Gene Therapy (TSHA-102) for Rett Syndrome

Recruiting at 9 trial locations

Overseen By Taysha Gene Therapies Medical Information

Age: < 65

Sex: Female

Trial Phase: Phase 3

Sponsor: Taysha Gene Therapies, Inc.

Disqualifiers: Other neurodevelopmental disorders, Brain injury, Atypical Rett, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called TSHA-102 for adult women with Rett syndrome, a condition affecting brain development that can cause issues like loss of speech and movement problems. Researchers aim to assess the treatment's safety and effectiveness by trying two different dose levels. Women with a confirmed diagnosis of classic Rett syndrome caused by a specific gene mutation (MECP2) are suitable candidates for this study.

As a Phase 1/Phase 2 trial, the study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group. Participants have the opportunity to be among the first to potentially benefit from this innovative therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more information.

Is there any evidence suggesting that TSHA-102 is likely to be safe for humans?

Research has shown that TSHA-102, a gene therapy for Rett syndrome, is still under study to ensure its safety. This therapy aims to add a smaller version of the MECP2 gene to cells, crucial for brain function. Early results indicate that researchers are testing this treatment in both adults and children with Rett syndrome.

The therapy is administered directly into the spinal fluid to help it reach the brain. Similar treatments have tolerated this method well, but specific safety information for TSHA-102 is still being gathered. Since the trial is in its early stages, researchers are closely monitoring for any side effects. The trial aims to determine the safety and tolerability of different TSHA-102 doses. Although detailed safety information is not yet available, its presence in a clinical trial suggests some initial confidence in its safety.

As the study progresses, more information will emerge about how well participants tolerate TSHA-102. Participants must stay informed about potential risks and discuss them with their healthcare providers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike current treatments for Rett Syndrome, which mainly manage symptoms with medications like antiepileptics and physical therapy, TSHA-102 offers a potential breakthrough by targeting the root cause. This gene therapy works by delivering a functional copy of the MECP2 gene directly into the brain cells, addressing the genetic mutation responsible for the condition. Researchers are excited because this approach could lead to more lasting improvements in neurological function, offering hope for significant and sustained benefits beyond symptom management.

What evidence suggests that TSHA-102 might be an effective treatment for Rett syndrome?

Research shows that TSHA-102, a gene therapy for Rett syndrome, adds a small version of the MECP2 gene to cells. This gene is crucial for brain function, and its malfunction causes Rett syndrome. Studies have shown promise because TSHA-102 is delivered directly into the spinal fluid, effectively reaching the nervous system. Early data suggest that some patients experience symptom improvements, indicating potential benefits. The therapy remains under study in this trial, with participants receiving different dose levels in separate cohorts. These initial results offer encouragement for those living with Rett syndrome. ^{1 4 6 7 8}

Who Is on the Research Team?

Medical Monitor, M.D.

Principal Investigator

Taysha Gene Therapies

Are You a Good Fit for This Trial?

This trial is for adult females with classical Rett syndrome confirmed by a specific MECP2 gene mutation. Candidates must be open to blood transfusions if needed and cannot require invasive breathing support, have uncontrolled seizures, other progressive genetic syndromes, significant brain injuries affecting the nervous system, or abnormal development in early infancy.

Inclusion Criteria

I am willing to receive blood or blood products if needed for an adverse event.

I have Rett syndrome with a confirmed MECP2 gene mutation.

Exclusion Criteria

I have a MECP2 mutation, but it doesn't cause Rett syndrome.

I need a machine to help me breathe.

I cannot undergo spinal procedures or take certain medications due to my health conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation

Participants receive a single intrathecal administration of TSHA-102 at escalating dose levels to evaluate safety and tolerability

12 months

Dose-expansion

Participants receive a single intrathecal administration of TSHA-102 at expanded dose levels to further evaluate safety and preliminary efficacy

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Long-term follow-up

Participants are monitored for long-term safety and efficacy

15 months

What Are the Treatments Tested in This Trial?

Interventions

• TSHA-102

Trial Overview The REVEAL Adult Study tests TSHA-102, a gene therapy for Rett syndrome in women. It's an early-stage trial to see how safe it is and how well it works at two different doses over up to 63 months.

How Is the Trial Designed?

Group I: Part B Pivotal Cohort Experimental Treatment 1 Intervention

TSHA-102 at Selected Dose (Dose Level 2): 1.0 × 10¹⁵ total vector genomes (vg) Participants receive a single intrathecal (IT) administration of TSHA-102 at Dose Level 2 (1.0 × 10¹⁵).

Group II: Part A Cohort 2 Experimental Treatment 1 Intervention

TSHA-102 Dose Level 2: 1.0×10¹⁵ total vector genomes (vg) Participants receive a single intrathecal (IT) administration of TSHA-102 at Dose Level 2 (fully enrolled, 4 participants).

Group III: Part A Cohort 1 Experimental Treatment 1 Intervention

TSHA-102 Dose Level 1: 5.7×10¹⁴ total vector genomes (vg). Participants receive a single intrathecal (IT) administration of TSHA-102 at Dose Level 1 (fully enrolled, 2 participants).

