#1TAYSHA IGENE THERAPIES Bringing New Cures to Life Roadshow Presentation September 2020#2Legal 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 operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words "anticipate," "believe," "estimate," "expect," "intend," "may." "might," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. 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T#3Offering Summary Issuer Ticker/ Exchange Base Offering Size Overallotment option Filing range Use of proceeds Bookrunners Manager Expected pricing Lock up Taysha Gene Therapies, Inc. TSHA / Nasdaq Global Market 6,578,950 shares (~$125 million gross proceeds based on midpoint of the range, 100% primary) 986,842 shares (100% primary, 15% of base deal) $18.00-$20.00 per share Fund discovery and IND-enabling activities, manufacturing and quality control testing for the clinical programs and preclinical programs in the IND-enabling stage in the pipeline Clinical trial, regulatory and medical activities for TSHA-101, TSHA-102, TSHA-103, TSHA-104 and TSHA-118 Establishment of an in-house manufacturing facility A portion of the proceeds of the remaining net proceeds may also be used to in-license, acquire or invest in complementary businesses, technologies, products or assets The remainder for working capital and other general corporate purposes Goldman Sachs & Co. LLC, Morgan Stanley, Jefferies Chardan September 23, 2020 180 days for the Company's directors, executive officers and substantially all existing security holders 3#41011 11 F. 101011 Driven by a relentless focus on discovering, developing, and commercializing novel AAV-based gene therapies for devastating disorders of the central nervous system#5Taysha Investment Highlights Multiple product candidates with anticipated near- term catalysts to enhance value Portfolio of 18 CNS gene therapy programs across 3 distinct franchises UT Southwestern Gene Therapy Program strategic alliance Validated capsid, manufacturing system and route of delivery Proven management team and investor syndicate Gene therapy for GM2-Gangliosidosis anticipated to enter clinical studies later this year Gene therapy for CLN1 received approval for IND; anticipated to dose first patient in 2021 Four INDS expected to be submitted by the end of 2021; along with several product candidates in IND-enabling studies Current pipeline of 18 AAV gene therapy programs with options to acquire an additional 4 programs Portfolio addressing over 500,000 patients (US+EU) across monogenic CNS diseases, including neurodegenerative diseases, neurodevelopmental disorders, and genetic epilepsies Led by Drs. Steven Gray and Berge Minassian; established to accelerate R&D, with integration of translational research, clinical development and GMP manufacturing Exclusive access to resources, expertise, and novel technology platforms for delivery and dosing of gene therapies Clinically and commercially proven AAV9 vector platform Highly scalable suspension HEK293 manufacturing process with excellent yield Intrathecal route of administration enables direct targeting to the CNS with validated biodistribution and safety Deep expertise in the development of gene therapies for rare diseases Key leadership team members and investors previously led the development and commercialization of Zolgensma", the first FDA-approved gene therapy for CNS disease 5#61 differentiated strategic partnership with a world class academic institution Taysha by the numbers 8888 4 INDs expected to be submitted by the end of 2021 Ţ 18 programs in development with options to acquire an additional 4 programs 500,000+ US+EU patients addressable through current pipeline programs#7Diverse pipeline focused exclusively on monogenic disorders of the central nervous system Neurodegenerative Diseases Diseases characterized by the progressive degeneration of the structures and function of the CNS and PNS Neurodevelopmental Disorders Multi-faceted conditions characterized by impairments in cognition, behavior, and motor function T Genetic Epilepsies Disorders characterized by recurrent seizures often leading to abnormal development of the brain 7#8Unparalleled gene therapy pipeline focused exclusively on monogenic CNS disorders PROGRAM NEURODEGENERATIVE DISEASES TSHA-101 GRT TSHA-118/ ABO-202 GRT TSHA-104 GRT TSHA-112 GRT/miRNA TSHA-111 GRT/MURNA TSHA-119 MIRNA TSHA-115 mIRNA TSHA-102 Regulated GRT TSHA-106 shANA TSHA-116 shANA TSHA-117 Regulated GRT TSHA-107 GAT TSHA-108 GRT TSHA-109 GAT GENETIC EPILEPSILS TSHA-103 GRT TSHA-105 GRT NEURODEVELOPMENTAL DISORDERS TSHA-110 GAT GM2 Gangliosidosis CLN1 SURF1 Deficiency Lafora Tauopathies GSD INDICATION Rett Syndrome Angelman Syndrome Fragile X Syndrome Prader-Willi Syndrome FOXG1 Syndrome Autism Spectrum Disorder Inborn Error of Metabolism Inherited Metabolism Disorder SLC6A1 SLC13AS KONO DISCOVERY PRECLINICAL PHASE 1/2 CTA submission 2020 Currently open IND IND submission 2021 IND submission 2021 IND submission 2021 PHASE 2/3 GLOBAL COMMERCIAL RIGHTS TAYSHA TAYSHA TAYSHA *Option rights **Taysha has exclusive options to acquire an additional four programs from UT