Ketone bodies to protect tissues from damage by ionizing radiation
Inventors
Veech, Richard Lewis • Clarke, Kieran
Assignees
Tdeltas Ltd • US Department of Health and Human Services
Publication Number
US-11234953-B2
Publication Date
2022-02-01
Expiration Date
2033-11-05
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Abstract
Described herein is the surprising discovery that ketone bodies protect cell and tissues from ionizing radiation. Based on this finding, methods of protecting animal tissue and cells from damage caused by radiation exposure are disclosed which include, contacting the tissue with a therapeutically effective amount of an agent including at least one ketone ester, thereby protecting the tissue from radiation damage. Ketone esters can be used to minimize, reduce and/or prevent tissue damage following intentional and accidental radiation exposure, as well as increasing the therapeutic efficacy of radiation therapies by protecting non-target tissue from incidental radiation damage.
Core Innovation
The invention discloses that ketone bodies, specifically (R)-3-hydroxybutyrate and acetoacetate, protect cells and tissues from damage caused by ionizing radiation. Methods are provided for protecting animal tissue from radiation damage by contacting the tissue with a therapeutically effective amount of agents comprising ketone esters, which elevate blood ketone levels to reduce, ameliorate, or block radiation-induced tissue damage, including cell death through apoptosis due to DNA and RNA damage.
Radiation exposure leads to chemical changes in cells, producing free radicals that cause permanent damage and induce apoptosis, primarily affecting tissues with high cell turnover. There is a significant need for effective radioprotectants to minimize such damage from accidental, intentional, or therapeutic radiation exposure.
The invention solves this problem by utilizing compositions containing esters and oligomers of (R)-3-hydroxybutyrate, which serve as precursors to ketone bodies. These compounds, when administered orally or parenterally, increase circulating ketone body concentrations to therapeutically effective levels, thereby protecting cells and tissues from radiation-induced injury. This approach improves tissue survival and may increase the therapeutic efficacy of radiation therapies by protecting non-targeted tissues from incidental radiation damage.
Claims Coverage
The patent includes one independent method claim which broadly covers protection of animal tissue from radiation damage using specific ketone-containing agents. The claims emphasize the use of (R)-3-hydroxybutyrate salts, esters, and oligomers with defined chemical structures, administration timing relative to radiation exposure, and various routes of administration and dosing regimens.
Method of protecting tissue with (R)-3-hydroxybutyrate-containing ketogenic materials
A method comprising contacting animal tissue with a therapeutically effective amount of an agent comprising at least one (R)-3-hydroxybutyrate-containing ketogenic material selected from salts, esters, and oligomers with defined chemical structures to protect the tissue from radiation damage.
Protection of personnel exposed to ionizing radiation
Employing the method of tissue protection by contacting tissue of personnel exposed to radioactive substances or ionizing radiation with the therapeutically effective agent.
Timing of administration relative to radiation exposure
Administering the ketone agent before, during, or after radiation exposure, specifically within two weeks prior to, during, and/or within two weeks following exposure, with examples including administration within four days before and up to about one day after exposure.
Broad coverage of radiation types
Protection against acute or chronic exposure to ionizing or non-ionizing radiation, including radiation from nuclear fission, fusion, X-rays, and radionuclides.
Enhancement of radiotherapy therapeutic window
Use of the method to enhance the therapeutic window of radiotherapy by protecting tissue prior to radiation treatment.
Use in various radiation exposure scenarios
Application in radiation exposures including diagnostic X-rays, radiation therapy, CAT scans, mammograms, radionuclide scans, interventional radiological procedures, ingestion of contaminated food or water, accidental radiation exposure, nuclear weapon fallout, radioactive spills, cosmic radiation, and space flight-associated radiation.
Specific agent chemical structures
Utilizing agents comprising ketone esters specifically derived from (R)-1,3-butanediol esters of (R)-3-hydroxybutyrate and oligomers thereof with defined formulas and structural parameters such as n equal to 3.
Multiple administration routes and dosing levels
Administering the agent via topical, buccal, intraocular, oral, subcutaneous, intramuscular, intravenous, intraarterial, transdermal, intranasal, rectal, peritoneal, or inhalation routes, with dosing sufficient to raise blood ketone body concentrations to ranges between 0.1 mM and 20 mM, preferably between 2 mM and 8 mM, and oral doses ranging from about 5 grams to about 170 grams per day or dosed per kilogram body weight.
The claims cover methods of protecting animal tissues from radiation damage by administering specific (R)-3-hydroxybutyrate-containing ketogenic agents with defined chemical structures, covering timing of administration, type of radiation, administration routes, and dosing, including applications in both accidental and therapeutic radiation exposure.
Stated Advantages
Ketone esters protect cells and tissues from ionizing radiation damage by reducing apoptosis and DNA damage.
Administration before or after radiation exposure can decrease radiation damage and improve cell survival.
The use of ketone esters enhances the therapeutic efficacy of radiation therapies by protecting non-target tissues from incidental damage.
The compounds provide radioprotection with fewer or lesser undesirable side effects by enhancing natural energetic pathways.
The disclosed agents are stable at room temperature and suitable for use in emergency radiological events.
Documented Applications
Minimizing, reducing, and preventing tissue damage following intentional and accidental radiation exposure.
Increasing the therapeutic window and efficacy of radiation therapies by protecting non-target normal tissue during cancer treatment.
Protecting personnel exposed to radioactive substances or ionizing radiation from environmental sources, nuclear weapons, or accidents.
Protection against diagnostic and interventional radiological procedures including X-rays, CAT scans, mammograms, radionuclide scans, and fluoroscopy-guided interventions.
Protecting against radiation exposure from ingestion of contaminated food or water and cosmic radiation, including space flight-associated radiation.
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