Taysha Gene Therapies, Inc. (TSHA)

Item 2. Management’s Discussion and Analysis of Financial Condition and Results of Operations.

The following discussion and analysis of our financial condition and results of operations should be read in conjunction with our unaudited condensed consolidated financial statements and related notes included in this Quarterly Report on Form 10-Q and the audited financial statements and notes thereto as of and for the year ended December 31, 2025 and the related Management’s Discussion and Analysis of Financial Condition and Results of Operations, included in our Annual Report on Form 10-K for the year ended December 31, 2025, or Annual Report, filed with the Securities and Exchange Commission, or the SEC, on March 19, 2026. Unless the context requires otherwise, references in this Quarterly Report on Form 10-Q to “we,” “us,” and “our” refer to Taysha Gene Therapies, Inc. together with its consolidated subsidiaries.

Forward-Looking Statements

The information in this discussion contains forward-looking statements and information within the meaning of Section 27A of the Securities Act of 1933, as amended, or the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act, which are subject to the “safe harbor” created by those sections. These forward-looking statements include, but are not limited to, statements concerning our strategy, future operations, future financial position, future revenues, projected costs, prospects and plans and objectives of management. The words “anticipates,” “believes,” “estimates,” “expects,” “intends,” “may,” “plans,” “projects,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. 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 that we make. These forward-looking statements involve risks and uncertainties that could cause our actual results to differ materially from those in the forward-looking statements, including, without limitation, the risks set forth in Part I, Item 1A, “Risk Factors” in our Annual Report. The forward-looking statements are applicable only as of the date on which they are made, and we do not assume any obligation to update any forward-looking statements.

Note Regarding Trademarks

All brand names or trademarks appearing in this report are the property of their respective holders. Unless the context requires otherwise, references in this report to the “Company,” “we,” “us,” and “our” refer to Taysha Gene Therapies, Inc.

Overview

We are a clinical-stage biotechnology company focused on advancing AAV-based gene therapies for the treatment of severe monogenic diseases of the central nervous system, or CNS. Our lead clinical program TSHA-102 is in development for the treatment of Rett syndrome, a rare neurodevelopmental disorder with no approved disease-modifying therapies that address the genetic root cause of the disease. With a singular focus on developing transformative medicines, we aim to address severe unmet medical needs and dramatically improve the lives of patients and their caregivers. Our management team has proven experience in gene therapy development and commercialization. We leverage this experience, our manufacturing process and a clinically and commercially proven AAV9 capsid in an effort to rapidly translate treatments from bench to bedside.

We are evaluating TSHA-102 for the treatment of females with Rett syndrome in our REVEAL and ASPIRE clinical trials.

The REVEAL Phase 1/2 Adolescent and Adult Trial, also known as Part A, is a first-in-human, open-label, randomized, dose-escalation and dose-expansion study evaluating the safety and preliminary efficacy of TSHA-102 as a single lumbar intrathecal administration in adolescent and adult females aged 12 years and older with Rett syndrome due to MECP2 loss-of-function mutation. The trial is taking place in Canada and the United States. A total of six patients aged 15 to 21 years were treated with TSHA-102 in this study, and enrollment for this trial is complete. Part A also includes the REVEAL Phase 1/2 Pediatric Trial, which is a first-in-human, open-label, randomized, dose-escalation and dose-expansion study evaluating the safety and preliminary efficacy of TSHA-102 as a single lumbar intrathecal administration in pediatric females aged 5 to 8 years with Rett syndrome due to MECP2 loss-of-function mutation. The trial is taking place in the United States and Canada. A total of six patients aged 6 to 8 years were treated with TSHA-102 in this study, and enrollment for this trial is also complete.

We have completed dosing of the 12 patients aged 6 to 21 years in Part A of both REVEAL trials, which includes eight patients in cohort two (high dose, 1x1015 total vg) and four patients in cohort one (low dose, 5.7x1014 total vg).