Southwestern GRT: Gene replacement therapy miRNA: microRNA shRNA: short hairpin RNA#9Our three distinct franchises have the potential to address over half a million patients (US+EU) 500,000 Estimated Patient Population (US + EU) SURF1 = 350 Neurodegenerative W CLN1 = 600 wwwwwwww Lafora = 700 APBD = 1000 GSDs = 20,000 Tauppathies¹ = 40,000 FOXGI * 20,000 Neurodevelopmental Rett syndrome = 25,000 Angelman Syndrome = 30,000 Prader-Willi + 40,000 Fragile X syndrome = 96,000 Additional Programs - 200,000 Genetic Epilepsy SLC1345 SLC6A1 = 16,000 KCNQZ = 17,000 TAYSHA ||||| GENE THERAPIES "Tauopathies only include MAPT-FTD, PSP, CBD. In addition, Taysha intends to pursue development of our MAPT program in subpopulations of patients with Alzheimer's Disease Additional programs include TSHA-107, TSHA-108 and TSHA-109#10Our 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 U TAYSHA BIGENE THERAPIES LU AAV9 vector for delivery of therapeutic transgene Demonstrated safety and efficacy across multiple CNS indications Intrathecal (IT) route of administration - Enables direct targeting to CNS Validated biodistribution and safety profile Proven HEK293 Suspension Process Highly scalable and excellent yields Access to GMP capacity at 500L scale, with total capacity up to 600L 10#11B Creating a sustainable business model for gene therapy Traditional chronic dosing model business a # G a a B ^ a ‒‒‒‒‒‒ a One-time dosing business model T Taysha's sustainable gene therapy platform business model ~ T 0 S 8 11#12Leadership team and investor syndicate uniquely positioned to deliver on corporate mission Leadership RA Session II Founder, President & CEO Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer Kamran Alam, CPA, MBA Chief Financial Officer Fred Porter, PhD Chief Technical Officer Mishima Gerhart Chief Regulatory Officer Sean McAuliffe Chief Commercial Officer Jim Rouse Chief Information Officer Emily McGinnis Chief Patient Officer & Head of Government Affairs Dan Janiak, PhD SVP, Corporate Strategy & Business Development Niren Shah, PharmD, MBA VP, Program & Alliance Management and Chief of Staff AUDENTES BIOMARIN SANOFI GENZYME rocket Land gsk & NOVARTIS REATA PTC) bridgebio Steven Gray, PhD Chief Scientific Advisor SANOFI GENZYME PTC) Baxalta REATA REATA NOVARTIS NPS Pharma 10 bridgebio REATA PTC OVATION Mercury Fund NOVARTIS Berge Minassian, MD Chief Medical Advisor Sean Nolan Chairman Paul Manning Phillip Donenberg Advisors RA Session II Sukumar Nagendran, MD UT Southwestern Medical Center. Board of Directors UT Southwestern Medical Center. INTERMUNEREATA PBM CAPITAL AVROBIO REATA TAYSHA 12#13Our 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 neurologist with expertise in neurodegenerative diseases, neurodevelopmental disorders, and genetic forms of epilepsy Discovered MECP2 CNS isoform (Rett syndrome) Steven Gray, PhD, Director of Viral Vector Core, Associate Professor Dept of Peds AAV-based vector engineering expertise and optimizing CNS delivery of transgenes Administered the first AAV9-based therapy to patients via intrathecal route Exclusive access to a flexible, scalable, and well-characterized GMP manufacturing suite that utilizes a suspension HEK293 process - Exclusive access to next generation platform technologies, including novel redosing platform, transgene regulation (miRARE), and capsid development UT Southwestern Medical Center 13#14The Taysha Approach - Leveraging our unique strengths to accelerate the development of novel gene therapies Seamless integration of translational research, GMP manufacturing, clinical development, and commercial capabilities UT Southwestern Medical Center Target identification Translational research Tox material & clinical material IND-enabling studies Clinical scale GMP manufacturing Natural history studies T TAYSHA GENE THERAPIES Commercial scale GMP manufacturing Regulatory activities Clinical development Patient advocacy 14#15Neurodegenerative Disease Franchise F. S 15#16GM2 gangliosidosis is a family of severe neurodegenerative disorders GM2 gangliosidosis results from a deficiency in the B-hexosaminidase A (Hex A) enzyme B-hexosaminidase A enzyme is composed of 2 subunits encoded by the HEXA and HEXB gene, respectively Mutations of the HEXA gene cause Tay-Sachs disease (TSD) while mutations of the HEXB gene cause Sandhoff disease (SD) - The estimated prevalence of GM2 is 350 patients (US+EU) GMZA Cytoplasmic membrane GM2 ganglioside Lysosome with normal HexA F. Release of cleavage products of GM2 for further use by cell DOPO Lysosome with mutant HexA Accumulation of unbroken GM2 in lysosome Effects of HexA mutation Accumulation of membrane cytoplasmatic bodies (lysosomes) containing ganglioside A * • Destruction of neurons Proliferation of microglia Accumulation of complex lipids in macrophages . Hypotension . Inability to sit and hold head Eye movement anomalies Dysphagia . Convulsions Hypomyelinization, etc . Ataxia . Dysarthria Development of dysphagia Progression of hypotension and seizures . Gradual reduction of motor, cerebral and spinocerebellar functions 16#17Residual Hex A activity determines the