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DNL 151 - LRRK2 protein inhibitor for Parkinson's disease treatment
The preclinical studies presented that reduction of LRRK2 activity or expression is neuroprotective.
Highlights
- Leucine-rich repeat kinase 2 (LRRK2) is a promising target for disease-modifying Parkinson's disease treatment
- The preclinical studies presented that reduction of LRRK2 activity or expression is neuroprotective
- Clinical trials of specific LRRK2-targeted therapies have already started, for example, LRKK2 kinase inhibitor DNL151 by Denali Therapeutics Inc.
Introduction
One of the most common monogenic (controlled by a single gene) forms of familial Parkinson's disease (PD) is caused by mutations in the LRRK2 gene coding a protein called leucine-rich repeat kinase 2 (LRRK2) or dardarin. The pathogenic mutations in the LRRK2 gene lead to an increase In LRRK2 kinase activity. Thanks to ongoing clinical trials, it is known now that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical PD. This discovery lately put the LRRK2 protein at the center of disease modification efforts in PD. LRRK2 is also suggested to play a role in the pathogenesis of idiopathic subtype PD, where LRRK2 therapies might also be beneficial (1).
Parkinson's disease (PD)
PD is a neurodegenerative disease that affects more than 6 million people worldwide, and its prevalence is expected to double by 2040. The characteristic symptoms comprise a set of movement abnormalities, such as slow movement, tremor, and rigidity of muscles. PD also has non-motor features such as constipation, anxiety, and dementia. The well-known pathological hallmark of this disease is Lewy bodies - aggregates of misfolded α-synuclein protein, leading to the loss of dopamine-producing neurons in the midbrain. There are no available disease-modifying therapies for PD. The treatment consists of dopamine replacement to alleviate the symptoms. The exact cause of PD is unknown as there are many subtypes of the disease, and it is believed to be a mix of genetics and environmental factors. Aging is the most significant risk factor for developing PD, but several environmental exposures such as head trauma, dairy consumption, and pesticide exposure are well known (1, 2).
Leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease - genetic classification
Parkinson's disease is a genetically heterogeneous and complex disorder. There are several monogenic forms of the illness and many genetic risk factors increasing the risk of developing PD. Monogenic forms (meaning a single mutation causes them in a dominantly or recessively inherited gene) are relatively rare but thoroughly researched. They make about 30% of the familial and 3%–5% of the sporadic (not inherited) cases (3). The PD genetics nomenclature consists of specific chromosomal regions called PARK numbered in chronological order of their identification. The PD-related gene coding LRRK2 kinase is in the PARK8 region. It is determined to be inherited in an autosomal dominant manner - autosomal meaning the gene is located on one of the non-sex chromosomes and dominant means that a sole copy of the mutation is enough to cause the disease (3). Genome-wide association studies have shown that some variants in the LRRK2 gene have a modest influence on the lifetime risk of idiopathic PD (iPD), suggesting that LRRK2 function influences susceptibility to iPD (4, 5). This observation raises the possibility that LRRK2-targeted therapies could be effective for a broader population of patients with PD (2).
The problem with LRRK2
LRRK2 is a complex GTPase/kinase - an enzymatic protein that is able to send signals between other proteins by means of phosphorylation. It involved in the cytoskeletal dynamics in the cell (6) such cytoskeletal actin polymerization and endolysosomal pathway including endocytosis and autophagy - forms of cell transport (7). It has been known to be linked with PD for at least 15 years by now (8, 9). It interacts with multiple partners and phosphorylates of a group of proteins called Rab GTPases (10). LRRK2 kinase maintains a healthy cellular environment by regulating lysosomal function. LRRK2 as a kinase is getting phosphorylated on its Serine 935 (pS935). Increased activity of LRRK2 leads to Rab GTPases phosphorylation (pRABs), both phosphorylated proteins are biomarkers of PD. In turn, it causes lysosomal dysfunction, neurodegeneration, and the formation of Lewy bodies, which are common pathologies of Parkinson's disease (11, 12). Overactive LRRK2 protein disrupts the normal functioning of the lysosomes, which are special compartments within cells that break down excess or destroyed cell parts and proteins.
