complementary AAV9 viral vector for AAV9 capsid rapid activation and stable expression CNS tropism & – Designed to deliver a functional copy of the favorable safety profile GM2A gene – CAG promoter drives high levels of expression –
Slide 62: TSHA-119 caused dose-dependent reduction of GM2 accumulation
TSHA-119 caused a dose-dependent TSHA-119 GM2 AB Variant reduction of GM2 accumulation in mice GM2 Accumulation at 20 Weeks in Midsection of Brain 0.15 ** 0.10 0.05 0.00 62 GM2/Total Gangliosides
Slide 63: TSHA-113: Tauopathies
TSHA-113 Tauopathies Tauopathies – Microtubule associated Protein Tau (MAPT) – Tauopathies are characterized by the accumulation of toxic tau protein in the brain that results in widespread neuronal dysfunction and loss – Tau accumulation is thought to underpin several neurodegenerative diseases, in
Slide 64: TSHA-113 in preclinical development
TSHA-113 Tauopathies TSHA-113 in preclinical development – Self-complementary AAV9 viral vector for rapid AAV9 capsid activation and stable expression CNS tropism & – Utilizes AAV-mediated gene silencing to deliver favorable safety profile life-long reduction of tau protein levels in neurons followi
Slide 65: Primary screen of human tau miRNA candidates
TSHA-113 Tauopathies Primary screen of human tau miRNA candidates Human MAPT Knock-down Secondary screening of top candidates: hTau4i, hTau5i, and hTau7i HumanTau miRNA Candidates Scr = scrambled tau miRNA 65 hTau = human-specific tau miRNA Relative Renilla/Firefly
Slide 66: TSHA-113 reduced K18 tau expression
TSHA-113 Tauopathies TSHA-113 reduced K18 tau expression miRNA Shuttles 66
Slide 67: TSHA-113 demonstrated widespread function and GFP expression
Mice dosed with TSHA-113 demonstrated widespread TSHA-113 Tauopathies function and GFP expression in neurons and glia ** 1.5 1.0 0.5 0.0 67 scAAV9/Tau5i-CBh-GFP Vehicle Relative hMAPT/GAPDH
Slide 68: Additional candidates targeting neurodegenerative diseases
Additional candidates targeting neurodegenerative diseases • miRNA targeting GYS1 to inhibit glycogen synthase in the brain to decrease abnormal glycogen formation TSHA-115 miRNA • This approach may enable the treatment of several glycogen storage disorders GSDs • Identical construct as TSHA-111-LAF
Slide 69: Neurodevelopmental Disorder Franchise
Neurodevelopmental Disorder Franchise 69
Slide 70: TSHA-102: Rett syndrome is one of the most common genetic causes of intellectual disabilities
= TSHA-102 Rett syndrome is one of the most common genetic Rett Syndrome causes of intellectual disabilities in women STAGE I ⎯ Rett Syndrome is caused by mutations in the X-linked 6-18 months (typical) Infants are generally described as MECP2 gene ≤6 months (early) having normal development until D
Slide 71: Rett syndrome is an X-linked neurodevelopmental disorder
TSHA-102 Rett syndrome (RTT) is an X-linked Rett Syndrome neurodevelopmental disorder ⎯ Characterized by mutations in methyl CpG-binding protein 2 (MECP2), a protein that is essential for WT neuronal and synaptic function in the brain. WT WT WT WT ⎯ Female heterozygous RTT patients are mosaic carrie
Slide 72: Development of a gene therapy for Rett syndrome requires regulated MECP2 expression
TSHA-102 Development of a gene therapy for Rett syndrome Rett Syndrome requires regulated expression of MECP2 ⎯ AAV9/MECP2 caused dose-dependent side effects after intraCSF administration in WT and KO mice AAV9 capsid Brain tropism & ⎯ We have developed a novel miRNA-responsive target sequence (miRA