27

Longer-Term Results from Part A of REVEAL Trials as of May 2026 Data Cutoff

Developmental milestones are defined as a functional gain of one or more of the 28 milestones defined in the natural history study. This is the primary evidence of efficacy that will support our planned BLA submission and the FDA’s review of efficacy in the REVEAL pivotal trial. In REVEAL Part A, developmental milestones were assessed by multiple independent raters through video-evidenced evaluation.

The 12 patients treated in REVEAL Part A ranged from 6 to 21 years of age at dosing, with post-treatment follow-up spanning 12 to 30 months. We enrolled patients across a broad spectrum of disease severity, as assessed by the Clinical Global Impression-Severity, or CGI-S, scale, a 7-point, clinician-rated assessment of illness severity ranging from 1 (normal/not at all ill) to 7 (among the most extremely ill). Baseline scores ranged from 4 to 6, reflecting moderately to severely ill patients.

As of the May 2026 data cutoff, 100% of the 12 patients in REVEAL Part A gained or regained ≥ one developmental milestone across the core functional domains of fine motor, gross motor and communication post-treatment with TSHA-102. These results were seen despite the broad range in age and disease severity, as depicted below:

Based on May 2026 data cutoff (N=12). Developmental milestone gains and regains were assessed by multiple independent central raters through video evidence.

A total of 31 developmental milestones were achieved across the 12 patients post-treatment, spanning the core functional domains of Rett syndrome of communication, fine motor, and gross motor function. These achievements represent the breadth of

28

response demonstrated and reflect meaningful improvements in daily living that are important to caregivers, families, and clinicians. The milestones achieved are depicted below:

Based on May 2026 data cutoff (N=12). Developmental milestone gains and regains were assessed by multiple independent central raters through video evidence.

Many patients achieved milestones as early as 3 months post-TSHA-102. These gains were persistent, and patients continued to accumulate additional milestones over time across all three core disease domains. The total number of developmental milestones achieved across the patients increased from 16 at 6 months to 27 at 12 months, representing a 69% increase, and to 31 at ≥12 months, representing a 94% increase. The majority of patients achieved multiple developmental milestones, with 75% of high-dose patients achieving two developmental milestones or more post-TSHA-102.

Based on May 2026 data cutoff (N=12). Developmental milestone gain and regains were assessed by multiple independent central rates though video evidence.

*N=7 patients with data 12 months post TSHA-102 and N=5 patients with 12-month data.

We also observed clinically meaningful skill gains and improvements in core disease characteristics beyond the 28 natural history-defined developmental milestones, which were assessed through rigorous video-evidenced evaluation and validated scales.

29

Together, the developmental milestones and additional skills and improvements reflect the totality of functional gains seen post-TSHA-102 that impact activities of daily living. At ≥12 months post-TSHA-102, a total of 310 functional gains were observed, translating to an average of 26 per patient. We believe these durable, multi-domain functional gains that accumulated over time reflect the broad functional impact of TSHA-102.

A summary of the total functional gains seen post-TSHA-102 is depicted in the chart below:

Based on May 2026 data cutoff (N=12).

1Gain/regain of ≥1 of the 28 natural history-defined developmental milestones from the REVEAL pivotal trial primary endpoint.

2Skill gains/improvements derived from MSEL-A, R-MBA and ORCA: N=8 patients with ORCA data, N=7 with MSEL-A data, and N=12 with R-MBA data.

*N=7 patients with data 12 months post-TSHA-102, N=5 patients with 12-month data.

Improvements were also observed across multiple clinician-assessed outcome measures, including Revised Motor Behavior Assessment, or R-MBA, Clinician Global Impression – Improvement, or CGI-I, and CGI-S, all of which corroborated the functional gains demonstrated post-TSHA-102.

R-MBA demonstrated a consistent and robust treatment effect across all 12 patients at both 6- and 12-months post-TSHA-102. Mean change from baseline showed statistically significant improvement at both time points compared to natural history data, as depicted in the graph below, which suggests a reversal of the expected disease trajectory. The treatment effect demonstrated greater statistical separation from natural history at 12 months than at 6 months, as reflected by a lower p-value. Beyond 12 months, the treatment effect continued to increase, with a clear dose-dependent separation. At ≥18 months, high-dose patients achieved a mean

30

improvement of 15.7 points compared to 7.8 points in the low-dose cohort. We believe these results support the therapeutic potential of TSHA-102.

