Researchers develop 'dimmer switch' to help control gene therapy
Delivery system fine tunes gene therapy expression levels and may pave
the way for a new wave of gene therapies to treat rare and complex diseases


Date:
July 28, 2021
Source:
Children's Hospital of Philadelphia
Summary:
In a major advancement in the field of gene therapy for rare and
devastating diseases, researchers have developed a "dimmer switch"
system that can control levels of proteins expressed from gene
therapy vectors.

The system is based on alternative RNA splicing using an orally
available small molecule and works effectively in tissues throughout
the body, including the brain.



FULL STORY ==========================================================================
In a major advancement in the field of gene therapy for rare and
devastating diseases, researchers at Children's Hospital of Philadelphia
(CHOP) have developed a "dimmer switch" system that can control levels
of proteins expressed from gene therapy vectors. The system is based
on alternative RNA splicing using an orally available small molecule
and works effectively in tissues throughout the body, including the
brain. The first research regarding this innovation was published today
in the journal Nature.


========================================================================== "We're taking the field of gene therapy to an entirely new level where
fine- tuned dosing is required for safety, utility and success," said
senior study author Beverly L. Davidson, PhD, Director of the Raymond
G. Perelman Center for Cellular and Molecular Therapeutics and Chief
Scientific Strategy Officer at Children's Hospital of Philadelphia. "This
study shows that by using a splicing modulator in combination with gene
therapy tools, the dose of protein expressed from gene therapy vectors can
be controlled for maximum therapeutic benefit." Many advancements in gene therapy have involved its delivery system, in the form of engineered viral vectors or lipid nanoparticles, but while improvements in these vehicles
have delivered treatments to tissues more effectively, the cargo being delivered and elements controlling the resulting gene expression have
not received the same amount of attention. Once gene therapy has been successfully delivered into the tissue, it is difficult to regulate the
levels of expression. Too much expression may have toxic effects on the patient, and too little expression may mean that the patient does not
receive the intended benefits of the therapy.

To address this problem, CHOP researchers developed a delivery system
called the Xon system, which can finely control protein translation by
using a "dimmer switch" to adjust the levels of expression up or down
as needed. This method employs alternative RNA splicing, a process that
allows a single gene to code for multiple proteins, depending on how the
RNA is spliced. Using the Xon system, a gene therapy vector's cargo is
inactive until the oral drug is used, which then drives the splicing of
the desired corrective gene into its active form.

"The newly developed switch not only controls protein levels, but if
needed, those proteins can be induced again and again by the simple
ingestion of an orally bioavailable drug," said Alex Mas Monteys, PhD,
a research assistant professor in Davidson's lab at CHOP and co-lead
author of the study.

In one example reported in this paper, the researchers used the Xon
system in mice to adjust levels of erythropoietin (Epo), which is used
to treat anemia associated with kidney disease. The researchers found
that their delivery system induced hematocrit levels to 60 to 70% above baseline levels depending on the dose, and once levels slowly dropped
to base levels, the system could be used again to safely re-induce the
levels as would be needed for patients with chronic kidney disease.

The research was conducted as part of a multi-year collaboration
with scientists at the Novartis Institutes for BioMedical Research
(NIBR). CHOP and NIBR are collaborating to develop next-generation small molecule splicing modulators and the Xon system to achieve fine-tuned
gene regulation across multiple clinical applications. The team has
also shown that the Xon system can be used to control expression of gene products that are toxic to the brain when expressed at high levels.

"The dose of a drug can determine how high you want expression to be,
and then the system can automatically 'dim down' at a rate related to
the half-life of the protein," Davidson said. "We can envision scenarios
where a drug would be given only once, such as for controlling the
expression of foreign proteins needed for gene editing, or with limited frequency. Since the splicing modulators we have tested are given orally, compliance to control protein expression from viral vectors employing
Xon-based cassettes should be high." Although the paper focuses on using
Xon with gene therapy delivered via viral vectors, the researchers note
it could also be engineered for use in cell engineering for CAR-T cell
therapy. Here, the Xon system could be used to pause therapy if needed
to give T-cells a rest.

The work was supported by NIBR, the Hereditary Disease Foundation and
National Institutes of Health grant 5T32HG009495-04, the Children's
Hospital of Philadelphia Research Institute.

Dr. Davidson is an inventor of the Xon system. CHOP has licensed this technology to Novartis. CHOP, and by extension Dr. Davidson, have
received compensation from Novartis in exchange for the licensing of
the Xon technology.

CHOP's and Dr. Davidson's participation in this research was reviewed
and approved by CHOP's Conflict of Interest Committee.

========================================================================== Story Source: Materials provided by
Children's_Hospital_of_Philadelphia. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Alex Mas Monteys, Amiel A. Hundley, Paul T. Ranum, Luis Tecedor, Amy
Muehlmatt, Euyn Lim, Dmitriy Lukashev, Rajeev Sivasankaran,
Beverly L.

Davidson. Regulated control of gene therapies by drug-induced
splicing.

Nature, 2021; DOI: 10.1038/s41586-021-03770-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210728111307.htm

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