Taysha Gene Therapies : March 2024 Corporate Presentation

Corporate Presentation

March 2024

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 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. These forward-looking statements are subject to a number of risks, uncertainties and assumptions. Risks regarding our business are described in detail in our Securities and Exchange Commission filings, including in our Annual Report on Form 10-Kfor the year ended December 31, 2022, and our other filings with the SEC, which are available on the SEC's website at www.sec.gov. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements contained in this presentation reflect our current views with respect to future events, and we assume no obligation to update any forward-looking statements except as required by applicable law.

This presentation includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. All of the market data used in this prospectus involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications and third- party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions

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Key investment highlights

	• Ongoing REVEAL Phase 1/2 adolescent and adult trial in Canada and ongoing REVEAL Phase 1/2 pediatric trial in U.S. and U.K.
TSHA-102:	• Novel miRARE technology designed to mediate MECP2 expression on a cell-by-cell basis (enables protein production in MECP2-
	defieicnt cells, silences transgene expression in healthy cells) to address risks associated with under- and over-expression of MECP2
Lead Clinical Program
• High unmet medical need and significant market opportunity of 15,000-20,000 (U.S., EU+U.K.)1 with typical Rett syndrome caused
in Rett Syndrome
	by a MECP2 mutation
	• Potential to obtain Priority Review Voucher (PRV)
Transformative	• Data from first two adult patients dosed support TSHA-102 was generally well-tolerated with no treatment-emergent SAEs
• Sustained and new improvements demonstrated across key efficacy measures and clinical domains
Potential
• Similar patterns of response in patients with different genetic mutations and phenotypic expression
Proven and Well-	• Clinically and commercially proven AAV9 capsid with clinical activity and tolerability across multiple CNS indications
•	Intrathecal delivery in an outpatient setting targets key CNS regions and minimizes viral load, potentially reducing risk of systemic
Characterized Delivery		inflammatory response
	• Self-complementary technology facilitates more rapid transgene expression
Well-Capitalized	• $150 million private placement from new and existing investors along with cash and cash equivalents expected to extend cash
	runway into 2026
Proven Leadership	• Led by former AveXis management, who developed and launched ZOLGENSMA, the second one-time gene therapy FDA approved
• Strong relationships with key gene therapy stakeholders, including regulatory authorities, suppliers and other third parties
Near-Term Catalysts	• Q1 '24 - Expect updated clinical data from completed cohort one (low dose, n=2) in REVEAL adolescent and adult trial
•	Mid-2024 - Expect initial clinical data from pediatric low dose cohort (n = 3) in REVEAL pediatric trial

Source: 1IRSF; NORD; Amir RE, Van den Veyver IB, Wan M, et al. Rett Syndrome Is Caused by Mutations in X-Linked Mecp2,	3
Encoding Methyl-Cpg-Binding Protein 2. Nat Genet 232:185-188. 1999.

Progress in clinical-stageTSHA-102 program supports clinical evaluation across a broad range of ages and stages of Rett syndrome

REVEAL Phase 1/2 Adolescent and Adult Trial

in U.S. and Canada

• Completed dosing in cohort one (low dose, n=2) in Canada; encouraging initial safety and efficacy data
• Presented initial clinical data from the first two adult patients at the BPNA 2024 Annual Conference
• Health Canada authorized protocol amendment to include patients ≥12 years of age
• Received IDMC approval of Company's request to proceed to the high dose cohort earlier than planned
• Trial now expanding into the U.S. following submission of 12+ protocol to U.S. FDA

REVEAL Phase 1/2 Pediatric Trial in U.S. and

U.K.

• U.S. FDA cleared IND for TSHA-102 in pediatric patients
• Dosed first pediatric patient in the U.S.
• Received IDMC approval to dose second patient in cohort one (low dose)
• U.K. MHRA authorized CTA for TSHA-102 in pediatric patients
• ODD, RPDD and FTD from the U.S. FDA and ODD from the EU EMA

2024: significant clinical data generation expected in adult, adolescent and pediatric patients across three

geographies

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Rett syndrome: a rare, progressive X-linked neurodevelopmental disease

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⚬

⚬

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Caused by mutations in the X-linked MECP2 gene, a critical transcriptional regulator required for proper neuronal development and brain function1

Mutations in MECP2 inhibit neuronal development, leading to impaired brain development and function1 Primarily occurs in females

Female heterozygous patients are mosaic carriers of normal and mutated MECP2, and symptoms and severity vary, due in part to random X-inactivation2

Rett syndrome is divided into four key stages3

STAGE I

Developmental Arrest

6-18 months (typical)

≤6 months (early)

Symptom onset

	=
STAGE II	STAGE III	STAGE IV
Rapid Deterioration	Pseudo Stationary	Late Motor Deterioration
1-4 years	4-10 years	>10 years
Symptom progression	Symptom stabilization	Muscle wasting with age

Sources: 1Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185-188.2Braunschweig D, Simcox T, Samaco RC, LaSalle JM. X-Chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett

syndrome and Mecp2-/+ mouse brain. Hum Mol Genet. 2004;13(12):1275-1286.3Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett Syndrome: A Genetic Update and 5

Clinical Review Focusing on Comorbidities. ACS Chem Neurosci. 2018 Feb 21;9(2):167-176. doi: 10.1021/acschemneuro.7b00346. Epub 2017 Dec 15. PMID: 29185709.

