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RESEARCH & DEVELOPMENT DAY DAY 2

- June 29, 2021 | 9:00 AM - 12:00 PM CT Bringing New Cures to Life Exhibit 99.1

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Introductions RA Session II President,

TSHA-104 for SURF1-Associated Leigh

Syndrome TSHA-104 SURF1 deficiency Steven Gray, PhD Chief Scientific Advisor, UTSW Gene Therapy Program Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer and Head of R&D

TSHA-104 SURF1 deficiency SURF1

deficiency is the most common cause of Leigh syndrome A monogenic mitochondrial disorder Most common cause of cytochrome c oxidase deficient Leigh syndrome Leigh syndrome - severe neurological disorder that presents in the first year of life

Initially often presents with gastrointestinal symptoms Progressive loss of mental and movement abilities, often regression is episodic in nature Can result in death within two to three years ~10-15% have SURF1 mutation No approved therapies

Estimated prevalence of SURF1 deficiency is 300 to 400 patients (US+EU)

SURF1 deficiency - the most

challenging symptoms as reported by families and caregivers Breathing (3 caregivers) Breathing issues (x3) Strength (6 caregivers) Muscle weakness (x4) Inability to sit (x3) Head and trunk control (x2) Inability to stand Movement and motor skills (8

caregivers) Loss of balance (x4) Tremors (x4) Crawling (x2) Inability to walk Reaching Dystonia and chorea Feeding/nutrition (6 caregivers) Failure to thrive (x3) Feeding issues (x2) Swallowing issues (x2) Constipation (x2) Vomiting Vision (4

caregivers) Nystagmus (x4) Strabismus (x2) Speech (3 caregivers) Speech (x3) Other Sleep issues (x2) Scoliosis Nearly all caregivers cited a symptom related to movement; however, the specific symptom varied greatly based on the disease progression,

the child's interests, and age. For example, interests in drawing, writing, or school caused tremors to top the list. Several caregivers mentioned a symptom related to nutrition and/or strength. Nutrition was seen as the root of other issues

and caregivers felt improvements there could mean improvements in overall strength and other symptoms. While breathing issues were only experienced by a few, if children experienced breathing issues they most certainly topped the list. Caregiver

insights generated through workgroup TSHA-104 SURF1 deficiency

SURF1 deficiency natural history study

- Initial symptoms Review of 44 cases with SURF1 deficiency Median age for first symptom onset was 9.5 months (range 0-60 months); majority presented in the first year (32/44, 73%) Most frequently noted initial symptoms included poor

feeding/vomiting (frequently attributed to gastroesophageal reflux) and poor weight gain Neonatal period uneventful in majority of patients (41/44, 93%) Most (26/44, 59%) presented with combination of GI symptoms, poor weight gain and hypotonia

Developmental regression (loss of cognitive or motor skills) was initial symptom in 3/44 (7%) patients Wedatilake et al. Orphanet J Rare Dis 2013 TSHA-104 SURF1 deficiency Initial symptoms Number of patients (%) Age range of initial

presentation (months) poor feeding/vomiting 20 (46) 0-24 poor weight gain 19 (43) 1.5-20 developmental delay 10 (23) 9-51 hypotonia 9 (21) 0-10 movement disorder 3 (7) 10-24 developmental regression 3 (7) 10-18 ataxia 2 (5) 14-60 Initial symptoms in

44 patients with SURF1 deficiency

SURF1 deficiency natural history study

- Major clinical features Symptoms occurring in ~80%+: vomiting/feeding problems, growth failure, hypotonia, developmental delay and respiratory failure. Median time to onset of most symptoms was 1-2 years TSHA-104 SURF1 deficiency Wedatilake

et al. Orphanet J Rare Dis 2013

SURF1 deficiency natural history study

- Survival Among 44 patients with detailed clinical data, 5 were alive at time of writing (ages 2-19 years); current vital status was unknown for 3 Of the 36 deceased patients with known cause of death, the cause was central respiratory

failure in 29/36 (80%) Seven patients survived beyond 10 years of age Of these, 6 had neurological symptoms such as ataxia and motor developmental delay; of note, GI symptoms were not the prominent presenting feature in these cases. Furthermore,

these six patients also did not experience developmental regression Literature searches identified 98 SURF1-deficient cases with available survival data, which were pooled together with the data from the 44 cases. The Kaplan-Meier analysis compares

the survival experience of 142 SURF1-deficient cases to two other groups with LS due to nuclear gene mutations (56 with LRPPRC deficiency and 63 with nuclear-encoded complex I-deficient LS/"Leigh- like" disease) Median survival length

for SURF1 deficiency was 5.4 years (25th centile 3.0, 75th centile 10 years) TSHA-104 SURF1 deficiency Wedatilake et al. Orphanet J Rare Dis 2013 Survival Probability