Many patients with LRRK2-PD carry the Gly2019Ser (glycine in position 2019 of the protein chain is substituted by serine) LRRK2 mutation, which is associated with neuropathological changes, similar to those that happen in idiopathic PD. These changes include typical α- synuclein protein aggregates in the form of Lewy bodies and abnormal Lewy neurites due to faulty lysosomes, together with cell loss in vulnerable areas. The mutations increase the kinase activity of LRRK2 by two-to-three fold (13-16). LRRK2 is a promising target for potential PD-modifying treatments. Small-molecule LRRK2 inhibitors have neuroprotective effects proven in few in vitro and in vivo models of PD. These observations suggest blocking the LRRK2 activity or suppressing the LRRK2 expression as therapeutic disease-modifying approaches in PD. LRRK2-PD or PD linked to LRRK2 mutations has become a significant research priority in academia and industry, with Denali Therapeutics Inc as an example company (2).
Denali Therapeutics Inc.
In 2016 the Genentech company's efforts in PD therapy development were out-licensed to Denali for clinical development (DNL-201 and DNL-151). The exact structures of both compounds have not been revealed (17). Denali Therapeutics Inc. is a biotechnology company based in South San Francisco, California. It is developing an extensive range of small molecules and compounds to combat neurodegenerative diseases like Alzheimer's and Parkinson's. Following positive preclinical experiments in nonhuman primate lungs (18, 19), two small molecule inhibitors of LRRK2 developed by Denali called DNL201 and DNL151 are currently in clinical trials. A principal candidate for PD treatment, called DNL151, completed Phase 1b human clinical trials as a therapy against Parkinson's and was planned to move to late-stage clinical trials by the end of 2021 (20). DNL151 aims to restore lysosomal function, allowing them to remove Lewy bodies. DNL151 therapy directly combats proteostasis, a hallmark of aging due to restoring lysosomal function (13).
What is DNL151?
DNL151 is a potent, selective, and brain-penetrant small molecule inhibitor of LRRK2 and is Denali's clinical candidate for Parkinson's disease. As mentioned above, increased LRRK2 activity and pRab have been observed in people with LRRK2 mutation-caused Parkinson's disease but also in the PD independent of LRRK2 mutation status. Inhibition of LRRK2 can restore lysosomal function and reduce α- synuclein toxicity in PD models. The drug is developed in collaboration with Biogen and holds a synonym name BIIB122. Denali and Biogen want to advance BIIB122/DNL151 into two late-stage studies in PD – for PD patients carrying the LRRK2 mutations and the mutation-independent PD patients. BIIB122/DNL151 has not yet been approved by any Health Authority (13). DNL151 is an investigational, oral treatment shown to cross the blood-brain barrier, delivering therapy to the brain (5, 13).
The clinical trial timeline
According to ClinicalTrials.gov, Denali began Phase 1 in December 2017 on a 200-participant trial in the Netherlands. In July 2019, a Phase 1b safety study began in 34 people with PD. In January 2020, they announced that DNL151 met biomarker and safety goals after evaluating 153 healthy volunteers. Participants with or without an LRRK2 mutation were randomized to a low, middle, or high dose of DNL151 or placebo, taken daily for 28 days. The trial finished in December 2020, after enrolling 36 participants in eight centers in the U.S. and Europe. Denali stated that the trial met target and pathway engagement goals and will work on engagement of patients in second phase clinical trials (13). Most participants had no or mild adverse effects at all doses tested. DNL151 dose-dependently reduced LRRK2 kinase activity by up to 80 percent, based on measuring phosphorylation of LRRK2 (pS935) and its substrate pRab10 (pRABs) in blood. Urine levels of the lipid bis(mono-acylglycerol)phosphate BMP (21), a marker of lysosome dysfunction, were also reduced.