severity of GM2 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 first 4 years of life, and juvenile onset patients rarely survive beyond mid- teens Infantile (onset < 6 months) - Startle response Hypotonia Cherry-red macula Seizures . Macrocephaly - Progressive visual loss - Death 3-5 years <0.1% F. Juvenile (onset 1.5-5 years) - Cerebellar ataxia Decreased cognition -Progressive weakness Visual loss - Seizures - Death in mid-teens Early adulthood onset - Progressive weakness Cerebellar ataxia - * Normal life span 0.50% 2-4% Residual Hex A Enzyme Activity Psychosis Decreased cognition Age at death variable, normal life span possible 5-10% 17#18Novel bicistronic vector design allows consistent expression of HEXA and HEXB genes HEXA and HEXB genes are required to produce the subunits of the beta-hexosaminidase A enzyme The novel bicistronic vector design enables 1:1 expression of HEXA and HEXB transgenes under the control of a single promoter with a P2A-self- cleaving linker - SD mice received vehicle or varying doses of TSHA-101 after 6 weeks: High dose (2.5x10¹1¹ vg/mouse) Medium dose (1.25x10¹¹ vg/mouse) Low dose (0.625x10¹1 vg/mouse) - Vehicle controls SSAAV ITR F. CAG Drive high levels of gene expression Full copies of hHEXB and hHEXA genes separated by P2A self-cleaving linker hHEXB P2A AAV9 capsid Brain tropism & favorable safety profile * hHEXA SSAAV ITR 18#19Significant, dose-dependent improvement in survival observed in mice treated with TSHA-101 Survival (%) 100 50 0 0 20 40 60 Time (weeks) 80 100 - - Heterozygote/Vehicle (n=6) Knockout/2.5x10¹1 total vg (n=11) Knockout/1.25x10¹1 total vg (n=6) Knockout/0.625x10¹1 total vg (n=6) Knockout/Vehicle (n=6) * p-value=0.0141 p-value=0.0012 **** p-value<0.0001 * 19#20Dose-dependent improvements observed in rotarod assessments in mice treated with TSHA-101 Distance (cm) 3000 2000 1000 8 10 12 14 16 Heterozygote/Vehicle Knockout/2.5x10¹¹ total vg Knockout/1.25x10¹1 total vg 18 20 24 Time (weeks) T 28 32 36 Knockout/0.625x10¹1 total vg Knockout/Vehicle 40 44 7 48 52 * 20#21GM2 accumulation was significantly reduced in the mid-section of the brain following treatment with TSHA-101 after 16 weeks GM2 / GD1a N Treatment Type Heterozygote/Vehicle (n=6) Knockout/2.5x10¹¹ total vg (n=11) Knockout/1.25x10¹¹ total vg (n=6) Knockout/0.625x10¹¹ total vg (n=6) Knockout/Vehicle (n=6) **** p-value<0.0001 * p-value=0.0179, 0.0295 * 21#22TSHA-101 for the treatment of GM2 Gangliosidosis to enter clinic by end of 2020 Study design and duration Patient cohort (n=4) Intervention Key clinical assessments Key biomarker assessments . . • • . Open-label, single center, Phase 1/2 trial Patients evaluated for "one year, followed by longer-term extension Age younger than 1 (inclusive) Pathogenic confirmation of mutation in HEXA or HEXB gene Patients not on ventilator support Single total dose of 5x1014 vg of AAV9/HEXB-P2A-HEXA Delivered intrathecally Safety and tolerability Gross motor and fine motor milestones Bayley score, CHOP-INTEND Bulbar function/vocalization Respiratory function Seizure frequency/medications QOL and caretaker burden assessments Hex A enzyme in CSF and serum GM2 accumulation in CSF LDH/AST in CSF MRI changes T * 22#23CLN1 is a severe neurodegenerative lysosomal storage disease Severe, progressive, neurodegenerative lysosomal storage disease, with no approved treatment Caused by mutations in the CLN1 gene, encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) - The absence of PPT1 leads to the accumulation of palmitoylated substrate within the lysosome Disease onset is typically within 6-24 months, with progression visual failure, cognitive decline, loss of fine and gross motor skills, seizures, and death usually occurring by 7 years of age The estimated prevalence of CLN1 disease is 600 patients (US+EU) - Currently an open IND for this program Enables rapid onset and stable expression SCAAV ITR F. CBh Drive high levels of gene expression Full copy of hCLN1 gene hCLNI * AAV9 capsid Brain tropism & favorable safety profile SCAAV ITR Enables rapid onset and stable expression 23#24Survival of PPT1 KO mice after IT delivery of TSHA-118/ ABO-202 Percent Survival 100 75 50 25 0 3 6 I I I | 1 11 1 9 12 Age (Months) 15 + 18 21 24 1 1 1 1 IT administration of TSHA-118 significantly extended survival of PPT1 KO mice for all ages and at all dose levels Untreated Het * Untreated KO 4 week IT 7x10¹1 vg/mouse 12 week IT 7x10¹¹ vg/mouse#25TSHA-118/ ABO-202 increases plasma PPT1 Activity in CLN1 mice 105 104 10³ 10² 10¹ <10⁰ Het KO Untreated WT Het Time Post-Treatment: 1.5 to 8.5 months 4 20 26 Treatment Age (weeks) WT-Untreated Het-untreated KO-untreated IT 7x10¹¹ vg/mouse PPT1 enzyme activity was measured in serum at selected timepoints following TSHA-118 delivery by IT administration at 4, 20, or 26 weeks of age Supraphysiological levels of active PPT1 were observed in all TSHA-118 treated mice and persisted through the study endpoint T * 25#26Deep pipeline of gene therapies targeting neurodegenerative diseases TSHA-104 GRT SURF1 Deficiency IND-enabling studies TSHA-112 GRT/miRNA APBD Preclinical TSHA-111 GRT/miRNA