AAV9 capsid Brain tropism &

favorable safety profile TSHA-104 IND/CTA submission expected by YE 2021 Recombinant AAV9 viral vector with engineered transgene encoding the human SURF1 protein Designed to deliver a functional copy of the SURF1 gene Received orphan drug and rare

pediatric disease designations TSHA-104 SURF1 deficiency

Slight increase in COX1 activity

significantly improved clinical phenotype Of 17 samples, 14 were assayed 8 Leigh syndrome & 6 healthy donors (hets) Severely affected individuals had roughly 50% of normal activity Mildly affected individuals had roughly 58% of normal activity A

relatively small difference in activity could have significant clinical consequences Other studies measuring COX activity have shown roughly 20% of normal activity for affected individuals Potential reason - "healthy" donors are

heterozygote parents of affected children; this and their age may affect their COX activity. In other studies, healthy children were used for reference TSHA-104 SURF1 deficiency Healthy (Het)

Reduction in COX activity

correlated with disease worsening - Patient fibroblast data TSHA-104 SURF1 deficiency Mild Healthy (Het) Severe

Vector transduction efficiency and

efficacy - Part I COX activity assay in various tissues RNAScope for hSURF1opt mRNA expression COX content level using MT-CO1 protein as marker TSHA-104 SURF1 deficiency

TSHA-104 increased COX1 activity in

brain and muscle in dose-dependent manner in SURF1 KO mice Ling Q et al. ASGCT 2020 TSHA-104 SURF1 deficiency * * Relative Activity * Relative Activity Change in relative COX1 activity * * Relative Activity

Improvement in MT-CO1 abundance 4

weeks post-injection TSHA-104 SURF1 deficiency

Biochemical COX activity correlated

with histological COX content level TSHA-104 SURF1 deficiency

Efficacy Part II - Long-term

rescue TSHA-104 SURF1 deficiency

TSHA-104 restored elevation of blood

lactate on exhaustive exercise in dose-dependent manner in SURF1 KO mice lactate 10 months Change in lactate (post exhaustion lactate-pre-exhaustion lactate) of mice from all tested groups at 10 months old. Data shown as mean +SEM **p<0.01,

***p<0.001, and ****p<0.0001 **** **** ** *** TSHA-104 SURF1 deficiency

Non-GLP Toxicology in Mice No

significant differences detected in viral vector-treated animals 4 weeks post-dosing No severe damages detected in tissue integrity 12 months post-injection, some mild abnormalities mostly due to aging Summary Efficacy in SURF1 KO Mice Effectively

induced mRNA expression of hSURF1opt in various brain regions and spinal cord Diminished exhaustive exercise-induced lactic acidosis 9 months post-dosing Partially restored COX content in varies brain regions Partially restored COX activity in

brain, liver and muscle IT administration demonstrated benefit GLP Toxicology in Rats Ongoing IND-enabling toxicology study in normal rats TSHA-104 SURF1 deficiency

TSHA-104 Phase 1/2 study design plan

TSHA-104 SURF1 deficiency Goals and Targets of Trial Product Details and Dose Cohorts Route and Method of Administration Dose Cohorts Participants below the age of 4 years will receive a calculated dose based on brain volume 5 x 1014 total vg (n=4)

Goals Primary - Safety: clinical and laboratory assessments Secondary - Efficacy: pathologic, physiologic, functional and clinical markers Target Recruitment Patients will roll in from ongoing prospective natural history study Up to 12

subjects, ages 1-18 years old Pathogenic confirmation of mutation in SURF1 gene All cohorts will be open for accrual concurrently Technique to Improve Transduction Trendelenburg position (15-30o ) During infusion & 1 hour post infusion

