Gene Therapy for Rare Genetic Neurodevelopmental Disorders: The Basics

Quick Overview

Dr. Sharyl Fyffe-Maricich gave a talk on gene therapy for rare genetic neurodevelopmental disorders at the 2022 FAST Science Summit. She explained the basics of gene therapy, including the use of viral vectors like adeno-associated viruses (AAVs) and lentiviruses to deliver therapeutic genetic material to cells. AAVs are non-integrating vectors that can target non-dividing cells like neurons, while lentiviruses are integrating vectors that can target dividing and non-dividing cells. Dr. Fyffe-Maricich discussed the advantages and challenges of each vector and highlighted the importance of understanding disease biology, optimizing delivery parameters, and developing appropriate outcome measures for successful gene therapy. She also mentioned the need for large-scale vector manufacturing and optimal immunosuppression protocols. While there have been approved gene therapies for some diseases, there is still ongoing research and clinical trials for neurodevelopmental disorders.

Gene therapy has emerged as a promising approach for treating rare genetic neurodevelopmental disorders. By transferring corrective genetic material to patients, gene therapy aims to correct disease-causing mutations and alleviate the symptoms of these disorders. In this talk, we will explore the basics of gene therapy, including the main approaches, delivery methods, and challenges associated with this innovative treatment.

What is Gene Therapy?

Gene therapy treats diseases by transferring corrective genetic material to patients. It aims to correct disease-causing mutations by altering the genes involved. The genetic material is typically delivered using modified viruses that cannot replicate or cause disease. These viruses act as vehicles to deliver the therapeutic genetic material to the cells. Once inside the cells, the genetic material enables the production of functional proteins, which are essential for improving the condition. The ultimate goal of gene therapy is to alleviate symptoms and potentially offer a cure for genetic diseases.

Main Approaches in Gene Therapy

There are three main approaches in gene therapy: addition, inhibition, and editing.

  1. Addition: This approach is used when a mutation causes loss of function, meaning the protein produced by the gene is not functioning properly or not produced at all. In this case, a functional version of the gene is added to the cells to restore their normal function.

  2. Inhibition: Inhibition is used when a gene produces a protein that is either overexpressed or different from its normal form, leading to toxic effects. In this approach, an inhibitory sequence is used to shut down the expression of the gene and restore normal cellular function.

  3. Editing: Editing involves altering the DNA by adding, removing, or replacing base pairs at specific locations. This approach uses engineered nucleases to cut out the mutated DNA and replace it with healthy DNA.

Delivery Methods in Gene Therapy

Gene therapy can be delivered to the body using two main methods: in vivo and ex vivo.

  1. In vivo: In this method, the genetic material is delivered directly into the patient’s body, typically through injections. It can be injected into the muscle, bloodstream, or even directly into the brain. In vivo delivery is suitable for targeting non-dividing cells, such as neurons.

  2. Ex vivo: Ex vivo gene therapy involves isolating cells from the patient, treating them with the therapeutic vector in the laboratory, and then reintroducing the modified cells back into the patient’s body. This method is commonly used for lentiviral vectors and allows for precise targeting of specific cell types.

Advantages and Challenges of AAV and Lentiviral Vectors

Two commonly used viral vectors in gene therapy are adeno-associated viruses (AAVs) and lentiviruses. Each has its own advantages and challenges.

AAV Vectors:

  • Advantages: AAV vectors are ideal for in vivo delivery and targeting non-dividing cells, such as neurons. They have a low integration rate, reducing the risk of oncogenesis. Multiple capsid choices allow for tailored cellular tropism.

  • Challenges: AAV vectors have a limited capacity for genetic material, limiting the size of genes that can be delivered. They require a single dose, as the body develops neutralizing antibodies against the vector after the initial treatment. Pre-existing neutralizing antibodies can make patients ineligible for AAV gene therapy. Targeting a sufficient number of neurons in the brain remains a challenge.

Lentiviral Vectors:

  • Advantages: Lentiviral vectors are suitable for ex vivo gene therapy and can target dividing or non-dividing cells. They infect a wide variety of cell types and provide long-term and stable gene expression.

  • Challenges: Lentiviral vectors have a medium genome size limit, limiting the size of genes that can be delivered. Integration into the host genome poses a higher risk of oncogenesis and potential activation of neighboring genes. Like AAV vectors, they also require a single dose.

Key Steps in Gene Therapy

The key steps in gene therapy include:

  1. Identifying a therapeutic gene and designing the vector and delivery strategy.
  2. Inserting the therapeutic gene into an appropriate vector.
  3. Delivering the therapeutic gene or vector to the patient through in vivo or ex vivo methods.
  4. The vector delivering the therapeutic gene to the nucleus of the cell.
  5. The cell producing functional proteins from the therapeutic gene.


Gene therapy holds great promise for treating rare genetic neurodevelopmental disorders. While there have been successful FDA-approved gene therapies for certain diseases, there is still much work to be done, especially for neurodevelopmental disorders. Each gene therapy strategy and delivery vehicle has its own advantages and challenges, and success depends on a deep understanding of the disease biology, clinical presentation, and optimization of delivery parameters. With ongoing research and development, gene therapy has the potential to significantly improve the lives of patients with rare genetic neurodevelopmental disorders.

This talk is based on a presentation by Dr. Sharyl Fyffe-Maricich at the 2022 FAST Science Summit.

Talk details

  • Title: Gene Therapy for Rare Genetic Neurodevelopmental Disorders: The Basics
  • Author(s): Sharyl Fyffe-Maricich
  • Author(s)’ affiliation: Ultragenyx Pharmaceutical
  • Publication date: 2022-12-15
  • Collection: 2022 FAST Science Summit