Greenland sharks can live up to 500 years, while adult mayflies are fortunate to exist for just a day. Although our cellular clocks differ dramatically, scientists argue that human aging is one of the highest risk factors for a host of degenerative and deadly conditions. To better understand, control, and even reverse the aging process, researchers are exploring the promise of regenerative medicine—a groundbreaking field that focuses on repairing or replacing damaged cells, tissues, and organs to restore normal function.
GEN spoke to several leaders in the field about their regenerative medicine programs and the applications they are pursuing. One approach utilizes the massive computing power of AI to identify safe drug combinations that can simultaneously target and treat multiple age-related biological pathways. Cells can be rejuvenated by harnessing the directorial capabilities (on/off switch) of epigenetics with engineered adeno-associated viruses (AAV) carrying transcription factors. An implantable bio-hybrid organ bearing healthy human pancreatic cells has shown promise in correcting type 1 diabetes (T1D). Parkinson’s disease may be treatable by transplanting precursor stem cells that can differentiate into function-restoring mature cells. While suitable aging models are still a challenge, one model system force-ages stem cells in a dish, couples this with CRISPR screenings, and has shown promise in identifying rejuvenation genes.
“Age-related diseases are driven by interconnected biological changes that evolve with age, described as the hallmarks of aging,” explains Ann Beliën, PhD, founder and CEO of Rejuvenate Biomed. She continues, “Understanding this complexity is crucial for the development of targeted interventions that can effectively change the course of disease and enhance the quality of life for the aging population.”
Ann Beliën, PhD
Founder, CEO
Rejuvenate Biomed
One therapeutic challenge is that single-target drugs often do not fully address such complex multifactorial processes. According to Beliën, the company is addressing this need by pursuing synergistic combinations of therapeutics that can impact multiple pathways simultaneously to enhance clinical benefit. “We are using drug combinations with established safety profiles for derisking clinical development and shortening the development time. This approach thus presents an opportunity to address medical unmet needs in severe diseases of aging.”
The company identifies and assesses the combos using two synergistic platforms: the AI-enabled CombinAgeTM and in vivo CelegAgeTM platforms. “These enable a biology-first and disease-agnostic approach,” informs Beliën.
The CombinAge platform sifts through vast datasets of biomedical knowledge on hundreds of individual drugs already proven safe for older adults and “analyzes pathways linked to hallmarks of aging, such as mitochondrial dysfunction, epigenetic alterations, and intercellular communication, to uncover combinations of those individual drugs that can impact multiple aging pathways simultaneously.”
After an additional safety check on the identified drug combination, its impact on health span is assessed in vivo via CelegAge, a platform that employs C. elegans worms. Beliën summarizes, “This model focuses on outcomes like movement, speed, and overall mobility, key indicators of aging and vitality, to validate CombinAge’s predictions.”
Following these analyses, the company goes back to CombinAge, which contains disease-specific data, to predict which age-related disease the drug combination could most effectively treat. The combination is then ready for the typical preclinical process and suitable to be advanced in Phase II trials directly, after the proof of principle is demonstrated in animal models.
The company has built a pipeline of five unique combination drugs targeting neuromuscular, musculoskeletal, metabolic, cardiovascular, nephrological, and neurodegenerative diseases. Beliën asserts that its lead Phase II-ready asset, RJx-01, has already demonstrated significant potential in treating sarcopenia. “We look forward to initiating a Phase II trial to evaluate sarcopenia in patients with chronic obstructive pulmonary disease this year.”
Aging has historically been viewed to result from random wear and tear on the body that accumulates throughout a person’s life. Life Biosciences says that these biological aging processes are modifiable. Sharon Rosenzweig-Lipson, PhD, CSO, provides a perspective: “As we age, the epigenetic code that regulates gene expression drifts, leading to altered patterns of gene expression. This shift is associated with changes in epigenetic markers called methyl groups that may lead to dysfunction.”
Sharon Rosenzweig-Lipson, PhD
CSO, Life Biosciences
The company is focusing on partial epigenetic programming based on the Nobel-Prize-winning discovery of Yamanaka factors. These four transcription factors can completely dial back and reprogram mature cells to become pluripotent. Rosenzweig-Lipson explains, “Life Bio is leveraging our partial epigenetic reprogramming platform using three factors, OSK (Oct4, Sox2, Klf4), to reset the epigenetic code and reverse age-related epigenetic changes. This allows for cellular rejuvenation to a younger state, without the loss of cell identity, to prevent or reverse age-related diseases. This approach targets a key root cause of aging at the epigenetic level, thereby offering the potential to address a wide range of age-related diseases with significant unmet medical needs.”
Life Biosciences’ lead candidate is ER-100. Rosenzweig-Lipson elaborates, “ER-100 utilizes a dual vector AAV2 tet-on system containing an AAV2 with a transactivator and an AAV2 that can express OSK in the presence of oral doxycycline. This permits the expression of OSK within target cells to reprogram the epigenome in a controlled manner.”