LaFora Preclinical TSHA-113 miRNA Tauopathies Preclinical TSHA-115 miRNA GSDs Preclinical SURF1 protein implicated in mitochondrial translation and assembly of cytochrome C oxidase complex; most frequent cause of Leigh syndrome Patients develop difficulty in swallowing and subsequent failure to thrive. Death ensues through respiratory failure by approximately age 10 Estimated prevalence of 300 patients in the US and EU GBE1 is responsible for the creation of branches during glycogen synthesis and a reduction yields elongated glycogen changes that form poorly soluble aggregates Prime of life disease, with onset between 40-50 years; patients have sensory loss in the legs, progressive muscle weakness, gait disturbances, and cognitive impairment Estimated prevalence of 1,000 patients in the US and EU • EPM2A and EPM2B genes are involved in forming of glycogen metabolism, and without the proteins, poorly branched Lafora bodies aggregate Adolescents typically present with myoclonus, progressive dementia, refractory epilepsy, cerebellar ataxia and respiratory failure, and generally results in death within about a decade Estimated prevalence of 700 patients in the US and EU Tau accumulation is thought to underpin several neurodegenerative diseases, including Alzheimer's, frontotemporal dementia, and parkinsonism linked to chromosome 17 We are employing tau-specific miRNA shuttles that have been designed to target mRNA for all six isoforms of tau found in the human brain and/or mouse brain Estimated prevalence of 40,000 patients in the US and EU miRNA targeting GYS1 to inhibit glycogen synthase in the brain to decrease abnormal glycogen formation This approach may enable the treatment of several glycogen storage disorders Estimated prevalence of 20,000 patients in the US and EU * 26#27Neurodevelopmental Disorder Franchise F. 27#28Rett syndrome is one of the most common genetic causes of intellectual disabilities in women Rett Syndrome is caused by mutations in the X-linked MECP2 gene MeCP2 regulates the expression of many genes involved in normal brain function A brief period of normal development is followed by a devastating loss of speech and purposeful hand use along with the emergence breathing abnormalities Disease reversibility described in animal models as demonstrated by Sir Adrian Bird¹ The estimated prevalence of Rett syndrome is 25,000 patients in the US and EU 1. Guy J et al. Science 2007 = || & STAGE I 6-18 months (typical) 36 months (early) Developmental Arrest Symptom Onset STAGE II 1-4 years Rapid Deterioration Symptom progression-regression STAGE III 4-10 years Pseudo stationary Symptoms stabilize/improve 00 Infants are generally described as having normal development until approximately 6 to 18 months of age Hallmark Rett symptoms appear: Hand wringing or squeeze, clapping. rubbing, washing, or hand to mouth movements After a period of rapid deterioration neurological symptoms stabilize, with some even showing slight improvements STAGE IV >10 years Late Motor Deterioration Muscle wasting that worsens with age wasting with age 85-90% of affected people may experience growth failure and muscle 28#29Rett syndrome (RTT) is an X-linked neurodevelopmental disorder Characterized by mutations in methyl CpG-binding protein 2 (MeCP2), a protein that is essential for neuronal and synaptic function in the brain. Female heterozygous RTT patients are mosaic carriers of normal and mutated MECP2 RTT falls along a spectrum of MeCP2 activity and toxicity from gene therapies is linked to unregulated expression of MECP2 MECP2 expression must be regulated to correct the deficiency, while avoiding toxicity associated with overexpression T Skewed inactivation loss WT mosaicism WT WT WT WT normal (WT) WT WT WT WT WT WT Skewed inactivation overexpression 00 29#30Development of a gene therapy for Rett syndrome requires regulated expression of MECP2 AAV9/MECP2 caused dose-dependent side effects after intraCSF administration in WT and KO mice We have developed a novel miRNA-responsive target sequence (miRARE) that regulates the expression of the MECP2 transgene Our approach provides a superior therapeutic profile to that of competitor unregulated MECP2 gene replacement Enables rapid onset and stable expression SCAAV ITR MP426 miniMECP2 gene with miRARE panel to regulate MECP2 expression miniMECP2 Fragment of the endogenous MECP2 promoter that mimics cell-specificity of MECP2 AAV9 capsid Brain tropism & favorable safety profile miRARE 00 SCAAV ITR Enables rapid onset and stable expression 30#31miRARE is a targeting panel for endogenous miRNAs which regulate MECP2 expression 1 Viral genome in nucleus 2 mRNA in cytoplasm MECP2 Translation and nuclear localization 3 miRNA-responsive target sequence in untranslated region 5 Mature miRNAS bind to mRNA in cytoplasm to regulate its expression MECP2 In this conceptual loop, the 3'UTR features targets for miRNAs. The viral genome does not encode miRNAs. F. mature miRNA miRNA expression MECP2 drives expression of many endogenous miRNAs 00 31#32miRARE tightly regulated expression of miniMeCP2-myc protein in mice WT ID# T25.85 WT ID# T27.110 NeuN DAPI NeuN DAPI Control: 1E11 vg PHP. B/MeP426- miniMECP2-myc-RDH1pA myc videspread physiologically representative merge MID myc SUB merge CTX CA1 TH CAS WT ID# T26.96 WT ID# T26.99 T NeuN DAPI NeuN DAPI 1E11 vg PHP.B/MeP426-miniMECP2- myc-(miRARE)-RDH1pA myc my visible at higher magnif merge myc myc visible at higher magnification merge CA1-3, regions of hippocampus; CTX, cortex; MID, midbrain; SUB, subiculum; TH, thalamus. Gain settings for experimental images were matched to those of control images. 