The future
Denali, together with Biogen, is planning the launch of two late-stage clinical trials. The phase 3 LIGHTHOUSE and phase 2b LUMA trials are expected to be run in 2022, led by Biogen. They will evaluate the impact of DNL151 in PD patients with and without LRRK2 mutations. LIGHTHOUSE study aims to enroll around 400 Parkinson's patients with LRRK2 mutations with treatment running for at least 96 weeks. The LUMA Phase 2b study aims to enroll 640 patients without LRRK2 mutations and run for at least 48 weeks to support a request for DNL151 regulatory approval (22). A positive outcome of these trials would give the first hope for PD patients to stop the disease instead of only alleviating the symptoms.
References
1. Day JO, Mullin S. The genetics of parkinson’s disease and implications for clinical practice. Genes. 2021;12(7):1006.
2. Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020;16(2):97-107.
3. Klein C, Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. 2012;2(1):a008888-a.
4. Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT. LRRK2 and idiopathic Parkinson’s disease. Trends in Neurosciences. 2022.
5. Schneider SA, Hizli B, Alcalay RN. Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism. Neurotherapeutics. 2020:1-15.
6. Civiero L, Cogo S, Biosa A, Greggio E. The role of LRRK2 in cytoskeletal dynamics. Biochem Soc Trans. 2018;46(6):1653-63.
7. Roosen DA, Cookson MR. LRRK2 at the interface of autophagosomes, endosomes and lysosomes. Molecular Neurodegeneration. 2016;11(1):73.
8. Farrer M, Stone J, Mata IF, Lincoln S, Kachergus J, Hulihan M, et al. LRRK2 mutations in Parkinson disease. Neurology. 2005;65(5):738-40.
9. Foroud T. LRRK2: both a cause and a risk factor for Parkinson disease? Neurology. 2005;65(5):664-5.
10. Iannotta L, Greggio E. LRRK2 signaling in neurodegeneration: two decades of progress. Essays in Biochemistry. 2021;65(7):859-72.
11. Kumar A, Cookson MR. Role of LRRK2 kinase dysfunction in Parkinson disease. Expert Rev Mol Med. 2011;13:e20.
12. Dachsel JC, Farrer MJ. LRRK2 and Parkinson disease. Arch Neurol. 2010;67(5):542-7.
13. Denali Therapeutics Presents Positive Results from Phase 1 and Phase 1b Studies of Its LRRK2 Inhibitor, BIIB122/DNL151, Supporting Late-Stage Development Plans in Parkinson’s Disease. Denali Therapeutics Inc. 2021.
14. Poewe W, Seppi K, Marini K, Mahlknecht P. New hopes for disease modification in Parkinson's Disease. Neuropharmacology. 2020;171:108085.
15. Reed X, Schumacher-Schuh A, Hu J, Bandres-Ciga S. Advancing Personalized Medicine in Common Forms of Parkinson’s Disease through Genetics: Current Therapeutics and the Future of Individualized Management. Journal of Personalized Medicine. 2021;11(3):169.
16. Schapira AH. The importance of LRRK2 mutations in Parkinson disease. Arch Neurol. 2006;63(9):1225-8.
17. Shi Y, Mader M. Brain penetrant kinase inhibitors: learning from kinase neuroscience discovery. Bioorganic & medicinal chemistry letters. 2018;28(11):1981-91.
18. Baptista MA, Merchant K, Barrett T, Bhargava S, Bryce DK, Ellis JM, et al. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Science translational medicine. 2020;12(540).
19. Fuji RN, Flagella M, Baca M, Baptista MA, Brodbeck J, Chan BK, et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Science translational medicine. 2015;7(273):273ra15-ra15.
20. Ntetsika T, Papathoma P-E, Markaki I. Novel targeted therapies for Parkinson’s disease. Molecular Medicine. 2021;27(1):1-20.
21. Alcalay RN, Hsieh F, Tengstrand E, Padmanabhan S, Baptista M, Kehoe C, et al. Higher urine bis (Monoacylglycerol) phosphate levels in LRRK2 G2019S mutation carriers: implications for therapeutic development. Movement Disorders. 2020;35(1):134-41.