Based on May 2026 data cutoff (N=12 at 6 and 12 months, N=7 at ≥18 months post-TSHA-102). Statistical analyses are based on May 2026 data cutoff (N=12).

1R-MBA assessed in Rett syndrome NHS at ~6 and ~12 months; MBA natural history data converted to R-MBA; mean scores reported were calculated from baseline to 6 and 12 months: Accessed from International Rett Syndrome Foundation (IRSF). ClinicalTrials.gov: NCT02738281: a prospective cohort of individuals with a pathologic mutation in the MECP2 gene, commonly associated with RTT.

TSHA-102 drove early, sustained global improvement in CGI-I, with dose-dependent effects that deepened overtime, as summarized in the table below. 100% of the patients demonstrated an improved CGI-I score of 3 or less at multiple post-treatment assessments. Mean CGI-I scores in the high dose cohort were less than 3 at all assessments and improved overtime, reaching 1.7 in the high-dose cohort at 18 months post-treatment.

Based on May 2026 data cutoff (N=12). CGI-I average scores based on latest assessment for each patient.

TSHA-102 demonstrated robust, clinically meaningful responses at both 6 and at 12 months and beyond across multiple key outcome measures. Importantly, we observed an 83% response rate at 6 months and a 100% response rate at 12 months, exceeding the FDA-aligned minimum threshold for the pivotal trial (33% response rate), which further bolsters our confidence in our pivotal trial 6-month interim analysis, in addition to total functional gains observed, R-MBA, CGI-I, and CGI-S data all demonstrating significant and consistent response at 6 months, 12 months and beyond. Further, the FDA has agreed that our clinical and final commercial m

[Excerpt truncated for page length; source filing is linked above.]

Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations.

The following discussion and analysis of our financial condition and results of operations should be read in conjunction with our consolidated financial statements and related notes.

Overview

We are a clinical-stage biotechnology company focused on advancing AAV-based gene therapies for the treatment of severe monogenic diseases of the central nervous system, or CNS. Our lead clinical program TSHA-102 is in development for the treatment of Rett syndrome, a rare neurodevelopmental disorder with no approved disease-modifying therapies that address the genetic root cause of the disease. With a singular focus on developing transformative medicines, we aim to address severe unmet medical needs and dramatically improve the lives of patients and their caregivers. Our management team has proven experience in gene therapy development and commercialization. We leverage this experience, our manufacturing process and a clinically and commercially proven AAV9 capsid in an effort to rapidly translate treatments from bench to bedside.

We are evaluating TSHA-102 for the treatment of females with Rett syndrome in our REVEAL and ASPIRE clinical trials.

The REVEAL Phase 1/2 Adolescent and Adult Trial, also known as Part A, is a first-in-human, open-label, randomized, dose-escalation and dose-expansion study evaluating the safety and preliminary efficacy of TSHA-102 as a single lumbar intrathecal administration in adolescent and adult females aged 12 years and older with Rett syndrome due to MECP2 loss-of-function mutation. The trial is taking place in Canada and the United States. A total of six participants aged 15 to 21 years were treated with TSHA-102 in this study, and enrollment for this trial is complete. Part A also includes the REVEAL Phase 1/2 Pediatric Trial, which is a first-in-human, open-label, randomized, dose-escalation and dose-expansion study evaluating the safety and preliminary efficacy of TSHA-102 as a single lumbar intrathecal administration in pediatric females aged 5 to 8 years with Rett syndrome due to MECP2 loss-of-function mutation. The trial is taking place in the United States and Canada. A total of six participants aged 6 to 8 years were treated with TSHA-102 in this study, and enrollment for this trial is also complete.

