Pipeline

Thousands of patients are affected by monogenic CNS diseases.

At Taysha, we aim to address this devastating need through our pipeline of AAV-based gene therapies.

Our gene therapy candidates are designed to target the unique, underlying biology of diseases of the CNS. We are focused on advancing our lead clinical program in Rett syndrome.

Program

Indication

Discovery

Preclinical

Phase 1/2

Pivotal

Rett Syndrome

TSHA-102

Regulated GRT

REVEAL Adult Study Canada

Preclinical

TSHA-102

Regulated GRT

REVEAL Pediatric Study U.S.

Phase 1/2

Other Clinical Stage Programs

TSHA-120

GRT

Giant Axonal Neuropathy

Phase 1/2

TSHA-118

GRT

CLN1 Disease

Phase 1/2

TSHA-105

GRT

SLC13A5 Deficiency

Phase 1/2

GRT: Gene replacement therapy

We have deprioritized the company sponsored evaluation of TSHA-120 for GAN, TSHA-118 for CLN1 and TSHA-105 for SLC13A5 and are seeking external strategic options to potentially enable further program development.

TSHA-120

TSHA-120 is a clinical-stage AAV9 gene therapy program being developed for the treatment of giant axonal neuropathy, or GAN, which is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin and the accumulation of intermediate filaments. TSHA-120 is a fully optimized, AAV9 self-complementary viral vector that encodes the full length human gigaxonin protein.

TSHA-102

TSHA-102 is a self-complementary intrathecally delivered AAV9 gene transfer therapy in clinical evaluation for Rett syndrome, a neurodevelopmental disorder and one of the most common genetic causes of severe intellectual disability, characterized by rapid developmental regression and in many cases caused by heterozygous loss of function mutations in MECP2, a gene essential for neuronal and synaptic function in the brain. TSHA-102 is constructed from a neuronal specific promoter, MeP426, coupled with the miniMECP2 transgene, a truncated version of MECP2, and miRNA-Responsive Auto-Regulatory Element, or miRARE, our novel miRNA target panel, packaged in self-complementary AAV9, which enables cellular regulation of both endogenous and exogenous MECP2 expression.

TSHA-118

TSHA-118 is being developed for the treatment of CLN1 disease, also known as infantile Batten disease, a rapidly progressing rare lysosomal storage disease with no approved treatment. TSHA-118 is a self-complementary AAV9 viral vector that expresses human codon-optimized CLN1 complementary deoxyribonucleic acid under control of the chicken ß-actin hybrid promoter.

Publications

General

Prasad, S. et al. Immune Responses and Immunosuppressive Strategies for Adeno-Associated Virus–Based Gene Therapy for Treatment of Central Nervous System Disorders: Current Knowledge and Approaches. Human Gene Therapy. DOI: 10.1089/hum.2022.138

Goodspeed, K, et al. Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies. Frontiers in Neurology. 2022 Jun; https://doi.org/10.3389/fneur.2022.805007

Prasad, S, et al. Accepting the Challenge: Innovative Approaches and Translational Strategies in Gene Therapy Development. Abstract/Presentation. American Society of Gene and Cell Therapy Annual Meeting 2022.

Gray, SJ. Timing of Gene Therapy Interventions: The Earlier, the Better. Mol. Ther. 2016 Jun; 24(6): 1017-1018

Rett

Prasad, S, et al. Safety and Biodistribution Assessment in Non-Human Primates (NHPs) of a miniMECP2 AAV9 Vector for Gene-Replacement Therapy of Rett Syndrome. Abstract/Presentation. American Society of Gene and Cell Therapy Annual Meeting 2022; International Rett Syndrome Foundation Rett Syndrome Scientific Meeting 2022.

Prasad, S, et al. Safety Assessment of High-Dose miniMECP2 AAV9 Gene-Replacement Therapy (TSHA-102) for Rett Syndrome in Rats. Abstract/Presentation. American Society of Gene and Cell Therapy Annual Meeting 2022; International Rett Syndrome Foundation Rett Syndrome Scientific Meeting 2022.