TSHA-102 is already approved in United States, Canada, United Kingdom for the following indications:

Approved in United States as TSHA-102 for:

• Rett syndrome (investigational)

Approved in Canada as TSHA-102 for:

• Rett syndrome (investigational)

Approved in United Kingdom as TSHA-102 for:

• Rett syndrome (investigational)

Who Is Running the Clinical Trial?

Taysha Gene Therapies, Inc.

Lead Sponsor

Trials

5

Recruited

60+

Published Research Related to This Trial

Gene therapy using viral vectors has shown promise in treating lympho-hematopoietic disorders, particularly in trials for primary immunodeficiencies, where gene-corrected lymphoid precursors can effectively reconstitute the immune system.

For hemoglobin disorders like beta-thalassemia and sickle cell disease, achieving clinical success will require significantly higher levels of gene transfer into stem cells and a high expression of the corrective globin gene, but recent developments indicate that successful trials may be on the horizon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward safe and effective gene therapy for beta-thalassemia and sickle cell disease. Lebensburger, J., Persons, DA.[2012]

Gene therapy using adeno-associated virus (AAV) is a promising approach for treating hereditary diseases, with five therapies already approved for conditions like spinal muscular atrophy and hemophilia, indicating its potential for durable and possibly curative effects.

AAV gene therapy is advantageous because it does not integrate into the patient's genome and has low immunogenicity, making it a safer option for patients compared to other gene therapy methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Clinical Applications of In Vivo Gene Therapy with AAVs. Mendell, JR., Al-Zaidy, SA., Rodino-Klapac, LR., et al.[2022]

Gene therapy using gamma-retroviral vectors has shown promise in treating genetic diseases, but it carries significant safety risks, including the potential for malignant transformation of cells due to proto-oncogene upregulation.

In response to adverse events in previous trials, there has been a push to develop safer gamma-retroviral vectors and conduct thorough biosafety studies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biosafety considerations using gamma-retroviral vectors in gene therapy. Deichmann, A., Schmidt, M.[2019]

Onasemnogene abeparvovec, the first approved gene-replacement therapy for spinal muscular atrophy, has been shown to have manageable safety risks, with 101 out of 102 patients experiencing at least one treatment-emergent adverse event (AE) during clinical trials.

Key safety concerns include hepatotoxicity, which resolved with treatment, and transient decreases in platelet counts, while thrombotic microangiopathy (TMA) was noted in postmarketing data, indicating the need for monitoring and potential medical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Day, JW., Mendell, JR., Mercuri, E., et al.[2022]

Rett Syndrome, primarily affecting females, is a neurodevelopmental disorder characterized by cognitive impairment, communication difficulties, stereotypic movements, and growth failure, often caused by mutations in the MECP2 gene.

Currently, there is no specific treatment for Rett Syndrome, highlighting the need for careful long-term care planning and a multidisciplinary approach to support affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical characteristics of Rett Syndrome]. Abbes, Z., Bouden, A., Halayem, S., et al.[2011]

A novel gene therapy approach using a codon-optimized genomic form of rhodopsin (co-sgRho) combined with RNA interference to suppress mutant alleles showed promise in improving visual function in a mouse model of retinitis pigmentosa (RP).

The use of DNA nanoparticles, compacted with a cell-penetrating peptide, allowed for effective delivery of the therapeutic agents into the sub-retinal space, demonstrating a potential new strategy for treating autosomal dominant RP caused by rhodopsin mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomic form of rhodopsin DNA nanoparticles rescued autosomal dominant Retinitis pigmentosa in the P23H knock-in mouse model. Mitra, RN., Zheng, M., Weiss, ER., et al.[2019]

In a double-blind crossover study involving 30 girls with Rett syndrome, mecasermin (rhIGF-1) did not show significant improvement in symptoms compared to placebo, and some measures indicated worsening of symptoms.

While the treatment was generally safe with mostly mild to moderate adverse events, serious adverse events were reported, and EEG parameters also showed deterioration, suggesting caution in its use for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. O'Leary, HM., Kaufmann, WE., Barnes, KV., et al.[2019]

Gene therapy trials show better outcomes when the brain is not the primary target, and early intervention is crucial, especially in pre-symptomatic stages, to potentially prevent the onset of symptoms in conditions like Rett syndrome.

Successful gene therapy requires careful consideration of timing, administration routes, and overcoming challenges such as dosing and safety concerns, particularly for therapies targeting the MeCP2 gene associated with Rett syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders-Implications for Individuals with Rett Syndrome: A Systematic Review. Singh, J., Goodman-Vincent, E., Santosh, P.[2023]

Gene therapy (GT) appears to be a safe procedure for improving bone marrow function in patients with Fanconi anemia, as shown in a systematic review of three clinical trials involving nine patients, with no serious adverse effects reported after one year.

