CIRM Session on In Utero and Gene Therapies 📚

Overview

• Introduction by session host
  • Speakers from California and Tennessee
  • Focus on in utero and gene therapies for genetic diseases
  • Speakers: Dr. Tippi MacKenzie (UCSF), Dr. Matt Spear (Poseida Therapeutics), Dr. Steve Gottschalk (St. Jude's Children's Hospital)

Dr. Tippi MacKenzie (UCSF)

Topic: In Utero Cellular-Based Therapies for Genetic Diseases

• Focus: Alpha Thalassemia
• Concept: Treating deadly genetic diseases before birth
• UCSF's pioneering work in fetal surgery since the 1980s
  • Open, laparoscopic, and fetoscopic surgeries
  • Current focus: stem cell and gene therapies via umbilical vein

Why Fetal Therapy?

• Unique immune system of the fetus can be tolerized to new proteins
• Protect the brain before the blood-brain barrier forms
• Access migrating stem cells (e.g., from liver to bone marrow)

Current Work & Clinical Trials

• Phase 1 trial: Fetal stem cell transplants for alpha thalassemia major
• Additional techniques: enzyme replacement, gene therapy
• Unique immune tolerance developed by fetuses
• Maternal cells preferable for in utero transplants

Case Studies & Preclinical Experiments

• Success in animal models (dogs)
  • Maternal cells show good engraftment and tolerance
• Concept: Two-step process (in utero transplant followed by postnatal booster)
• Human trials showing feasibility and safety

Outcomes & Future Directions

• International registry to track outcomes
• UCSF's pipeline for fetal molecular therapies
  • Working towards expanding indications, optimizing protocols
• Ethical considerations
  • Non-directive counseling, patient representation

Acknowledgements

• Funding from CIRM
• Collaboration with UCSF teams and international colleagues

Dr. Matt Spear (Poseida Therapeutics)

Topic: Developing CAR-T and Gene Therapies

Key Technologies

• Super PiggyBac Transposon System: For gene transfer
  • Advantages include large cargo capacity, favoring specific cell types
• Cas-CLOVER Gene Editing System: Low off-target editing, edits resting T cells

CAR-T Cell Development

• Autologous CAR-T Cells: Starting point, targeting BCMA in multiple myeloma
• Allogeneic CAR-T Cells: Using one donor for multiple patients
• Advancements in gene therapy for inborn errors of metabolism

Trials and Results

• Positive outcomes in clinical trials for multiple myeloma (P-BCMA-101)
  • Low incidence of cytokine release syndrome
  • High response rates
• Developments in prostate cancer (P-PSMA-101)
  • Efficacy in preclinical models
  • Clinical trials recently initiated

Future Directions

• Multi-targeted CAR-T cells
  • Example: Using large cargo capacity to target multiple tumor antigens
• Expand to treat other cancers beyond multiple myeloma and prostate cancer
• Supported by CIRM

Dr. Steve Gottschalk (St. Jude's Children’s Hospital)

Topic: Gene Therapy for X-Linked SCID

• Also known as Bubble Boy Disease
• Traditional treatment: Bone marrow transplants
• New approach: Lentiviral vector gene therapy

Clinical Trial Details

• Marrow from patients genetically modified and reinfused
• 16 patients treated (~2-14 months old)
• Using new, safer lentiviral vectors

Results

• High levels of functional T cells, including naive T cells
• B cells produced antibodies, responded to vaccines
• Long-term presence of genetically modified cells
• No malignant transformations observed

Future Goals

• Continue monitoring long-term safety and efficacy
• Extend trials to other institutions
• Acknowledge collaborative efforts in the success of the trial

Q&A Highlights

• Discussion on chimerism and immune tolerance in in utero transplants
• Challenges and future directions in improving engraftment and efficacy
• Comparisons between retroviral, lentiviral vectors, and transposon systems
• Integration sites and long-term safety for gene therapies

Conclusion

• Recognition of CIRM's support in innovative therapies
• Emphasis on transforming patient lives with cell and gene therapies