Patient Education Webinar: Gene Therapy Routes of Administration

On August 25th, 2022, the American Society of Gene & Cell Therapy held a webinar as part of its Lunch and Learn series, which is intended to help people living with genetic illnesses learn more about the technology of gene therapy. This edition of the series was titled “Routes of Administration,” and was mostly focused on delivery methods that have been developed or are being explored for gene therapy. Gene therapies have to the potential to be a highly effective or even curative treatment method for a wide variety of genetic disorders and diseases.

The primary speaker for the program was Kimberly Goodspeed, MD, MSCS, Assistant Professor of Pediatrics, Neurology, and Psychiatry, University of Texas Southwestern Medical Center.

Dr. Goodspeed first distinguished between in-vivo and ex-vivo gene therapies. In the in-vivo form, the transport mechanism, a viral vector, is conditioned in the lab setting to transport a health copy of the affected gene, which is then administered to the patient. In an ex-vivo gene therapy, cells are first extracted from the patient, are treated in the lab setting with the therapy, and then reintroduced to the body of the patient.

Immunosuppression is critical for these methods to work. The ex-vivo form in particular requires more extensive conditioning in order for the treated cells to be accepted by the body. This usually means radiation or chemo.

Routes of administration for gene therapies generally include the cerebrospinal fluid, the blood, and directly into specific organ systems. Routes for a given therapy are decided based on several factors:

  • What worked in pre-clinical studies?
  • Which organs are being affected?
  • Ex-vivo vs in-vivo
  • What dose level is expected to be used?
  • Age of the patient
  • Are there other medical issues?

Blood, or intravenous route (IV), is a direct method for administering a gene therapy. This allows for a therapy to be spread throughout the body.

Other pros of this method include:

  • Relatively easy to administer
  • Effective for both ex-vivo and in-vivo methods

Potential cons of this route include:

  • Off-target effects
  • Interactions with antibodies that could neutralize the therapy
  • Triggers a strong immune reaction
  • Often requires a large quantity of vector (transporters, typically modified viruses)

Zolgensma for spinal muscular atrophy (SMA), one the the first approved gene therapies, is administered in this way. Other routes are being investigated for this therapy.

The cerebrospinal fluid (CSV) method actually involves multiple potential routes. One of which is the lumbar intrathecal route, in which the therapy is delivered to the lower spine.


  • Avoids interactions with antibodies
  • A lower dose can be used


  • More technically difficult
  • Risk of off-target effects
  • More invasive compared to IV
  • Structural difficulty (deformities, scoliosis, etc.)

An ongoing trial for a gene therapy being developed to treat giant axonal neuropathy (GAN), a rare neuromuscular disorder, is using this route.

Another CSF method is the intra-cisterna-magna (ICM) route, in which the therapy is delivered to the upper spine and lower brain, for distribution to other areas. The advantages and disadvantages are similar to the lumbar intrathecal route; however, ICM is more invasive.

An ongoing study is investigating a gene therapy using this route for Krabbe disease, a rare and deadly neurodegenerative disorder.

The most invasive CSF technique is the intracerebroventricular route. This is also the most difficult from a technical standpoint as it requires entry into the brain with a catheter. However, this may be the most effective method for conditions involving the brain, or when deformities render other routes unusable.

A study using this route for the treatment of mucopolysaccharidosis type 1 (MPS 1) is currently underway.

This is just part of what you can learn through this program. If you would like to view the webinar presentation in full, click here

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