While GT led to stabilization in blood lineages, the limited number of studies and short follow-up duration highlight the need for further research to understand the long-term clinical outcomes and potential of GT as a standard treatment for Fanconi anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions. Shafqat, S., Tariq, E., Parnes, AD., et al.[2022]

The phase I study demonstrated that recombinant-methionyl human neurotrophin-3 (r-metHuNT3) is safe and well tolerated in healthy volunteers, with no serious adverse events reported across doses from 3 to 500 microg/kg/day.

Common mild side effects included injection-site pain, diarrhea, and elevated liver function tests, but there were no significant changes in neurological function, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects. Chaudhry, V., Giuliani, M., Petty, BG., et al.[2019]

AAVrh.10hARSA, a gene therapy vector for treating metachromatic leukodystrophy, was administered safely at a low dose in nonhuman primates, showing no significant adverse effects.

At a high dose, while localized CNS abnormalities were observed, they did not lead to clinical consequences, indicating a need to understand dose limits for safe administration of AAV vectors in the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy. Rosenberg, JB., Chen, A., De, BP., et al.[2022]

Hematopoietic stem cell-targeted gene transfer has shown significant success in treating primary immunodeficiencies, even with low levels of genetically modified stem cells, due to the strong selective advantage of corrected lymphoid precursors.

For beta-thalassemia and sickle cell disease, achieving at least 20% engraftment of modified stem cells is crucial for clinical success, and recent trials have reported promising results, including a therapeutic effect in a patient with beta-thalassemia after gene modification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders. Persons, DA.[2016]

The diagnostic criteria for Rett syndrome (RS) include specific developmental milestones and symptoms, such as normal early development followed by loss of hand skills and impaired language, which are essential for accurate diagnosis.

These criteria aim to improve communication among researchers and enhance the quality of clinical and epidemiological studies on Rett syndrome, with a tentative diagnosis typically made between 2 to 5 years of age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnostic criteria for Rett syndrome. The Rett Syndrome Diagnostic Criteria Work Group. [2022]

A phase I trial of mecasermin (recombinant human IGF-1) in 9 children with Rett syndrome showed significant improvements in breathing symptoms, although a subsequent phase II trial did not find consistent primary outcome improvements.

RNA sequencing revealed that children who improved in breathing (Responder group) had distinct gene expression profiles related to immune responses and IGF-1 signaling, suggesting these profiles could serve as biomarkers for treatment response in Rett syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome. Shovlin, S., Delepine, C., Swanson, L., et al.[2023]

Gene therapy has significant potential for treating genetic diseases by delivering a normal copy of a mutated gene to the appropriate tissue, but it faces various challenges before it can be approved for clinical use.

This paper discusses the successful design and evaluation of clinical trials that led to the FDA's first approval of an adeno-associated virus (AAV) gene therapy, highlighting the importance of regulatory interactions in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trial by "Firsts": Clinical Trial Design and Regulatory Considerations in the Development and Approval of the First AAV Gene Therapy Product in the United States. Reape, KZ., High, KA.[2023]

Citations

1. reverserett.org reverserett.org/news/articles/a-review-of-gene-therapy-clinical-trials/

A Review of Gene Therapy Clinical Trials The Treatment: Taysha's gene therapy for Rett syndrome, called TSHA-102, adds a shortened “mini-gene” version of the MECP2 gene to cells.

2. ir.tayshagtx.com ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-presents-new-supplemental-data-analysis

Taysha Gene Therapies Presents New Supplemental Data ... TSHA-102 is a self-complementary intrathecally delivered AAV9 investigational gene transfer therapy in clinical evaluation for Rett syndrome.

3. ir.tayshagtx.com ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-fda-breakthrough-therapy

Taysha Gene Therapies Announces FDA Breakthrough ... TSHA-102 is a self-complementary intrathecally delivered AAV9 investigational gene transfer therapy in clinical evaluation for Rett syndrome.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06152237

Safety and Efficacy of TSHA-102 in Pediatric Females With ... Participant has a confirmed diagnosis of classical/typical Rett Syndrome with a documented mutation of the MECP2 gene that results in loss of function.

5. neurology.wustl.edu neurology.wustl.edu/novel-gene-therapy-clinical-trial-targets-rett-syndrome/

Novel Gene Therapy Clinical Trial Targets Rett Syndrome A pioneering clinical trial evaluating TSHA-102, an investigational gene therapy for the treatment of Rett syndrome, a severe neurodevelopmental disorder ...

6. ir.tayshagtx.com ir.tayshagtx.com/static-files/13d0b9a1-1b34-42d8-9231-79c861547884

Safety and Efficacy Data on TSHA-102 AAV9 Investigational ⚬ TSHA-102 is a one-time gene therapy for Rett syndrome, designed to enable optimal and controlled transgene expression of MECP2 across the ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06152237

Safety and Efficacy of TSHA-102 in Pediatric Females With ... Participant has a confirmed diagnosis of classical/typical Rett Syndrome with a documented mutation of the MECP2 gene that results in loss of function.

8. ir.tayshagtx.com ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-positive-clinical-data-across

Taysha Gene Therapies Announces Positive Clinical Data ... Additionally, the patient showed improvement in posture and stability at week 25 post-treatment. We believe these longer-term clinical data ...