Gadalla, KKE, et al. Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome. Mol Ther Methods Clin Dev. 2017 Apr 22; 5:180-190

Sinnett, SE, et al. A New Approach for Designing a Feedback-Enabled AAV Genome Improves Therapeutic Outcomes of MiniMeCP2 Gene Transfer in Mice Modeling Rett Syndrome. Abstract 92. 2020 Mol Ther. Apr 28;28(4S1):47

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

Sinnett, SE, et al. Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery. Mol Ther Methods Clin Dev. 2017 Apr 19; 5:106-115

Sinnett, SE and Gray, SJ. Recent endeavors in MECP2 gene transfer for gene therapy of Rett syndrome. Discov Med. 2017 Oct; 24(132)153-159

SLC13A5

Goodspeed, K. et al. SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes 2022; 2022 Volume: 13 Issue: 9 Pages: 1655

Bailey, L, et al. Gene Therapy Treatment in Young SLC13A5 Deficient Mice. Abstract/Presentation. American Society of Gene and Cell Therapy Annual Meeting 2022.

Yang, QZ, et al. Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder. Child Neurol Open. 2020 Jun 8;7:2329048X20931361

CLN1

Leal-Pardinas, F, et al. Designing a first-in-human gene replacement therapy clinical trial for CLN1. Abstract/Presentation. WORLDSymposium 2022.

Haque, E, et al. Development of an assay to measure PPT1 activity in human cerebrospinal fluid (CSF) and serum for the evaluation of preliminary effectiveness of AAV9 gene therapy for CLN1 disease. Abstract/Presentation. WORLDSymposium 2022.

Chandra, G, et al. Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders. Hum Mol Genet. 2015 Oct1;24(19):5416-32

Koster, KP and Yoshii, A. Depalmitoylation by Palmitoyl-Protein Thioesterase 1. Neuronal Health and Degeneration. Front Synaptic Neurosci. 2019 Aug 29;11:25

Masten, MC, et al. CLN1 Natural History. Abstract #260. Molecular Genetics and Metabolism. 2020

Schulz, A, et al. NCL diseases – Clinical Perspectives. Biochim Biophysic Acta. 2013 Nov;1832(11):1801-06

GAN

Bailey, R, et al. Vagus Nerve Delivery of AAV9 to Treat Autonomic Nervous System Dysfunction in Giant Axonal Neuropathy. Abstract/Presentation. American Society of Gene and Cell Therapy Annual Meeting 2022.

Bharucha-Gobel D, et al. Giant axonal neuropathy: cross sectional analysis of a large natural history cohort. Brain 2021 awab179

Armao D, et al. Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease. Clin Auton Res. 2016 Aug;26(4):307-13

Bailey RM, et al. Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy. Mol Ther Methods Clin Dev. 2018 Jun 9;9:160-171

Bailey RM, et al. Comparison of Intra-Cisterna Magna and Lumbar Puncture Intrathecal Delivery of scAAV9 Gene Therapy for Giant Axonal Neuropathy. Abstract 604. Mol Ther. 2016 May;24(S1):239

Bailey RM, et al. Direct Vagus Nerve Injection of AAV9 as a Treatment Approach for Autonomic Dysfunction in Giant Axonal Neuropathy. Abstract 936. Mol Ther. Apr 28;28(4S1):405

Bharucha-Goebel D, et al. A Systematic Analysis of the Immunologic Effects of Intrathecal AAV9 Mediated Gene Transfer Targeting the Nervous System in Giant Axonal Neuropathy. Abstract 49. Mol Ther. Apr 28;28(4S1):24

Johnson‐Kerner, BL, et al. Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis. Muscle Nerve. 2014 Oct;50(4):467-76

Saade D, Gray SJ et al. Review of Safety and Interim Analysis of Efficacy in the First in Human Intrathecal Gene Transfer Trial for Giant Axonal Neuropathy. Abstract 610. Mol Ther. Apr 28;28(4S1):271