Fengfeng Bei, PhD, is the principal investigator of the Bei Lab in the Department of Neurosurgery at Brigham and Women’s Hospital and Gene Cell Therapy Insitute investigator at Mass General Brigham. His research focuses on neural regeneration and gene therapy, addressing the challenge of repairing damage in the central nervous system (CNS), which has a limited capacity for self-repair. The goal of his work is to develop strategies to restore neural circuits damaged by CNS injuries and neurodegenerative diseases, including optic nerve damage and spinal cord injuries.

Dr. Bei’s lab is advancing gene therapy techniques, particularly by developing novel AAV9 variants that penetrate the blood-brain barrier (BBB). These vectors hold the potential for treating CNS disorders, including rare genetic diseases. His team is working on translating these findings into clinical applications, combining therapeutic genes with delivery technologies to target the CNS effectively. In this Q&A, Dr. Bei answers questions on…

Q: What is neural regeneration and why it is such a challenging process in the central nervous system?

Bei: Neural regeneration is a strategy to repair CNS damage. It is a challenging process because almost all the neurons in the mammalian CNS do not have the natural ability to regenerate.

Q: Why is enhancing axon conduction a key factor in neural repair, particularly in conditions like optic nerve injuries?

Bei: Neurons are connected via their axons to form functional circuits. Axonal damage affects many conditions, such as the optic nerve, spinal cord injuries, and neurodegenerative disorders. We find regenerated axons through genetic and pharmacological approaches, and because they are nascent, they are incapable of conducting electrical signals as efficiently as their parent axons. Enhancing the conduction of regenerated axons is a key factor in restoring neural function in neural regeneration.

Q: What are the next steps for translating your findings into potential clinical therapies for neurodegenerative diseases or optic nerve injuries?

Bei: We are applying gene therapy to regenerate neural circuits damaged in CNS injuries and neurodegenerative diseases. In our previous studies, we identified several good candidates for therapeutic genes. We recently made a breakthrough in developing a clinically applicable gene vector that can efficiently deliver genes into the CNS. Our next step would be to combine our gene therapy technologies we developed and test them in disease models.

Q: In your recent work, you developed AAV9 variants with improved ability to penetrate the blood-brain barrier (BBB). How does this technology advance the promise of gene therapy in neural regeneration?

Bei: The BBB is a major obstacle for treating the CNS including gene therapy. The AAV9 variants we developed are safe viral vectors that can cross the BBB not only in rodents but also in primates. With our industrial partners, we are actively exploring their application in developing gene therapies for central nervous system disorders.

Q: How do you see this technology impacting the future of gene therapy for CNS disorders?

Bei: We believe the brain-penetrant AAV vectors we developed could serve as a good tool for gene therapies against a variety of central nervous system disorders. They are particularly useful in treating several rare genetic diseases such as mucolipidosis type IV, Farber disease, and Rett syndrome. We anticipate our AAV technology will be tested in human patients within less than two years.

Q: The role of transcription factors in promoting axon growth is an emerging area of research. What is the potential of using transcription factors to reprogram adult neurons into a growth-competent state, and the challenges involved in this approach?

Bei: Despite the potential of using transcriptional factors to reprogram neurons to regenerate, there remain tremendous challenges in applying such an approach for clinical use. One key issue would be how to apply such an approach safely.

Q: Looking ahead, what are the most promising directions for research in neural regeneration and gene therapy? What key challenges do you anticipate?

Bei: Delivery has been a major hurdle for gene therapy in the central nervous system. The field has witnessed significant progress recently including engineering of brain-penetrant AAV viral vectors. Several of these AAV vectors are under active development for rare genetic diseases. We are optimistic that gene therapy is becoming the forefront in treating the CNS diseases.