Slide 73: miRARE is a targeting panel for endogenous miRNAs regulating MECP2
TSHA-102 miRARE is a targeting panel for endogenous Rett Syndrome miRNAs which regulate MECP2 expression 73
Slide 74: Safety: TSHA-102 not associated with early death in WT mice
TSHA-102 Safety: Intrathecal TSHA-102 was not Rett Syndrome associated with early death in WT mice 100 80 60 0 vg, n=13 40 Low dose AAV9/MECP2(v2), n=12 Low dose AAV9/mini, n=12 Low dose TSHA-102, n=12 High dose AAV9/MECP2(v2), n=6 20 High dose AAV9/mini, n=8 High dose TSHA-102, n=9 0 15 20 0 5 10 2
Slide 75: Safety: no adverse behavioral side effects in WT mice
TSHA-102 Safety: TSHA-102 did not cause adverse Rett Syndrome behavioral side effects in WT mice 0 vg, n=20 Low dose AAV9/MECP2(v2), n=12 8 Low dose AAV9/mini, n=12 6 Low dose TSHA-102, n=12 High dose AAV9/MECP2(v2), n=10 4 High dose AAV9/mini, n=12 2 High dose TSHA-102, n=9 0 4 8 12 16 20 24 28 32
Slide 76: Efficacy: TSHA-102 outperformed unregulated AAV9/mini in KO mice
TSHA-102 Efficacy: TSHA-102 outperformed unregulated Rett Syndrome AAV9/mini in MECP2 KO mouse survival study 100 80 WT, 0 vg, n=13 60 KO, 0 vg, n=18 40 KO, High dose AAV9/MECP2(v2), n=12 20 KO, High dose AAV9/mini, n=12 KO, High dose TSHA-102, n=12 0 0 5 10 15 20 25 30 35 Age (weeks) Mice were dose
Slide 77: IND/CTA filing for TSHA-102 in Rett syndrome expected 2H 2021
TSHA-102 IND/CTA filing for TSHA-102 in Rett Rett Syndrome syndrome expected in 2H 2021 • Open-label, dose-ranging, randomized, multi-center Phase 1/2 trial Study design and duration• Safety and preliminary efficacy • Each cohort randomized 3:1 (one patient is a delayed treatment control) Key inclus
Slide 78: TSHA-106: Angelman syndrome is a rare neurogenic disorder
TSHA-106 Angelman syndrome is a rare, neurogenic Angelman Syndrome disorder due to genomic imprinting – Caused by a deletion or loss of function of the maternally inherited allele of the UBE3A gene resulting in loss of the UBE3Q protein expression in neurons and abnormal communications between neuro
Slide 79: No approved treatments for Angelman syndrome
TSHA-106 There are currently no approved Angelman Syndrome treatments for Angelman syndrome – Signs and symptoms include developmental delay, severe impairments in behavior, motor function, communication and sleep as well as intellectual disability, debilitating seizures and ataxia – Normal lifespan
Slide 80: TSHA-106 targets UBE3A-ATS transcript through shRNA knock-down
TSHA-106 TSHA-106 for Angelman targets UBE3A- Angelman Syndrome ATS transcript through shRNA knock-down – AAV9 viral vector designed for shRNA-mediated knockdown of UBE3A-ATS, the antisense transcript AAV9 capsid governing the expression of UBE3A through the CNS tropism & favorable safety profile pa
Slide 81: shRNA candidates knock down UBE3A-ATS
TSHA-106 TSHA-106 targets UBE3A-ATS transcript Angelman Syndrome through shRNA knock-down shRNA Candidates 4.0 UBE3A UBE3A-ATS 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Testing in neuroblast cell line demonstrated consistent knockdown of UBE
Slide 82: Additional candidates targeting neurodevelopmental disorders