We have completed dosing of the 12 patients in Part A of both REVEAL trials, which includes eight patients in cohort two (high dose, 1x1015 total vg) and four patients in cohort one (low dose, 5.7x1014 total vg). We reported positive clinical data in May 2025, demonstrating that all patients gained or regained one or more developmental milestone across communication, fine motor and gross motor function following administration of TSHA-102 as of the May 19, 2025, data cutoff. Patients also showed improvements across multiple standardized Rett syndrome assessments. There have been no treatment-related serious adverse events or dose-limiting toxicities across the 12 patients treated with TSHA-102 as of the March 2026 data cutoff. An update on longer-term safety and efficacy data from the Part A REVEAL Phase 1/2 trials is expected in the second quarter of 2026.

The TSHA-102 clinical development program is designed to support the potential future approval of TSHA-102 for a broad population of patients aged 2 years and older with Rett syndrome through an efficient and rigorously designed pathway. In close collaboration with the FDA, Taysha designed the TSHA-102 pivotal program so that efficacy data from the REVEAL pivotal trial in participants aged 6 to 22 years who have reached developmental plateau can be used to represent patients aged 2 to 6 years, while safety data in younger children are generated through the separate ASPIRE trial to support the potential for a broad label for TSHA-102.

The REVEAL pivotal trial, also known as Part B, is a single-arm, open-label study evaluating the efficacy and safety of TSHA-102 in females with Rett syndrome, with each patient serving as their own control. Each participant will receive a single administration of the high dose (1x1015 total vg) of TSHA-102 delivered by lumbar intrathecal injection. The study will enroll 15 females aged 6 to 22 years in the developmental plateau population of Rett syndrome; these patients have an exceedingly low likelihood (0% to 6.7%) of gaining new or regaining developmental milestones that were lost after a defined number of years, based on our analysis of the NIH-funded International Rett Syndrome Foundation’s natural history study data. The primary endpoint will assess response rate, defined as the percentage of patients who gain or regain at least one developmental milestone from a list of 28 defined milestones across the core functional domains of communication, fine motor and gross motor, following administration of TSHA-102. Standardized milestone assessments will be administered and captured on video at pre- and post-treatment timepoints, with determination of milestone gain/regain upon video-evidence review by independent, blinded central raters based on prespecified definitions of achievement for each milestone.

We have finalized FDA alignment on the REVEAL pivotal trial protocol and statistical analysis plan, which includes a 6-month interim analysis that may serve as the basis for BLA submission. Multiple patients have been dosed in the REVEAL pivotal trial, with the first patient dosed in the fourth quarter of 2025. Additional patient enrollment continues to advance across multiple clinical trial sites. There have been no treatment-related serious adverse events or dose-limiting toxicities across the participants

84

treated with TSHA-102 in the REVEAL pivotal trial as of the March 2026 cutoff. We expect to complete dosing of all patients in the REVEAL pivotal trial in the second quarter of 2026.

We also obtained written alignment from the FDA on an extrapolation approach in a separate safety-focused study, the ASPIRE trial, and the data for inclusion in the planned BLA submission to enable broad labeling of TSHA-102 for patients aged ≥2 years with Rett syndrome. ASPIRE will enroll three females aged 2 to 4 years with Rett syndrome to evaluate the safety and preliminary efficacy of a single IT administration of high dose TSHA-102 (1x1015 total vg), scaled to account for the lower brain volume in 2 to 4‑year‑olds. A minimum of three months of ASPIRE safety data will be included in the planned BLA submission, while efficacy in the 2 to 4-year-old population will be extrapolated from data collected in the REVEAL pivotal trial, to support the potential for a broad label for TSHA-102 in patients aged ≥2 years with Rett syndrome. We expect to complete dosing in the ASPIRE trial in the second quarter of 2026.

