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Driven by a relentless focus on discovering, developing, and
commercializing novel AAV-based gene therapies for devastating disorders of the central nervous system 3
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
catalysts to enhancevalue - Submit four IND/CTA filings, including Rett syndrome, in 2021 - Advancement of four product candidates in IND-enabling studies, four in discovery in 2021 - Current pipeline of 26 AAV gene therapy
programs Portfolio of 26 CNS gene therapy - Portfolio addressing over 500,000 patients (US+EU) across monogenic CNS diseases, including programs across 3 distinct franchises neurodegenerative diseases, neurodevelopmental disorders, and genetic
epilepsies - Led by Drs. Steven Gray and Berge Minassian; established to accelerate R&D, with integration of UT Southwestern Gene Therapy translational research, clinical development and GMP manufacturing Program strategic alliance -
Exclusive access to resources, expertise, and novel technology platforms for delivery and dosing of gene therapies - Clinically and commercially proven AAV9 vector platform Validated capsid, manufacturing system - Highly scalable
suspension HEK293 manufacturing process with excellent yield and route of delivery - Intrathecal delivery enables direct targeting to the CNS with validated biodistribution and safety - Deep expertise in the development of gene therapies
for rare diseases Proven management team - Key leadership team members and investors previously led the development and commercialization of Zolgensma , and investorsyndicate the first FDA-approved gene therapy for CNS disease
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 Alam,
CPA, MBA Chief Financial Officer Board of Directors Fred Porter, PhD Sean Nolan Chief Technical Officer Chairman Mishima Gerhart Paul Manning Chief Regulatory Officer and Head of Quality Sean McAuliffe Phillip Donenberg Chief Commercial Officer Jim
Rouse Sukumar Nagendran, MD Chief Information Officer Emily McGinnis Laura Sepp-Lorenzino, PhD Chief Patient Officer & Head of Government Affairs Tim Douros, JD Kathleen Reape, MD Chief Legal Officer and Corporate Secretary Tracy Porter, M.Ed.,
SPHR RA Session II Chief People Officer 5
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 Education; BioMarin
Pharmaceutical Boyd Consultants; Royal Colleges of Physicians; University of Alan Boyd, BCc, MB, ChB, Birmingham Medical School; AstraZeneca; FRSB, FFLM, FRCP, FFPM Ark Therapeutics Ltd Columbia University; Simons Foundation Autism Wendy K. Chung,
MD, PhD Research Initiative (SFARI) David P. Dimmock, MD Rady Children's Institute for Genomic Medicine; FDA; CDC The Neuroscience Research Center Michael W. Lawlor, MD, PhD at the Medical College of Wisconsin; Solid Biosciences David Geffen
School of Medicine at University of California, Los Gerald S. Lipshutz, MD, MS Angeles; Wellcome Trust, UK; NIH 6
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 2021 additional 4
programs programs academic institution 7
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 characterized by
impairments in seizures often leading to abnormal structures and function of the CNS cognition, behavior, and motor development of the brain and PNS function 8
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 Disease Currently open IND
TSHA-119 GRT GM2 AB Variant TSHA-104 GRT SURF1-Associated Leigh Syndrome IND/CTA submission 2H21 TSHA-112 miRNA APBD TSHA-111-LAFORIN miRNA Lafora Disease TSHA-111-MALIN miRNA Lafora Disease TSHA-113 miRNA Tauopathies TSHA-115 miRNA GSDs Undisclosed
GRT/shRNA Undisclosed Undisclosed GRT Undisclosed NEURODEVELOPMENTAL DISORDERS TSHA-102 Regulated GRT Rett Syndrome IND/CTA submission 2H21 TSHA-106 shRNA Angelman Syndrome TSHA-114 GRT Fragile X Syndrome TSHA-116 shRNA Prader-Willi Syndrome
TSHA-117 Regulated GRT FOXG1 Syndrome TSHA-107 GRT Autism Spectrum Disorder TSHA-108 GRT Inborn Error of Metabolism TSHA-109 GRT Inherited Metabolism Disorder Undisclosed GRT Undisclosed Undisclosed mini-gene Undisclosed GENETIC EPILEPSY TSHA-103
GRT SLC6A1 Haploinsufficiency Disorder TSHA-105 GRT SLC13A5 Deficiency TSHA-110 mini-gene KCNQ2 Undisclosed mini-gene Undisclosed GRT: Gene replacement therapy miRNA: microRNA shRNA: short hairpin RNA 9
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 Willi
40,000 Rett syndrome 25,000 FOXG1 20,000 GSDs Tauopathies 20,000 (MAPT-FTD, PSP, CBD) 13,000 APBD 10,000 GAN CLN1 2,400 GM2, Lafora 900 GM2 AB variant SURF1 700 650 300-400 1 Tauopathies only include MAPT-FTD, PSP, CBD. 10 2 Additional programs
include TSHA-107, TSHA-108 and TSHA-109 Estimated Patient Population (US + EU)
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 -
Program couples validated technology with novel Intrathecal (IT) route of administration targeted payload design (GRT, miRNA, shRNA, regulated - Enables direct targeting to CNS GRT, mini-gene) - Validated biodistribution and safety
profile Proven HEK293 Suspension Process - Highly scalable and excellent yields - 3-pronged approach to manufacturing including UTSW, Catalent and internal cGMP facility AAV9 vector for delivery of therapeutic transgene -
Demonstrated safety and efficacy across multiple CNS indications 11