Additional candidates targeting neurodevelopmental disorders • FMR1 is the most common single gene cause of autism and cognitive impairment TSHA-114 GRT • Fragile X Syndrome is characterized by anxiety, aggression, hyperactivity, attention deficits, Fragile X syndrome and sleep/communication disrupt
Slide 83: Genetic Epilepsy Franchise
Genetic Epilepsy Franchise 83
Slide 84: TSHA-105: SLC13A5 deficiency
TSHA-105 SLC13A5 deficiency results in persistent SLC13A5 deficiency seizures and developmental delays NORMAL SLC13A5 mutation ⎯ Bi-allelic loss of function in the SLC13A5 gene, resulting in a loss or reduction in citrate transport and aberrant cellular metabolism ⎯ Patients have impaired motor func
Slide 85: TSHA-105 currently in IND/CTA-enabling studies
TSHA-105 TSHA-105 currently in IND/CTA- SLC13A5 deficiency enabling studies – Recombinant single-stranded AAV9 AAV9 capsid expressing human SLC13A5 protein under the CNS tropism & control of a single promoter vector design favorable safety profile – Delivered intrathecally – Received orphan drug and
Slide 86: TSHA-105 decreased plasma citrate levels in KO mice
TSHA-105 TSHA-105 decreased plasma citrate SLC13A5 deficiency levels in SLC13A5 KO mice KO Veh 0.8 0.8 KO + AAV9 CSF * 0.6 0.6 ** 0.4 0.4 0.2 0.2 0.0 0.0 WT Months Post-injection KO 86 Bailey, R. 2020 Citrate (mM) Citrate (mM)
Slide 87: TSHA-105 improved EEG activity in KO mice
TSHA-105 TSHA-105 improved EEG activity in SLC13A5 deficiency SLC13A5 KO mice Dark Cycle Dark Cycle WT + Vehicle 0.0262 0.0568 * 30 WT + Vehicle KO + Vehicle KO + Vehicle KO + TSHA-105 IC CS M F 20 KO + TSHA-105 IT 10 KO + TSHA-105 CSF 0 87 Bailey, R. 2020 Spike Trains
Slide 88: TSHA-105 reduced seizure susceptibility in KO mice
TSHA-105 TSHA-105 reduced seizure susceptibility SLC13A5 deficiency in SLC13A5 KO mice TSHA-105 reduced seizure susceptibility in SLC13A5 KO mice 100 75 WT + Vehicle (n=8) 50 KO + Vehicle (n=9) KO + TSHA-105 CSF (n=6) 25 0 0 1 2 3 4 5 6 7 8 PTZ Injection 88 Bailey, R. 2020 Survival (%)
Slide 89: TSHA-103: SLC6A1 haploinsufficiency disorder
TSHA-103 SLC6A1 haploinsufficiency disorder results in SLC6A1 haploinsufficiency disorder persistent seizures and developmental delays ⎯ Autosomal dominant genetic disorder characterized by the loss of function of one copy of the SLC6A1 gene ⎯ SLC6A1 encodes the GABA transporter protein type 1 (GAT1
Slide 90: TSHA-103 in IND/CTA-enabling studies
TSHA-103 SLC6A1 haploinsufficiency disorder TSHA-103 in IND/CTA-enabling studies – Self-complementary AAV9 viral vector designed to deliver AAV9 capsid a functional copy of hSLC6A1 CNS tropism & favorable safety profile – JeT promoter drives ubiquitous expression, clinically validated in GAN – Proof
Slide 91: TSHA-103 improved nesting and EEG activity in KO mouse model
TSHA-103 TSHA-103 improved nesting and EEG SLC6A1 haploinsufficiency disorder activity in SLC6A1 KO mouse model WT + Vehicle Nesting 2 months post-injection SLC6A1 KO Vehicle WT KO Vehicle KO TSHA-103 SLC6A1 KO TSHA-103 91
Slide 92: Deep pipeline of gene therapies targeting genetic epilepsies
Deep pipeline of gene therapies targeting genetic epilepsies • Diminished KCNQ2 function results in seizures in the first week of life, accompanied by TSHA-110 GRT developmental delay involving one or more domains of motor, social, language, or cognition KCNQ2 • Some children may have autistic featu
Slide 93: Platform Technologies
Platform Technologies 93