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Highlights
- Leucine-rich repeat kinase 2 (LRRK2) is a promising target for disease-modifying Parkinson's disease treatment
- The preclinical studies presented that reduction of LRRK2 activity or expression is neuroprotective
- Clinical trials of specific LRRK2-targeted therapies have already started, for example, LRKK2 kinase inhibitor DNL151 by Denali Therapeutics Inc.
Introduction
One of the most common monogenic (controlled by a single gene) forms of familial Parkinson's disease (PD) is caused by mutations in the LRRK2 gene coding a protein called leucine-rich repeat kinase 2 (LRRK2) or dardarin. The pathogenic mutations in the LRRK2 gene lead to an increase In LRRK2 kinase activity. Thanks to ongoing clinical trials, it is known now that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical PD. This discovery lately put the LRRK2 protein at the center of disease modification efforts in PD. LRRK2 is also suggested to play a role in the pathogenesis of idiopathic subtype PD, where LRRK2 therapies might also be beneficial (1).
Parkinson's disease (PD)
PD is a neurodegenerative disease that affects more than 6 million people worldwide, and its prevalence is expected to double by 2040. The characteristic symptoms comprise a set of movement abnormalities, such as slow movement, tremor, and rigidity of muscles. PD also has non-motor features such as constipation, anxiety, and dementia. The well-known pathological hallmark of this disease is Lewy bodies - aggregates of misfolded α-synuclein protein, leading to the loss of dopamine-producing neurons in the midbrain. There are no available disease-modifying therapies for PD. The treatment consists of dopamine replacement to alleviate the symptoms. The exact cause of PD is unknown as there are many subtypes of the disease, and it is believed to be a mix of genetics and environmental factors. Aging is the most significant risk factor for developing PD, but several environmental exposures such as head trauma, dairy consumption, and pesticide exposure are well known (1, 2).
Leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease - genetic classification
Parkinson's disease is a genetically heterogeneous and complex disorder. There are several monogenic forms of the illness and many genetic risk factors increasing the risk of developing PD. Monogenic forms (meaning a single mutation causes them in a dominantly or recessively inherited gene) are relatively rare but thoroughly researched. They make about 30% of the familial and 3%–5% of the sporadic (not inherited) cases (3). The PD genetics nomenclature consists of specific chromosomal regions called PARK numbered in chronological order of their identification. The PD-related gene coding LRRK2 kinase is in the PARK8 region. It is determined to be inherited in an autosomal dominant manner - autosomal meaning the gene is located on one of the non-sex chromosomes and dominant means that a sole copy of the mutation is enough to cause the disease (3). Genome-wide association studies have shown that some variants in the LRRK2 gene have a modest influence on the lifetime risk of idiopathic PD (iPD), suggesting that LRRK2 function influences susceptibility to iPD (4, 5). This observation raises the possibility that LRRK2-targeted therapies could be effective for a broader population of patients with PD (2).
The problem with LRRK2
LRRK2 is a complex GTPase/kinase - an enzymatic protein that is able to send signals between other proteins by means of phosphorylation. It involved in the cytoskeletal dynamics in the cell (6) such cytoskeletal actin polymerization and endolysosomal pathway including endocytosis and autophagy - forms of cell transport (7). It has been known to be linked with PD for at least 15 years by now (8, 9). It interacts with multiple partners and phosphorylates of a group of proteins called Rab GTPases (10). LRRK2 kinase maintains a healthy cellular environment by regulating lysosomal function. LRRK2 as a kinase is getting phosphorylated on its Serine 935 (pS935). Increased activity of LRRK2 leads to Rab GTPases phosphorylation (pRABs), both phosphorylated proteins are biomarkers of PD. In turn, it causes lysosomal dysfunction, neurodegeneration, and the formation of Lewy bodies, which are common pathologies of Parkinson's disease (11, 12). Overactive LRRK2 protein disrupts the normal functioning of the lysosomes, which are special compartments within cells that break down excess or destroyed cell parts and proteins.