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
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, non- therapeutic transgene in AAV capsids limited gene expression coding sequences of RNA that result in silencing of Built-in regulation system to Mini-genes designed to gene expression) replace dose-sensitive genes overcome
limited AAV Comprised of a codon-optimized safely and at therapeutic packaging capacity DNA transgene that encodes the Transgenes designed to levels wild type gene of interest express short-hairpin RNA Collaboration with
Cleveland (shRNA), which reactivate a Uses miRARE, our novel Clinic to advance next- Transgene (or mini-gene) silenced gene upon binding miRNA target panel generation mini-gene payloads coupled with a promoter to the target of
interest initially for genetic epilepsies selected to ensure expression in and neurodevelopmental the cell or tissue-type of interest disorders 13
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
machine learning, capsid shuffling and genome mining directed evolution Efficient targeting of vagal neurons demonstrated in adult rats, with Designed for safely regulated transgene Allows rapid identification of capsids
potential to improve autonomic expression levels in the brain with improved properties in mice and nervous system symptoms in humans Non- Human Primates (NHPs) to Needed in disorders like Rett syndrome maximize translational relevance
Normal vagal nerve fibers and where high doses of transgene- neurons post AAV delivery to the expressing vectors may be harmful Potential to drive new product vagus nerve in dogs while low doses may avoid toxicity but candidates with
novel biodistribution be sub-therapeutic and transduction profiles into pipeline Built-in regulation system harnesses endogenous systems 14
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
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
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
and commercial early-phase and pivotal supply manufacturing Active technical collaboration and knowledge sharing for process information and Strategic partnership in place with Catalent Initial build includes two vector
analytical methods Gene Therapies manufacturing trains, one fill/finish suite, QC and technical development labs First program is ongoing Two programs ongoing Building secured in Durham, NC Able to leverage process,
methods and Capabilities materials across programs Growing hub for gene therapy 50L tox production manufacturing Current Capabilities 200L available by EOY Facility timing 200/400L tox
production 500L GMP manufacturing Kicked off 1Q 2021 800L GMP manufacturing GMP operations began in December 2020 Office and development labs operational in Full support for release and stability
testing In-house support for critical release and 1Q 2022 stability testing GMP ready in 2023 16
Neurodegenerative Disease Franchise 17
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
Giant Axonal Neuropathy Neuron Cell Body Good candidate for gene transfer approach Small gene that is easy to package into AAV9 capsid High transduction to target organ Low-level expression may restore function
Abnormal Accumulation of Axon A clear model for other disorders with similar mechanism such Neurofilaments as GM2 gangliosidosis, CLN1 disease, SURF1-associated Leigh Axonal Neurofilaments Degenerated Swelling syndrome and amyotrophic
lateral sclerosis (ALS) and Thin Myelin Sheath CNS Myelin Sheath PNS Normal GAN 18
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-function
gigaxonin gene mutations Majority of children with GAN show symptoms and features before age 5 Dull, tightly curled hair Progressive scoliosis Contractures Giant axons Spinal cord atrophy Spinal Cord
White Matter White matter abnormality Giant Axons Atrophy Abnormality No approved disease-modifying treatments available Symptomatic treatments attempt to maximize physical development and minimize deterioration
Early- and late-onset phenotypes - shared physiology Late-onset often categorized as Charcot-Marie-Tooth Type 2 (CMT2), with lack of tightly curled hair and CNS symptoms, and relatively slow progression Represents 1% to 6% of
all CMT2 diagnosis Late-onset poor quality of life but not life-limiting Murphy SM et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012;83:706-10. Gess
B et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord 2013;23:647-51. 19 Estimated prevalence of GAN is 2,400 patients (US+EU) Antoniadi et al 2014 Bacquet J
et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation. BMJ Open. 2018
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), optic neuropathy / decreased visual acuity Scoliosis and progressive contractures 8-11 yrs Loss of independent ambulation Dysphagia Stridor and respiratory insufficiency 13-18 yrs CNS
- intellectual disability, seizures, spasticity 20+ yrs *** Respiratory failure, death *** Late-onset GAN 0-5 yrs Asymptomatic 5-25 yrs Delayed early motor development, unsteady gait 25-50+ yrs Variable foot deformity
Progressive imbalance Distal weakness, atrophy, hypotonia Ambulation issues (stairs, uneven surfaces) Decreased deep tendon reflexes Fine motor skills issues (gripping objects) Considerable impact to
Quality of Life 20 Disease progression