00 32#33At higher magnification, expression was detectable in miRARE-treated mice PHP.B/mini PHP.B/mini-miRARE NeuN DAPI NeuN DAPI Thalamus myc mèrge myc merge Hippocampus NeuN DAPI NeuN DAPI myc merge myc merge NeuN T DAPI NeuN DAPI Brain Stem myc merge myc merge MECP2 expression is controlled with miRARE constructs compared to unregulated miniMECP2 00 33#34Safety: Intrathecal TSHA-102 was not associated with early death in WT mice % Survival 100 80 60 40 20 0 0 0 vg, n=13 1x10¹1 vg AAV9/mini, n=12 1x10¹2 vg AAV9/MECP2(v2), n=6 1x10¹2 vg TSHA-102, n=9 5 10 15 Diamond = vet-requested euthanasia for prolapse or bullying-related injury 20 1x10¹¹ vg AAV9/MECP2(v2), n=12 1x10¹¹ vg TSHA-102, n=12 1x10¹2 AAV9/mini, n=8 Age (weeks) Mice were dosed P28-35 T 25 30 35 00 34#35Safety: TSHA-102 did not cause adverse behavioral side effects in WT mice Aggregate score 12 10 8 6 2 8 12 16 20 24 Age (weeks) Mice were dosed P28-35 28 32 12% (3/24) of AAV9/mini-treated WT mice developed lesions and prolapses 0% (0/24) of AAV9/miRARE-treated WT mice developed lesions and prolapses T 00 0 vg, n=20 1x10¹¹ vg AAV9/MECP2(v2), n=12 1x10¹1 vg AAV9/mini, n=12 - 1x10¹¹ vg TSHA-102, n=12 - 1x10¹2 vg AAV9/MECP2(v2), n=10 1x10¹2 vg AAV9/mini, n=12 1x10¹2 vg TSHA-102, n=9 *p<0.05 35#36Efficacy: TSHA-102 outperformed unregulated AAV9/mini in MECP2 KO mouse survival study % Survival 100 80 60 40 20 0 0 5 10 15 20 25 Age (weeks) Mice were dosed P28-35 Diamond = vet-requested euthanasia, primarily for lesions. Lesions have been observed with varying frequencies among saline-treated KO mice, virus-treated WT and KO mice, as well as untreated RTT weanlings. WT, 0 vg, n=13 KO, 0 vg, n=18 KO, 1x10¹2 vg AAV9/MECP2(v2), n=12 KO, 1x10¹2 vg AAV9/mini, n=12 KO, 1x10¹2 vg TSHA-102, n=12 30 35 00 36#37TSHA-102 for the treatment of Rett syndrome to submit IND by end of 2021 Study design and duration Key inclusion/exclusion criteria Intervention Key clinical assessments Open-label, dose-ranging, multi-center Phase 1/2 trial Stage II and III Rett patients Age 3-10 (inclusive) Pathogenic confirmation of mutation in MECP2 • Low-dose cohort (n=4): single total dose of 5x1014 vg of AAV9/MECP2-miRARE High-dose cohort (n=4): single total dose of 1x1015 vg of AAV9/MECP2-miRARE Delivered intrathecally • Safety and tolerability Rett Syndrome Clinical Severity Score Rett Syndrome Behavior Questionnaire Seizure frequency/medications • Clinical Global Impression • Caregiver burden and Qol . Cardiac assessments (QT interval) • Head circumference & other growth parameters Respiratory assessments and sleep apnea, including in-patient sleep study T 37#38Deep pipeline of gene therapies targeting neurodevelopmental disorders TSHA-106 shRNA Angelman syndrome Preclinical TSHA-114 GRT Fragile X syndrome Preclinical TSHA-116 shRNA Prader-Willi syndrome Preclinical TSHA-117 regulated GRT FOXG1 syndrome Preclinical • Imprinting disorder in which the maternal gene is deficient and the paternal copy of UBE3A is intact but silenced by a long non-coding RNA • • . . . The disease causes profound developmental delay, ataxia and gait disturbance Estimated prevalence of 30,000 patients in the US and EU FMR1 is the most common single gene cause of autism and cognitive impairment Fragile X Syndrome is characterized by anxiety, aggression, hyperactivity, attention deficits, and sleep/communication disruption Estimated prevalence of 96,000 patients in the US and EU Loss of function of genes along 15q11-q13 chromosome region due to an imprinting defect Patients have developmental delay, insatiable eating habits accompanied by obesity and overt diabetes Estimated prevalence of 40,000 patients in the US and EU Newly discovered gene with prevalence expected to steadily rise as more children as tested with autism spectrum disorder Development and intellectual disabilities, growth restriction with microcephaly, epilepsy, and hyperkinetic-dyskinetic movement disorder Estimated prevalence of 20,000 patients in the US and EU T 00 38#39Genetic Epilepsy Franchise F. 39#40Deep pipeline of gene therapies targeting genetic epilepsies TSHA-103 GRT SLC6A1 IND-enabling studies TSHA-105 GRT SLC13A5 Preclinical TSHA-110 GRT KCNQ2 Preclinical . SLC6A1 encodes for GAT1 transporter, responsible for the reuptake of GABA Lack of GAT1 function results in impaired brain development, attention deficit and seizures Estimated prevalence of 16,000 patients in the US and EU Bi-allelic loss of function in the SLC13A5 gene, resulting in diminished NaCT function Patients have impaired motor function, speech production, and seizures Estimated prevalence of over 220 