Many patients with LRRK2-PD carry the Gly2019Ser (glycine in position 2019 of the protein chain is substituted by serine) LRRK2 mutation, which is associated with neuropathological changes, similar to those that happen in idiopathic PD. These changes include typical α- synuclein protein aggregates in the form of Lewy bodies and abnormal Lewy neurites due to faulty lysosomes, together with cell loss in vulnerable areas. The mutations increase the kinase activity of LRRK2 by two-to-three fold (13-16). LRRK2 is a promising target for potential PD-modifying treatments. Small-molecule LRRK2 inhibitors have neuroprotective effects proven in few in vitro and in vivo models of PD. These observations suggest blocking the LRRK2 activity or suppressing the LRRK2 expression as therapeutic disease-modifying approaches in PD. LRRK2-PD or PD linked to LRRK2 mutations has become a significant research priority in academia and industry, with Denali Therapeutics Inc as an example company (2).
Denali Therapeutics Inc.
In 2016 the Genentech company's efforts in PD therapy development were out-licensed to Denali for clinical development (DNL-201 and DNL-151). The exact structures of both compounds have not been revealed (17). Denali Therapeutics Inc. is a biotechnology company based in South San Francisco, California. It is developing an extensive range of small molecules and compounds to combat neurodegenerative diseases like Alzheimer's and Parkinson's. Following positive preclinical experiments in nonhuman primate lungs (18, 19), two small molecule inhibitors of LRRK2 developed by Denali called DNL201 and DNL151 are currently in clinical trials. A principal candidate for PD treatment, called DNL151, completed Phase 1b human clinical trials as a therapy against Parkinson's and was planned to move to late-stage clinical trials by the end of 2021 (20). DNL151 aims to restore lysosomal function, allowing them to remove Lewy bodies. DNL151 therapy directly combats proteostasis, a hallmark of aging due to restoring lysosomal function (13).
What is DNL151?
DNL151 is a potent, selective, and brain-penetrant small molecule inhibitor of LRRK2 and is Denali's clinical candidate for Parkinson's disease. As mentioned above, increased LRRK2 activity and pRab have been observed in people with LRRK2 mutation-caused Parkinson's disease but also in the PD independent of LRRK2 mutation status. Inhibition of LRRK2 can restore lysosomal function and reduce α- synuclein toxicity in PD models. The drug is developed in collaboration with Biogen and holds a synonym name BIIB122. Denali and Biogen want to advance BIIB122/DNL151 into two late-stage studies in PD – for PD patients carrying the LRRK2 mutations and the mutation-independent PD patients. BIIB122/DNL151 has not yet been approved by any Health Authority (13). DNL151 is an investigational, oral treatment shown to cross the blood-brain barrier, delivering therapy to the brain (5, 13).
The clinical trial timeline
According to ClinicalTrials.gov, Denali began Phase 1 in December 2017 on a 200-participant trial in the Netherlands. In July 2019, a Phase 1b safety study began in 34 people with PD. In January 2020, they announced that DNL151 met biomarker and safety goals after evaluating 153 healthy volunteers. Participants with or without an LRRK2 mutation were randomized to a low, middle, or high dose of DNL151 or placebo, taken daily for 28 days. The trial finished in December 2020, after enrolling 36 participants in eight centers in the U.S. and Europe. Denali stated that the trial met target and pathway engagement goals and will work on engagement of patients in second phase clinical trials (13). Most participants had no or mild adverse effects at all doses tested. DNL151 dose-dependently reduced LRRK2 kinase activity by up to 80 percent, based on measuring phosphorylation of LRRK2 (pS935) and its substrate pRab10 (pRABs) in blood. Urine levels of the lipid bis(mono-acylglycerol)phosphate BMP (21), a marker of lysosome dysfunction, were also reduced.