Hallmark characteristics of Rett syndrome appear across multiple clinical domains impacting activities of daily living

The cortical architecture and function abnormalities observed across the CNS in Rett syndrome can have a significant impact on motor function, socialization and autonomic function

Gross Motor Function

1. Mobility issues

1. Loss of movement

and coordination abilities

1. Gait disturbances o Hypotonia
   o Dystonia

Fine Motor Function

1. Loss of hand function o Loss of purposeful
   hand use
   o Repetitive hand movements

Socialization

1. Loss of speech/ communication

1. Social withdraw o Behavioral issues
   o Intellectual disability

Autonomic Function

1. Seizures

1. Sleep disturbances o Breathing issues o Gastrointestinal
   issues
   o Cardiac function o Vasomotor
   disturbances

Sources: Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett Syndrome: A Genetic Update and Clinical Review Focusing on

Comorbidities. ACS Chem Neurosci. 2018 Feb 21;9(2):167-176. doi: 10.1021/acschemneuro.7b00346. Epub 2017 Dec 15. PMID:6 29185709. 2Armstrong, DD. J Child Neurol. 2005;20(9):747-753

No approved disease-modifying treatments address the genetic root cause of Rett syndrome

High unmet medical need

• Current standard of care focused on symptom management2
• High caregiver burden and significant impact on quality of life

Significant market opportunity

• Estimated prevalence of typical Rett syndrome caused by a MECP2 mutation is between 15,000 and 20,000 in major global markets (U.S., EU+U.K.)1
• Rett syndrome occurs worldwide in 1 of every 10,000 female births1

Sources: 1IRSF; NORD; Amir RE, Van den Veyver IB, Wan M, et al. Rett Syndrome Is Caused by Mutations in X-Linked Mecp2,	7
Encoding Methyl-Cpg-Binding Protein 2. Nat Genet 232:185-188. 1999 .2 Fu C, Armstrong D, Marsh E, et al. Consensus guidelines

on managing Rett syndrome across the lifespan. BMJ Paediatrics Open 2020;4:e000717. doi:10.1136/ bmjpo-2020-000717.

Gene Therapy Challenge: too much or too little MECP2 expression is harmful in Rett syndrome

Rett syndrome

WT

WT

WT

WT

Healthy individual

WT

WT

WT

WT

WT WT

MECP2 duplication syndrome

Some MECP2 deficiency	Normal MECP2 levels	Overexpressed MECP2
occurs due to random X-inactivation	in all cells	leads to harmful effects and
leading to a mixture of wild-type and		duplication syndrome
deficient cells

TSHA-102's novel miRNA-ResponsiveAuto-Regulatory Element (miRARE) technology

is designed to correct MECP2 deficiency and avoid toxic overexpression

Source: Van Esch H, Bauters M, Ignatius J, et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation	8
and progressive neurological symptoms in males. Am J Hum Genet. 2005;77(3):442-453.

TSHA-102: an investigational one-time gene therapy that regulates MECP2

⚬ TSHA-102 delivers a functional form of
⚬	MECP2 to cells in the CNS
Equipped with novel miRNA-responsive
	target sequence (miRARE) designed to
	mediate levels of MECP2 in the CNS on a
	cell-by-cell basis without risk of
	overexpression
	- Senses transgene and endogenous
	MECP2 levels to provide a superior
	therapeutic profile to that of unregulated
⚬	MECP2 gene replacement3
Delivered via intrathecal (IT) administration
	to target key CNS regions and minimize viral

AAV9 capsid

Clinically and commercially proven across multiple CNS indications

miniMECP2 allows for packaging of miRARE technology for

sophisticated regulatory control in a self-complementary design1

load using a routine, minimally invasive

procedure in an outpatient setting

MEP426 promoter allows targeted neuronal expression and capitalizes on endogenous transcriptional regulation

Self-complementary technology enables more rapid transgene expression due to ability to bypass the rate-limitingsecond-strand synthesis in host cells2

Sources: 1Tillotson R et al. 2017 Nature; 550:398-401; Sinnett SE et al. A New Approach for Designing a Feedback-Enabled AAV Genome Improves Therapeutic Outcomes of MiniMeCP2 Gene Transfer in
Mice Modeling RTT. 23rd Annual meeting for the American Society of Gene & Cell Therapy; April 28,2020. 2McCarty DM. Self-complementary AAV vectors: Advances and applications. Mol Ther.	9
2008;16(10):1648-1656.3Haque E et al. The microRNA-responsive autoregulatory element from TSHA-102 for Rett Syndrome modulates therapeutic transgene expression in response to cellular MeCP2 in

mouse and human cell lines. 30th Annual Congress of the European Society for Gene and Cell Therapy, 24-27 Oct 2023, Brussels, Belgium. Poster #P435.

miRARE prevents overexpression through RNA interference with binding sites for endogenous microRNA responsive to MeCP2 levels1

											MeCP2-deficient cell
TSHA-102				Healthy, MeCP2-expressing cell	TSHA-102

X

Designed to silence the miniMECP2 transgene in

cells that already express MeCP2

Designed to enable miniMeCP2 protein production

in MeCP2-deficient cells

TSHA-102 has demonstrated the ability to produce and maintain safe transgene expression levels in the CNS

in preclinical models1

Source: 1Sinnet, SE, et al. Engineered microRNA-based regulatory element permits safe high-	10
dose miniMECP2 gene therapy in Rett mice. Brain. 2021 awab182.