Administration Lumbar Intrathecal Infusion (IT) Amount and rate: 1 mL/min for total of 10-12 mL Immunosuppression regimen of prednisolone and sirolimus

TSHA-104 study clinical assessments

Disease-Specific/Global Assessments Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Gross Motor Function Measure (GMFM) Swallowing / Dysphagia Assessment Seizure Diary 100-Meter Walk Test Pediatric Balance Scale (PBS) Head Control

Scale Scale for the Assessment and Rating of Ataxia (SARA) Vineland-3 Bayley-III / WPPSI-IV / WISC-IV Communication Assessments Expressive and Receptive One-Word Picture Vocabulary Test (ROWPVT-4, EOWPVT-4) Observer-Reported Communication Ability

(ORCA) Biomarkers COX activity COX expression Lactate Pyruvate Quality of Life/Other Assessment Quality of Life Inventory Disability (QI-D) Infant Toddler Quality of Life Questionnaire (ITQOL) PedsQL Scales and Family Impact Module Study Participant

Feedback Questionnaire Clinical Global Impression Scale (CGI) Neurological Assessment EEG MRI/MRS TSHA-104 SURF1 deficiency

Anticipated next steps for TSHA-104

TSHA-104 SURF1 deficiency Complete GMP manufacturing using commercial process Submit IND/CTA in 2H 2021 Initiate Phase 1/2 interventional study by YE 2021 Continue enrollment in natural history study Complete IND-enabling toxicology study

Q & A TSHA-104 SURF1

TSHA-105 for SLC13A5 Deficiency

TSHA-105 SLC13A5 deficiency Rachel Bailey, PhD UTSW Gene Therapy Program Suyash Prasad, MBBS, MSc, MRCP, MRCPCH, FFPM Chief Medical Officer and Head of R&D

SLC13A5 deficiency is a rare

autosomal recessive disorder Bi-allelic loss of function in the SLC13A5 gene, resulting in a loss or reduction in citrate transport and aberrant cellular metabolism Patients have impaired motor function, speech production and seizures Signs and

symptoms include seizures within a few days of birth, persisting through life, encephalopathy, delayed speech/language development, developmental regression and abnormalities in tooth enamel First-line treatment is anti-seizure medications Estimated

prevalence of SLC13A5 deficiency is 1,900 patients in the US and EU Received orphan drug and rare pediatric disease designations Bhutia et al, Molecules 2017 TSHA-105 SLC13A5 deficiency NORMAL SLC13A5 mutation

SLC13A5 involvement in citrate

transport Disorder caused by mutations in both copies of the SLC13A5 gene which codes for a sodium dependent citrate transporter (NaCT) SLC13A5 mutations greatly reduce or eliminate citrate transporter activity Citrate is a key metabolite and plays

an important role in energy generation pathways in the cells NaCT expressed mainly in liver and brain NaCT can transport other molecules (succinate, alpha-ketoglutarate, and malate) SLC13A5 deficient patients have increased citrate levels in CSF and

blood TSHA-105 SLC13A5 deficiency

SLC13A5 deficiency results in

persistent seizures and developmental delays Seizures Affected children present with seizures within a few days of birth which persist throughout life Multiple seizure types; Anti-epileptic drugs (phenobarbital, valproate, and acetazolamide) have

varying success in controlling seizures Refractory to medication Children can succumb to complications of the seizures Movement Disorder Low muscle tone (hypotonia) and a lack of muscle control or coordination of voluntary movements, such as walking

or picking up an object (ataxia) Episodes of body stiffening or weakness (minutes to a few hours) Dystonia & chorea TSHA-105 SLC13A5 deficiency Yang et al. Child Neurology Open 2020 Developmental Delay Intellectual disability and global

developmental delay Limited to no speech production, but have receptive language Limited and slow motor progress with problems standing or walking independently Biomarkers Nearly all children have abnormal tooth enamel Brain MRIs appear normal or

have subtle changes in the white matter EEGs have a relatively well-preserved background for age, even in the face of frequent seizures Elevated citrate levels in blood, urine and CSF No currently approved therapies Patients require constant

supervision and care