Gene therapy strategy found effective in mouse model of hereditary disease TSC

January 08, 2021

BOSTON - Patients with tuberous sclerosis complex, a genetic disorder characterized by the growth of noncancerous tumors in multiple organs of the body, have limited treatment options. A team led by investigators at Massachusetts General Hospital (MGH) has now shown that gene therapy can effectively treat mice that express one of the mutated genes that cause the disease. The research is published in Science Advances.

The gene, called TSC2, codes for tuberin, a protein that acts to inhibit cell growth and proliferation. When mutations occur in TSC2, resulting in a lack of tuberin in cells, the cells enlarge and multiply, leading to the formation of tumors.

To restore the function of TSC2 and tuberin in a mouse model of tuberous sclerosis complex, researchers developed a form of gene therapy using an adeno-associated virus vector carrying the DNA that codes for a condensed form of tuberin (which fits within the vector's carrying capacity) and functions like the normal full-length tuberin protein. Mice with tuberous sclerosis complex had a shortened life span of about 58 days on average, and they showed signs of brain abnormalities consistent with those that are often seen in patients with the disease. When the mice were injected intravenously with the gene therapy treatment, however, their average survival was extended to 462 days, and their brains showed reduced signs of damage.

"Current treatments for tuberous sclerosis complex include surgery and/or lifelong treatment with drugs that cause immune suppression and potentially compromise early brain development. Therefore, there is a clear need to identify other therapeutic approaches for this disease," says co-lead author Shilpa Prabhakar, an investigator in the MGH departments of Neurology and Radiology. "Adeno-associated virus vectors have been used widely in clinical trials for many hereditary diseases with little to no toxicity, long-term action in nondividing cells, and improvement in symptoms," adds Prabhakar. She notes that benefits can be seen after a single injection, and some forms of the viral vector can efficiently enter the brain and peripheral organs after intravenous injection.

The U.S. Food and Drug Administration has approved a limited number of gene therapy products for use in humans, and the results from this study suggest that clinical trials are warranted to test the strategy's potential in patients with tuberous sclerosis complex.
-end-
Senior author Xandra Breakefield, PhD, is a geneticist in the departments of Neurology and Radiology at MGH and a professor of Neurology at Harvard Medical School.

This work was supported by the Department of Defense and National Institutes of Health.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020, Mass General was named #6 in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Gene Therapy Articles from Brightsurf:

Risk of AAV mobilization in gene therapy
New data highlight safety concerns for the replication of recombinant adeno-associated viral (rAAV) vectors commonly used in gene therapy.

Discovery challenges the foundations of gene therapy
An article published today in Science Translational Medicine by scientists from Children's Medical Research Institute has challenged one of the foundations of the gene therapy field and will help to improve strategies for treating serious genetic disorders of the liver.

Gene therapy: Novel targets come into view
Retinitis pigmentosa is the most prevalent form of congenital blindness.

Gene therapy targets inner retina to combat blindness
Batten disease is a group of fatal, inherited lysosomal storage disorders that predominantly affect children.

New Human Gene Therapy editorial: Concern following gene therapy adverse events
Response to the recent report of the deaths of two children receiving high doses of a gene therapy vector (AAV8) in a Phase I trial for X-linked myotubular myopathy (MTM).

Restoring vision by gene therapy
Latest scientific findings give hope for people with incurable retinal degeneration.

Gene therapy/gene editing combo could offer hope for some genetic disorders
A hybrid approach that combines elements of gene therapy with gene editing converted an experimental model of a rare genetic disease into a milder form, significantly enhancing survival, shows a multi-institutional study led by the University of Pennsylvania and Children's National Hospital in Washington, D.C.

New technology allows control of gene therapy doses
Scientists at Scripps Research in Jupiter have developed a special molecular switch that could be embedded into gene therapies to allow doctors to control dosing.

Gene therapy: Development of new DNA transporters
Scientists at the Institute of Pharmacy at Martin Luther University Halle-Wittenberg (MLU) have developed new delivery vehicles for future gene therapies.

Gene therapy promotes nerve regeneration
Researchers from the Netherlands Institute for Neuroscience and the Leiden University Medical Center have shown that treatment using gene therapy leads to a faster recovery after nerve damage.

Read More: Gene Therapy News and Gene Therapy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.