The future
Denali, together with Biogen, is planning the launch of two late-stage clinical trials. The phase 3 LIGHTHOUSE and phase 2b LUMA trials are expected to be run in 2022, led by Biogen. They will evaluate the impact of DNL151 in PD patients with and without LRRK2 mutations. LIGHTHOUSE study aims to enroll around 400 Parkinson's patients with LRRK2 mutations with treatment running for at least 96 weeks. The LUMA Phase 2b study aims to enroll 640 patients without LRRK2 mutations and run for at least 48 weeks to support a request for DNL151 regulatory approval (22). A positive outcome of these trials would give the first hope for PD patients to stop the disease instead of only alleviating the symptoms.
References
1. Day JO, Mullin S. The genetics of parkinson’s disease and implications for clinical practice. Genes. 2021;12(7):1006.
2. Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020;16(2):97-107.
3. Klein C, Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. 2012;2(1):a008888-a.
4. Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT. LRRK2 and idiopathic Parkinson’s disease. Trends in Neurosciences. 2022.
5. Schneider SA, Hizli B, Alcalay RN. Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism. Neurotherapeutics. 2020:1-15.
6. Civiero L, Cogo S, Biosa A, Greggio E. The role of LRRK2 in cytoskeletal dynamics. Biochem Soc Trans. 2018;46(6):1653-63.
7. Roosen DA, Cookson MR. LRRK2 at the interface of autophagosomes, endosomes and lysosomes. Molecular Neurodegeneration. 2016;11(1):73.
8. Farrer M, Stone J, Mata IF, Lincoln S, Kachergus J, Hulihan M, et al. LRRK2 mutations in Parkinson disease. Neurology. 2005;65(5):738-40.
9. Foroud T. LRRK2: both a cause and a risk factor for Parkinson disease? Neurology. 2005;65(5):664-5.
10. Iannotta L, Greggio E. LRRK2 signaling in neurodegeneration: two decades of progress. Essays in Biochemistry. 2021;65(7):859-72.
11. Kumar A, Cookson MR. Role of LRRK2 kinase dysfunction in Parkinson disease. Expert Rev Mol Med. 2011;13:e20.
12. Dachsel JC, Farrer MJ. LRRK2 and Parkinson disease. Arch Neurol. 2010;67(5):542-7.
13. Denali Therapeutics Presents Positive Results from Phase 1 and Phase 1b Studies of Its LRRK2 Inhibitor, BIIB122/DNL151, Supporting Late-Stage Development Plans in Parkinson’s Disease. Denali Therapeutics Inc. 2021.
14. Poewe W, Seppi K, Marini K, Mahlknecht P. New hopes for disease modification in Parkinson's Disease. Neuropharmacology. 2020;171:108085.
15. Reed X, Schumacher-Schuh A, Hu J, Bandres-Ciga S. Advancing Personalized Medicine in Common Forms of Parkinson’s Disease through Genetics: Current Therapeutics and the Future of Individualized Management. Journal of Personalized Medicine. 2021;11(3):169.
16. Schapira AH. The importance of LRRK2 mutations in Parkinson disease. Arch Neurol. 2006;63(9):1225-8.
17. Shi Y, Mader M. Brain penetrant kinase inhibitors: learning from kinase neuroscience discovery. Bioorganic & medicinal chemistry letters. 2018;28(11):1981-91.
18. Baptista MA, Merchant K, Barrett T, Bhargava S, Bryce DK, Ellis JM, et al. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Science translational medicine. 2020;12(540).
19. Fuji RN, Flagella M, Baca M, Baptista MA, Brodbeck J, Chan BK, et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Science translational medicine. 2015;7(273):273ra15-ra15.
20. Ntetsika T, Papathoma P-E, Markaki I. Novel targeted therapies for Parkinson’s disease. Molecular Medicine. 2021;27(1):1-20.
21. Alcalay RN, Hsieh F, Tengstrand E, Padmanabhan S, Baptista M, Kehoe C, et al. Higher urine bis (Monoacylglycerol) phosphate levels in LRRK2 G2019S mutation carriers: implications for therapeutic development. Movement Disorders. 2020;35(1):134-41.
Article reviewed by
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Dr. Ana Baroni MD. Ph.D.
Scientific & Medical Advisor
Quality Garant
Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.
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