patients in the US and EU Diminished KCNQ2 function results in seizures in the first week of life, accompanied by developmental delay involving one or more domains of motor, social, language, or cognition Some children may have autistic features Estimated prevalence of 17,000 patients in the US and EU T 40#41Flexible, scalable GMP manufacturing suite and PD/QC lab at UTSW UTSW GMP production suite overview Sartorius Biostat® STR 500L -Sartorius FlexAct® U/D filtration SartaFlow® Tangential flow filtration (TFF) ÄKTA FPLC chromatography Sartorius FlexPro® mixer / holding tank - Sartorius fill-it automated dispenser PD/QC Lab overview Sartorius Biostat® B Controller Stations (4) 10L glass bioreactors (4) 2L glass bioreactors Sartorius Biostat® STR 50L bioreactor Sartorius AMBR 250 PD bioreactor 102A 1028 251 202 204 T ROGA g 104 MECHANICAL CHASE 21298 214 218 Ma 224 232 410 2368 236 Process Development (PD)& Quality Control (QC) laboratory space GMP production suite *Partial list of equipment 472 41#42Well capitalized to advance robust pipeline with strong investor syndicate ~$126M gross proceeds raised since company formation ~$118M cash and cash equivalents* *As of June 30, 2020, after giving effect to the receipt of $107.1 million in proceeds from the sale and issuance of Series A and Series B convertible preferred stock in July and August 2020 Premier syndicate of long-term, life science investors PBM CAPITAL Nolan Capital G/ INVUS Octagon Fidelity ETHIN ARROWMARK CASDIN PERCEPTIVE ADVISORS venrock FRANKLIN TEMPLETON SANDS CAPITAL Other institutional mutual fund investors#43Focused on achieving near-term milestones and building long-term value 110 GM2 gangliosidoses to enter the clinic in 2020 CLN1 expected to dose first patient 2021 4 INDs expected to be submitted by the end of 2021 State-of-the-art GMP manufacturing online in 2020 Numerous value generating catalysts over the next 18 months 43#44Appendix F. 44#45Platform Technologies T L 45#46Utilizing machine learning, DNA shuffling, and directed evolution for capsid discovery High-content sequencing of recovered capsid pools - Using sequencing data from in vivo selection to feed machine learning algorithms, for in silico design of novel capsids - Development of new libraries, based on capsid- spanning modifications rather than just peptide insertions - Directed evolution to generate CNS-directed capsids, cross-compatible between mice and NHPs ITR Rep Cap ITR Capsid genes of AAV1-6, 8, 9, rh10,+ lab variants DNasel fragmentation Assembly and amplification Directed evolution of novel AAV variants Selection of cell type-specific AAV variants for vector development 46#47Vagus nerve delivery platform may enable AAV9 redosing The vagus nerve represents the main component of the parasympathetic nervous system (PNS) Direct delivery to the vagus nerve will provide broad coverage of the PNS and enable redosing by subverting the humoral immune response Proof of concept established in rodent and dog models Confirmatory studies in NHPs will be conducted 2H20, if successful, platform will be utilized to facilitate redosing of previously treated patients in the Giant Axonal Neuropathy AAV9 clinical trial¹ Parasympathetic System Nerve i Nerve V Nerve Nerve X (Vogus) Pelvic splanchnic nerves Constricts pupils Stimulates flow of saliva Constricts bronchi Slows Heartbeat Stimulates peristalsis and secretion Stimulates Bile Release GH CHE Stimulates vasodilation Contracts bladder Taysha has exclusive rights to the vagus nerve redosing platform in select indications. Hannah's Hope Foundation owns the rights to the Giant Axonal Neuropathy program. 47#48Vagus nerve injection of increasing doses of AAV delivery were well-tolerated in hounds observed over 13 days Body Weight (lbs) 60 Testing VN Delivery Rates High Mid Low Pre-surgery Day of 2 Weeks 1 Week Surgery Post-surgery Post-surgery Post-mortem vagal nerves and brain were microscopically normal Amount of Feces Post-surgery Afternoon Fecal Output Post-surgery Vocalization Day High Mid Low High Mid Low Taysha has exclusive rights to the vagus nerve redosing platform in select indications. Hannah's Hope Foundation owns the rights to the Giant Axonal Neuropathy program. 48#49miRARE is a targeting panel for endogenous miRNAs which can regulate various transgenes 1 Viral genome in nucleus 2 mRNA in cytoplasm Transgene Translation and nuclear localization 3 miRNA-responsive target sequence in untranslated region 5 Mature miRNAs bind to mRNA in cytoplasm to regulate its expression Transgene F. In this conceptual loop, the 3'UTR features targets for miRNAs. The viral genome does not encode miRNAs. 