We have a limited operating history. Since our inception, our operations have focused on organizing and staffing our company, business planning, raising capital and entering into collaboration agreements for conducting preclinical and clinical development activities for our product candidates. Our lead product candidate is still in the clinical stage. We do not have any product candidates approved for sale and have not generated any revenue from product sales. Through December 31, 2025, we have funded our operations primarily through: (i) the sale of equity, raising an aggregate of $961.0 million of gross proceeds from our initial public offering, or the IPO, sales of common stock pursuant to our Sales Agreement (as defined below), our October 2022 follow-on offering, our 2023 private placement, our June 2024 Offering (as defined below) and our May 2025 Offering (as defined below); (ii) pre-IPO private placements of our convertible preferred stock; (iii) our 2023 Term Loan Agreement (as defined below) and subsequently the 2025 Trinity Term Loan Agreement (as defined below); and (iv) the Astellas Transactions.

On November 13, 2023, or the 2023 Trinity Closing Date, we entered into a Loan and Security Agreement, or the 2023 Trinity Term Loan Agreement, by and among us, the lenders party thereto from time to time, or the Trinity Lenders, and Trinity Capital Inc., as administrative agent and collateral agent for the Trinity Lenders, or Trinity. The 2023 Trinity Term Loan Agreement provided for, on the 2023 Trinity Closing Date, $40.0 million aggregate principal amount of term loans, or, collectively, the 2023 Trinity Term Loans. We drew the 2023 Trinity Term Loans in full on the 2023 Trinity Closing Date. On August 7, 2025, we entered into the 2025 Trinity Term Loan Agreement (as defined below) with the 2025 Trinity Lenders (as defined below). We drew $50.0 million in term loans on the Trinity Refinance Date (as defined below). The existing 2023 Trinity Term Loan Agreement with the Trinity Lenders was terminated and the existing 2023 Trinity Term Loans were repaid in full concurrently with entry into the 2025 Trinity Term Loans (as defined below).

Since our inception, we have incurred significant operating losses. Our net losses were $109.0 million for the year ended December 31, 2025 and $89.3 million for the year ended December 31, 2024. As of December 31, 2025, we had an accumulated deficit of $711.3 million. We expect to continue to incur significant expenses and operating losses for the foreseeable future. We anticipate that our expenses will increase significantly in connection with our ongoing activities, as we:

•
continue to advance the clinical development of our product candidates and, if we determine to do so in the future, reprioritize the advancement of our preclinical and discovery programs;

•
conduct our ongoing clinical trials of TSHA-102 and any other current and future product candidates that we advance;

•
seek regulatory approval for any product candidates that successfully complete clinical trials;

•
work with CMOs for the manufacture of cGMP material for clinical trials or potential commercial sales;

•
establish a commercialization infrastructure and scale up internal and external manufacturing and distribution capabilities to commercialize any product candidates for which we may obtain regulatory approval;

•
continue to develop our gene therapy product candidate pipeline;

•
scale up our clinical and regulatory capabilities;

•
adapt our regulatory compliance efforts to incorporate requirements applicable to marketed products;

•
maintain, expand and protect our intellectual property portfolio;

•
hire additional clinical, manufacturing quality control, regulatory, manufacturing and scientific and administrative personnel;

•
add operational, financial and management information systems and personnel, including personnel to support our product development and planned future commercialization efforts; and

•
incur additional legal, accounting and other expenses in operating as a public company.

85

License Agreements

Research, Collaboration and License Agreement with The University of Texas Southwestern Medical Center

In November 2019, we entered into the UT Southwestern Agreement with The Board of Regents of the University of Texas System on behalf of UT Southwestern, as amended in April 2020.

In connection with the UT Southwestern Agreement, we obtained an exclusive, worldwide, royalty-free license under certain patent rights of UT Southwestern and a non-exclusive, worldwide, royalty-free license under certain know-how of UT Southwestern, in each case to make, have made, use, sell, offer for sale and import licensed products for use in certain specified indications. Additionally, we obtained a right of first refusal to negotiate for an exclusive license under certain additional patent rights and know-how of UT Southwestern. We are required to use commercially reasonable efforts to develop, obtain regulatory approval for, and commercialize at least one licensed product.

In connection with the UT Southwestern Agreement, we issued

[Excerpt truncated for page length; the complete text is on the linked full-MD&A page.]