Reinforced lipids are

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

molecules in which some of the

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

s contain

deuterium Deuterium (hydrogen-2, symbol H or D, also known as heavy hydrogen) is one of two stable isotopes of hydrogen; the other is protium, or hydrogen-1, H. The deuterium nucleus (deuteron) contains one proton and one neutron, whereas the far more c ...

. They can be used for the protection of living cells by slowing the

chain reaction A chain reaction is a sequence of reactions where a reactive product or by-product causes additional reactions to take place. In a chain reaction, positive feedback leads to a self-amplifying chain of events. Chain reactions are one way that sys ...

due to isotope effect on lipid peroxidation. The

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...

of the

cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

and

organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...

membranes contain

polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...

s (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, use of reinforced lipids that stop the chain reaction of lipid peroxidation has preventive and therapeutic potential.

Examples of reinforced lipids

There are a number of polyunsaturated fatty acids that can be reinforced by deuteration. They include (the names of the reinforced deuterated versions are separated by a slash): *

linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...

/ D₂-linoleic acid (D2-Lin) *

α-linolenic acid α-Linolenic acid, also known as ''alpha''-linolenic acid (ALA) (from Greek ''alpha'' denoting "first" and ''linon'' meaning flax), is an ''n''−3, or omega-3, essential fatty acid. ALA is found in many seeds and oils, including flaxseed, ...

/ D₄-α-linolenic acid (D4-Lnn) *

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

/ D₆-arachidonic acid (D6-ARA) *

eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...

/ D₈-eicosapentaenoic acid (D8-EPA) *

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...

/ D₁₀-docosahexaenoic acid (D10-DHA)

Mechanism of action

Hydrogen is a

chemical element A chemical element is a chemical substance whose atoms all have the same number of protons. The number of protons is called the atomic number of that element. For example, oxygen has an atomic number of 8: each oxygen atom has 8 protons in its ...

with atomic number 1. It has just one proton and one electron. Deuterium is the heavier naturally occurring, stable isotope of hydrogen. Deuterium contains one proton, one electron, and a neutron, doubling the mass without changing its properties significantly. Substituting deuterium for hydrogen yields deuterated compounds that are similar in size and shape to normal hydrogen compounds. One of the most pernicious and irreparable types of

oxidative damage Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...

inflicted by

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS) upon biomolecules involves the carbon-hydrogen bond cleavage (hydrogen abstraction). In theory, replacing hydrogen with deuterium "reinforces" the bond due to the

kinetic isotope effect In physical organic chemistry, a kinetic isotope effect (KIE) is the change in the reaction rate of a chemical reaction when one of the atoms in the reactants is replaced by one of its isotopes. Formally, it is the ratio of rate constants for t ...

, and such reinforced biomolecules taken up by the body will be more resistant to ROS. The deuterium-reinforced lipids resists the non-enzymatic

lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...

(LPO) through isotope effect — a non-antioxidant based mechanism that protects mitochondrial, neuronal and other lipid membranes, thereby greatly reducing the levels of numerous LPO-derived toxic products such as reactive carbonyls. Treating cells with deuterium-containing PUFAs (D-PUFAs) can prevent of ferroptosis. This treatment stops the autoxidation process through the kinetic isotope effect (KIE), as shown in Table 1 6 The efficacy of D-PUFAs in preventing ferroptosis has been demonstrated in models induced by erastin and RSL3, and has shown promising results in various disease models, especially those related to neurodegenerative disorders.

Laboratory and animal research

The concept of using reinforced lipids to inhibit lipid peroxidation has been tested in numerous cell and animal models, including: *

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

(MPTP and a-Syn models in mice and rats) *

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

(in mice) *

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

(APP/PS1 and ALDH2 mouse models) *

Diabetic retinopathy Diabetic retinopathy (also known as diabetic eye disease) is a medical condition in which damage occurs to the retina due to diabetes. It is a leading cause of blindness in developed countries and one of the lead causes of sight loss in the wor ...

(Akita mice) *

Age-related macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Some people experien ...

(light irradiation in rats, eye iron overload in mice) *

Atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

(Leiden mice)

Clinical research

Friedreich's ataxia

A double-blind comparator-controlled Phase I/II clinical trial of using D₂-linoleic acid ethyl ester (RT001) for

Friedreich's ataxia Friedreich's ataxia (FRDA) is a rare, inherited, autosomal recessive neurodegenerative disorder that primarily affects the nervous system, causing progressive damage to the spinal cord, peripheral nerves, and cerebellum, leading to impaired ...

, sponsored by

Retrotope Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes (reinforced lipids) protect living cells by making bonds within the delicate molecules inside and around ...

and Friedreich's Ataxia Research Alliance, was conducted to determine the safety profile and appropriate dosing for consequent trials. RT001 was promptly absorbed and was found to be safe and tolerable over 28 days at the maximal dose of 9 g/day. It improved peak workload and peak oxygen consumption in the test group compared to the control group who received the equal doses of normal, non-deuterated linoleic acid ethyl ester. Another randomised, double-blind, placebo-controlled clinical study began in 2019.

Infantile neuroaxonal dystrophy

An open-label clinical study for

infantile neuroaxonal dystrophy Infantile neuroaxonal dystrophy (INAD) is a rare pervasive developmental disorder that primarily affects the nervous system. Individuals with infantile neuroaxonal dystrophy typically do not have any symptoms at birth, but between the ages of abo ...

evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of RT001, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.

Phospholipase 2G6-associated neurodegeneration

In 2017, the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

granted RT001

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designation in the treatment of phospholipase 2G6-associated neurodegeneration (

PLAN A plan is typically any diagram or list of steps with details of timing and resources, used to achieve an Goal, objective to do something. It is commonly understood as a modal logic, temporal set (mathematics), set of intended actions through wh ...

Amyotrophic lateral sclerosis

In 2018, RT001 was given to a patient with

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

(ALS) under a "compassionate use scheme".

Progressive supranuclear palsy

In 2020, the FDA granted orphan drug designation RT001 for the treatment of patients with

progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...

(PSP). PSP is a disease involving modification and dysfunction of tau protein; RT001's mechanism of action both lowers lipid peroxidation and prevents mitochondrial cell death of neurons which is associated with disease onset and progression.

References

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