Approach

Our proven approach bridges the gap between innovation and a potential cure.

With our gene therapy approach, we’re changing the way we speak about disease.

Gene therapies have proven to deliver transformational benefit to patients who suffer from devastating diseases. Our mission at Taysha is to build upon these advancements to eradicate monogenic CNS diseases for the thousands affected. Through our proven gene therapy strategy and our unrivaled partnership with UT Southwestern, we are creating an engine for new cures.

A Proven Strategy

The fundamental components of our approach are based on recent success in gene therapy development and commercialization: an adeno-associated virus serotype 9 (AAV9) capsid, intrathecal delivery and an efficient manufacturing process.

AAV9 Capsid

We use an AAV9 capsid to deliver therapeutic genes engineered to replace a mutated gene, enhance the expression of a silenced gene or decrease the expression of a gene. AAV9 has a unique ability to cross the blood-brain barrier, making it an ideal vector for gene therapies in the CNS, and since its discovery more than 50 years ago, AAV has been one of the most well-studied vehicles for the delivery of gene therapies.

Intrathecal Delivery

We use intrathecal administration, which directly delivers our gene therapies to the cerebrospinal fluid to facilitate optimal biodistribution and cell transduction within the central nervous system. The procedure is routinely performed in an outpatient setting, and in comparison to intravenous administration, it allows for a lower dose of the therapy.

Efficient Manufacturing

Our flexible manufacturing processes allow us to produce our gene therapy product candidates efficiently at scale. Through our partnership with UT Southwestern, we have access to a GMP-compliant manufacturing suite that utilizes a suspension HEK293 process to produce AAV9.

Next-Generation Platform Technologies

We are developing next-generation technologies to optimize key components of our AAV-based gene therapies, including redosing, transgene regulation and capsid development.

AAV Redosing
Platform

There are challenges to delivering viral gene therapies. They can elicit an immune response, especially if the need to dose more than once arises due to the complexities of a disease.

In addition, appropriate distribution in the nervous system of CNS-specific therapies is technically challenging.
We are addressing those challenges by advancing a novel AAV dosing platform that enables:

  • Redosing by subverting the immune response
  • Delivery through the vagus nerve enabling broad coverage of the nervous system

We believe that direct administration of our AAV9 therapies to the vagus nerve could be useful to treat the peripheral and autonomic manifestations of the CNS diseases in our pipeline.

Pelvic splanchnic nerves Nerve IX Nerve VII Nerve III Nerve X (Vagus) Stimulates bile release Stimulates peristalsis and secretion Slows heartbeat Constricts bronchi Stimulates flow of saliva Contracts bladder Constricts pupils

Regulated Transgene Expression Using miRARE

In a number of disorders, including Rett syndrome and FOXG1 syndrome, the expression of a therapeutic transgene needs to be regulated. High doses of the engineered gene may be harmful, while low doses may not be effective. For disorders that require replacement of dose-sensitive genes, we have combined high-throughput microRNA (miRNA), profiling and genome mining to create miRARE, our novel miRNA target panel. This approach is designed to enable our product candidates to maintain safe transgene expression levels in the brain.

miRNA-responsive target sequence in untranslated region Translation and nuclear localization miRNA expression Transgene drives expression of many endogenous miRNAs Viral genome in nucleus mRNA in cytoplasm Mature miRNA 1 2 3 4 Transgene 5 Mature miRNAs bind to mRNA in cytoplasm to regulate its expression Transgene

Novel Capsid
Identification

Our novel AAV capsid platform allows us to:

  • Utilize machine learning, capsid shuffling and directed evolution to improve targeted delivery
  • Deliver targeted gene therapies at lower doses
  • Exhibit selective tropism for neurons, astrocytes and/or oligodendrocytes

We believe that our approach will allow us to rapidly identify new capsids to drive new product candidates for CNS disorders with novel biodistribution and transduction profiles into our development pipeline.

Capsid genes of AAV1-6, 8, 9, rh10, + lab variants DNasel Fragmentation Assembly and Amplification Directed evolution of novel AAV variants Selection of cell type-specific AAV variants for vector development ITR Cap Rep ITR
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