4 mature miRNA Transgene drives expression of many endogenous miRNAs miRNA expression 49#50Approaches 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 regulating intellectual ability Use positive results from high-throughput screening to filter and rank bioinformatics data Merged screening data and genomic sequence information Create a small synthetic (and potentially broadly applicable) regulatory panel T Regl miRARE High-throughout milNA screen harvest ACTORS CNS CNS RNA Expression for 1900 NA -RTT-speofic panel for top 3 futs Selection criteria to process UTR and create universa panag 38-01 How to use HTS expression data to process UTR sequence doto Sert targets from o UTR dota set according to the expression levot of their cognate mRNAs Torgets for miRNAs expressed in CNS are physiologely relevant and should be priorited for panel design Use pst date to select on expression threshald Eminata sorgets for mRNA expressed below this threshold Eminate targets for fute peative Nita that signently then use positives from HTS select dasase relevant targets from a short list of frequently Tully unique seed sequences aming peative hits (o single sead sequence can appear in mory ndogenous targets appear frequently among 3 UTRs of 12 dose-sensitive genes expressed in brain An Sorted data reveais a relationship between target frequency and tissue-specific expression of miRNAs VALLEY FRAME Amba FALLT WUND 2431 hugs To create a feedbock pen miRNAsxpressed noor injection site Frequency ered by uancy To make the panel broadly applicable select targets that appear in most of the selected UTR FELT WERK To maximize repression, p select torgets for 22 argets Then, to ensure success in a RTT model prioritize targets for h MANAS torgets that may y bind multiple MaCP2-driven mRNAs torgataected for 50#51451 targets annotated across both species for selected 3'UTRS # of mouse UTRs 11 10 9 8 7 ·6543 2 1 0 O 0 000 0 1 2 3 4 5 6 7 8 9 10 11 # of human UTRs - Many targets appear frequently among the 3'UTRs of dose- sensitive genes mediating disorders characterized by intellectual disability Bounded area: targets appear across 26 selected 3'UTRs Orange data points: corresponding miRNAs expressed in CNS tissue Squares: corresponding miRNAs are potentially MeCP2-responsive T New target panel miRARE • Compact (6 targets) • Useful for RTT .Possibly multipurpose • Translationally relevant MP426 Promoter miniMECP3-myc 51#52Additional Neurodegenerative Programs 52#53SURF1-related Leigh syndrome is an early onset neurodegenerative disorder - Deficiency in the SURF1 gene results in mitochondrial dysfunction and dysregulation of oxidative phosphorylation SURF1 mutations are implicated in Leigh syndrome as well as Charcot-Marie Tooth 4K Symptoms appear in late infancy and include episodic neurological regression, movement disorder, and respiratory failure - The estimated prevalence of SURF1 is 300 patients in the US and EU AAV9+ IXT hSURF1+ Intrathecal delivery ISIOON TAITOIN SURFI PET100 SUCLA MTFMT Age of onset t Age of death Age at last report Age of onset C Age of death last report Age of onset HD Age of death Age at last report Age of onset Age of death Age at last report Age of onset Age of death Age at last report Age of onset Age of death Age at last report * 102 244 215 22 241 212 264 274 24 300 42 104 53#54Adult polyglucosan body disease (APBD) is a progressive, "prime of life" illness - APBD is caused by reduced glycogen branching enzyme (GBE1) activity GBE1 mutations lead to uncontrolled glycogen elongation and the formation of polyglucosan bodies Symptoms include sensory loss in the legs, progressive muscle weakness, gait disturbances, urinary difficulties, and mild cognitive impairment - The estimated prevalence of APBD is 1,000 patients in the US and EU AAV9+ DAT hGBE1 Intrathecal delivery 444 ch * 54#55Lafora disease is a fatal disorder of glycogen metabolism Teenage onset disease, severe neurodegenerative epilepsy Caused by mutations in either EPM2A (laforin) or EPM2B (malin) Progressive and invariably fatal, leading to death 5-10 years after onset The estimated prevalence of Lafora disease is 700 patients in the US and EU AAV9+ AAV9 I DA hEPM2A+ hEPM2B+ 倉 NO Intrathecal delivery Intrathecal delivery Number of EPM2A And EPM2B Cases According To Ethnicity/Country Glycogen EPM2A or EPM2B mutation Laforin Malin ..... Lafora body Lafora disease 55#56Also developing a common approach to treat Lafora and APBD, with potential to treat other GSDs In Lafora disease and APBD, glycogen chain elongation outpaces glycogen branching Elongated glycogen molecules accumulate into toxic polyglucosan bodies Downregulation of glycogen synthase (GYS) can prevent polyglucosan body formation Taysha is pursuing a GYS-miRNA therapy for the treatment of Lafora and APBD The estimated prevalence of GSDs is 20,000 patients in the US and EU AAV9 IDATI GYS-miRNA Intrathecal delivery Hippocampal PB quantification (% area) N AM Ç Ma H Gbefy Gyst Gyenge Spa Activity | Gyst GYS-miRNA REDUCTION IN POLYGLUCOSAN Gys1 deficiency results In reduction of polyglucosan bodies 56#57Preliminary animal studies demonstrated the utility of GYS reduction Survival (%) 100- 50- WT Gys14 Gbe1ysys Gys1 Gbe1ywys 10 Age (months) 20 Genetic knockdown of GYS1 results in dramatic increase in survival Rescue of APBD mice achieved with 50% reduction in glycogen synthase activity Normalization in body mass observed in male and female APBD mice Disease progression-associated decline in body mass Male body mass (g) 40 30 Female body mass (g) 2 30- 20 7 Age (months) Age (months) 57#58The microtubule associated protein