Slide 94: miRARE targeting panel for endogenous miRNAs
miRARE is a targeting panel for endogenous miRNAs which can regulate various transgenes 94
Slide 95: Approaches to create a miRNA target panel for regulating MECP2
Approaches to create a miRNA target panel for regulating MECP2 expression ⎯ High-throughput screening of mouse CNS miRNAs upregulated after MECP2 gene therapy overdose ⎯ Identify endogenous miRNA targets that are conserved across species and appear frequently among the UTRs of dose-sensitive genes r
Slide 96: Targets annotated across both species for selected 3'UTRs
451 targets annotated across both species for selected 3’UTRs ⎯ Many targets appear frequently among the 3’UTRs of dose-sensitive genes mediating disorders characterized by intellectual disability ⎯ Bounded area: targets appear across ≥ 6 selected 3’UTRs ⎯ Orange data points: corresponding miRNAs ex
Slide 97: Opportunity to achieve human POC for vagus nerve redosing
Opportunity to achieve human POC for vagus nerve redosing Parasympathetic System ⎯ The vagus nerve represents the main component of the autonomic nervous system Constricts pupils ⎯ Direct delivery to the vagus nerve may provide broad Nerve III coverage of the autonomic nervous system and enable Stim
Slide 98: Robust GFP expression in the vagus nerve and nodose ganglia in rats
Robust expression of GFP in the vagus nerve and associated nodose ganglia in rats support redosing via vagus nerve injection Vagus Nerve Nodose Ganglia Study 1 0 4 8 Weeks: Tissue IT Injection: VN Injection: Analysis AAV9/GAN AAV9/GFP Study 2 0 16 20 Weeks: IT Injection: VN Injection: Tissue AAV9/GA
Slide 99: Transduction of brain neurons following redosing via vagus nerve
Successful transduction of relevant brain neurons following redosing via vagus nerve injection Nucleus Ambiguous Medulla Pre-Botzinger Complex 99 Courtesy of Dr. Diane Armao
Slide 100: Vagus nerve injection permits AAV9 redosing
Vagus nerve injection permits AAV9 redosing confirmed in brain slices of AAV9-immunized rats NTS NTS Area Postrema Area Postrema DMN X Sol N lat Sol N med DMN X Sol N lat XII XII AAV9 Pre-immunized Naive 100 Courtesy of Dr. Diane Armao
Slide 101: Vagus nerve injection well-tolerated in hounds
Vagus nerve injection of increasing doses of AAV delivery were well-tolerated in hounds observed over 13 days Post-surgery Afternoon Fecal Output Testing VN Delivery Rates High Mid Low High Mid Post-surgery Vocalization Low High Mid Low Post-mortem vagal nerves and brain were microscopically normal
Slide 102: Machine learning, DNA shuffling and directed evolution for capsid discovery
Utilizing machine learning, DNA shuffling, and directed evolution for capsid discovery ⎯ High-content sequencing of recovered capsid pools Rep Cap ITR ITR Capsid genes of ⎯ Using sequencing data from in vivo selection to feed machine AAV1-6, 8, 9, rh10, + lab variants learning algorithms, for in sil
Slide 103: Focused on achieving anticipated near-term milestones
Focused on achieving anticipated near-term milestones in 2021 and building long-term value 14 GAN clinical program update, including 3.5 x 10 total vg cohort GM2 gangliosidosis preliminary biomarker data in 2H 2021 CLN1 program to dose first patient in 2021 under open IND 4 open IND/CTAs expected by
Taysha Gene Therapies — Investor Presentation (April 2021) on 6ix