Gene Therapy (TSHA-102) for Rett Syndrome

Recruiting at7 trial locations

Age: Any Age

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Taysha Gene Therapies, Inc.

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

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing a new gene therapy called TSHA-102 in adult women with Rett syndrome. The therapy aims to fix the genetic problems causing the disorder by adding healthy genes to their cells. Researchers will study its safety and effectiveness over several years. TSHA-102 is a gene therapy aimed at addressing the genetic deficiencies in Rett syndrome by adding healthy MECP2 genes to the cells.

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.

What data supports the idea that Gene Therapy (TSHA-102) for Rett Syndrome is an effective treatment?

The available research does not provide specific data on the effectiveness of Gene Therapy (TSHA-102) for Rett Syndrome. Instead, it discusses other treatments like mecasermin, which showed some improvements in breathing symptoms in certain patients with Rett Syndrome. However, the results were not consistent across all trials. The research also suggests that gene therapies in general might be more effective when applied early in the disease progression and when the brain is not the primary target. This information could be useful for optimizing gene therapy approaches for Rett Syndrome in the future. ^{1 2 3 4 5}

What safety data exists for TSHA-102 gene therapy for Rett Syndrome?

The provided research does not contain specific safety data for TSHA-102 gene therapy for Rett Syndrome. The articles discuss safety data for other gene therapies and vectors, such as those used in Fanconi anemia, spinal muscular atrophy, and metachromatic leukodystrophy, but not for TSHA-102. ^{6 7 8 9 10}

Is the treatment TSHA-102 a promising treatment for Rett Syndrome?

Yes, TSHA-102 is a promising treatment for Rett Syndrome because gene therapy has shown potential in treating genetic diseases by providing a normal copy of a mutant gene, which can lead to effective and long-lasting benefits. ^{11 12 13 14 15}

Research Team

Meredith Schultz, M.D.

Principal Investigator

Taysha Gene Therapies

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• TSHA-102 (Gene Therapy)

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.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

Dose Level 2

Group II: Cohort 1 Experimental Treatment 1 Intervention

Dose Level 1

TSHA-102 is already approved in Canada for the following indications:

Approved in Canada as TSHA-102 for:

• Rett syndrome (investigational)

Who Is Running the Clinical Trial?

Taysha Gene Therapies, Inc.

Lead Sponsor

Trials

5

Recruited

60+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome. [2023]

4. Switzerland 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. [2023]

5. Tunisia pubmed.ncbi.nlm.nih.gov

[Clinical characteristics of Rett Syndrome]. [2011]

6. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions. [2022]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Biosafety considerations using gamma-retroviral vectors in gene therapy. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects. [2019]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Genomic form of rhodopsin DNA nanoparticles rescued autosomal dominant Retinitis pigmentosa in the P23H knock-in mouse model. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Progress toward safe and effective gene therapy for beta-thalassemia and sickle cell disease. [2012]

13. United States pubmed.ncbi.nlm.nih.gov

Current Clinical Applications of In Vivo Gene Therapy with AAVs. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

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

15. United States 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. [2023]