tau (MAPT) plays a key role in numerous neurodegenerative disorders Mutations in MAPT lead to changes in the propensity of tau to form toxic aggregates Tauopathies refer to a wide range of diverse diseases characterized by the aggregation of tau in neurons and/or glia, including: - Alzheimer's disease (AD); Progressive supranuclear palsy (PSP); Frontotemporal dementia (FTD), and; Parkinsonism linked to chromosome 17 (FTDP-17) - The estimated prevalence of these tauopathies, excluding AD is 40,000 patients in the US and EU AAV9+ IXAT Anti-Tau-miRNA + Intrathecal delivery PID (3R) MAPT MUTATIONS CBD (4R) Tau aggregation 9% = 4-2- 10 11 FTLD-tau SUBTYPES 1 PSP (4R) 13 GGT (4R) Cell-cell transmission 58#59Additional Neurodevelopmental Programs 59#60Angelman Syndrome is a rare neurodevelopmental disorder with multiple genetic mechanisms Angelman syndrome is caused by the loss of function of the maternal copy of the UBE3A gene Symptoms of AS include severe cognitive dysfunction, absent speech, seizures, ataxia, gait disorder, microcephaly, and happy affect The paternal copy of UBE3A is normal, but silenced, in all cases of AS Taysha is developing gene therapies to activate the paternal UBE3A using an shRNA construct The estimated prevalence of Angelman syndrome is 30,000 patients in the US and EU AAV9+ IXAT Anti-UBE3A- ATS shRNA Intrathecal delivery Maternal Paternal Maternal Paternal Ube3a-ATS noroor MMMM Ube 3a NMMMM Uka MIX TAYSHA Ube MMMM Ube3a MX NMNMNMNMUDca 00 60#61Fragile X Syndrome is one of the most common forms of inherited intellectual disability Mutations in FMR1 result in decreased FMRP, a protein necessary for normal brain development Fragile X Syndrome is characterized by a spectrum of physical, cognitive, and behavioral features including: - Low muscle tone Attention deficits and hyperactivity (ADHD) Behavior issues, shyness, anxiety, poor eye contact Speech and language delays The estimated prevalence of Fragile X is 96,000 patients in the US and EU AAV9+ IXT hFMR1 Intrathecal delivery mRNA FMRP Clinical Typical (CGG) <45 Normal Premutation (CGG) 55-200 Primary ovarian insufficiency (POI), fragile X-associated tremor ataxia syndrome (FXTAS) due to excess mRNA DO Full mutation (CGG) > 200 X Fragile X syndrome due to lack of FMRP 61#62Prader-Willi syndrome is caused by genetic errors on chromosome 15 Symptoms of PWS include neonatal hypotonia followed by hyperphagia and excessive weight gain that begins around 5-8 years of age and lasts until death Hyperphagia leads to severe obesity, metabolic disorder, and is a leading cause of morbidity and mortality Intellectual disability and developmental delay and psychiatric disorders are also common The average age of death is approximately 30 years The estimated prevalence of PWS is 40,000 patients in the US and EU AAV9 IXAT PWS shRNA Intrathecal delivery ubject ans of S HELLKLUM VERRER Number Selected clinical features reported for patients with Prader-Willi syndrome 3 WT Mat Feeding Difficulties SAUNA d usprucbredy Behavioral problems اسال SANGA/REMA ATS typopigmentation Eye Abnormalites Deliver targeted shRNA utilizing AAV9 to activate maternal gene expression Speech Defects 1999 Present Absent No deta 62#63Additional Genetic Epilepsies Programs F. 63#64SLC6A1 is a rare neurological condition that causes severe movement and speech disorders The SLC6A1 gene encodes the GABA transporter 1 (GAT-1) Patients with SLC6A1 have a deficiency of GAT-1, resulting in decreased GABA transport and aberrant neuronal activity The symptoms of SLC6A1 typically appear at 3-4 years and progressively worsen with age SLC6A1 has an estimated prevalence of 16,000 patients, which we believe is underestimation as there is an emerging epidemiology AAV9 IDAT hSLC6A1 NU Intrathecal delivery F GAT EAATI Gutamate veul transpor GARA BRIN SHATS 17 Postyc Gal Coll 64#65SLC13A5 deficiency results in persistent seizures and developmental delays SLC13A5 deficiency is caused by mutations in the SLC13A5 gene Epileptic episodes start within the first week of life and consists of severe, prolonged episodes Severe difficulty with speech production, movement and coordination problems and tooth enamel abnormalities are common - The estimated prevalence of SLC13A5 is 225 patients in the US and EU, which is likely higher due to patients being misdiagnosed as cerebral palsy AAV9 IAT hSLC13A5 + Intrathecal delivery F. 65#66Mutations in KCNQ2 result in severe neonatal epilepsy syndromes - KCNQ2 encodes voltage gated potassium channel subunit Kv7.2, a protein that complexes with other subunits to form potassium channels The majority of KCNQ2 cases are due to loss of function (LOF) mutations in the potassium channel KCNQ2 is characterized by dramatic onset with multiple seizures occurring daily. Apnea and bradycardia are common, and a range of intellectual disabilities have been observed The estimated prevalence of KCNQ2 is 17,000 patients in the US and EU AAV9+ IXT hKCNQZ Intrathecal delivery extracellular intracellular NH₂ The KCNQ2 subunit S1 S2 S3 S4 S5 KONC37 encades (IZA channel important for determining the excitability of neurons COOH S6 66