ER-100 is currently in late-stage preclinical development for both chronic and acute optic neuropathies including glaucoma and the rare eye disease non-arteritic anterior ischemic optic neuropathy (NAION). Rosenzweig-Lipson reveals, “ER-100 has demonstrated safety and efficacy in multiple pre-clinical animal models of disease. We are aiming to initiate the first human clinical studies evaluating ER-100 for optic neuropathies within a year.”
Regenerative medicine also provides a promising avenue for treating chronic diseases such as T1D, an autoimmune disorder that destroys the insulin-producing cells of the pancreas. Sernova is focusing on restoring the body’s natural ability to regulate insulin by combining its implantable Cell PouchTM bio-hybrid organ with therapeutic human cells.
Jonathan Rigby
CEO, Sernova
CEO Jonathan Rigby explains, “In the case of T1D, the therapeutic cells that are transplanted into the Cell Pouch chambers are pancreatic islets. Islets are clusters of alpha, beta, and delta cells, which create vital hormones called glucagon, insulin, and somatostatin. These hormones regulate blood glucose. By transplanting islets into the chambers of the Cell Pouch bio-hybrid organ, we aim to provide a location within the body for the long-term survival and function of the therapeutic cells.”
According to Rigby, the Cell Pouch is a small, chambered structure made from nontoxic, medical-grade, biocompatible materials previously approved by the FDA for permanent use in the body. “It is surgically implanted under the skin against the abdominal muscles, where it seamlessly integrates within the body to create an ideal vascularized tissue environment. The cells are transplanted into chambers of the Cell Pouch bio-hybrid organ.”
One of the hallmarks of T1D is destruction of insulin-producing pancreatic cells. Sernova is pioneering the use of an implantable Cell Pouch that houses healthy donor islet cells to create a bio-hybrid organ.
Rigby says the company is currently conducting Phase I/II clinical trials in combination with human donor islets. “The Cell Pouch has shown the ability to support the survival and function of transplanted islets for over five years. In addition, it has demonstrated complete retrievability with no evidence of fibrosis, while also showing promising signs of efficacy.”
However, Rigby believes that utilizing donor islets is not a commercially viable option for the future. He reports, “We have partnered with Evotec, a company that has developed induced pluripotent stem cell (iPSC)-derived islet-like clusters, which can be manufactured in nearly unlimited quantities. Notably, in preclinical studies, Evotec’s islet-like clusters have performed comparably to human islets when implanted within the chambers of a pre-vascularized Cell Pouch.”
In degenerative illnesses, such as Parkinson’s disease, cells undergo progressive deterioration and dysfunction, potentially leading to cell death. BlueRock Therapeutics is focusing on regenerative pluripotent stem cells (PSCs) that can differentiate into specific cell types that have the potential to replace the cells lost or damaged by disease.
Amit Rakhit, MD
Chief Medical Officer
BlueRock Therapeutics
Amit Rakhit, MD, chief medical officer, discusses, “Typically, by the time a person is diagnosed with Parkinson’s disease, approximately 80% of their dopamine-producing neurons are gone. This impacts a person’s cognitive, motor, and non-motor functions. Current standard of care, using small molecules or deep brain stimulation, can help mimic this loss of dopamine and provide symptomatic relief, but over time, their effectiveness declines.”
According to Rakhit, BlueRock Therapeutics is taking a different approach. They aim to replace the dopamine-producing neurons that are lost in Parkinson’s disease by administering PSCs differentiated into dopamine-producing neuron progenitors. “In a one-time surgical procedure, the dopamine-producing neuronal precursors are transplanted into a part of the brain called the putamen. When transplanted, these precursors have the potential to halt disease progression, by further developing into mature brain cells after implantation and reforming the neural networks that have been severely affected by Parkinson’s–restoring motor and non-motor function to patients.”
Last year, the company’s candidate therapy, named bemdaneprocel, completed an open-label Phase I clinical trial in 12 participants. Rakhit reports, “Based on the data from this trial and conversations with the FDA under a Regenerative Medicine Advanced Therapy designation, BlueRock plans to advance bemdaneprocel to a Phase III pivotal trial that is expected to start later this year. This will be the first registrational Phase III clinical trial for an investigational allogeneic stem cell-derived therapy for treating Parkinson’s disease.”
BlueRock also plans to initiate a Phase I clinical trial for an investigational iPSC-derived therapy, OpCT-001, for the treatment of primary photoreceptor diseases that cause irreversible vision loss in children and adults.
Rakhit believes that such allogeneic cell therapies offer the potential of achieving a global impact. “We look forward to continuing to work with our colleagues in cell therapy to advance the field and bring these cutting-edge treatment options forward, and aspire to transform medical practice of the future.”
Koby Baranes, PhD, head of science at Clock Bio, cautions, “Aging is not yet fully understood and existing models often fail to fully replicate the complexity of human aging, making it difficult to conduct high-throughput screening and accurately predict the efficacy and safety of potential interventions.”
Koby Baranes, PhD
Science Head, Clock Bio
Thus, the company is working to “reset the clock” by utilizing a stem cell model. Baranes elaborates, “We have developed a proprietary aging model–an aging intervention–that enables us to force age human iPSCs. By applying this intervention, we can faithfully recreate all known cellular hallmarks of aging.”
Baranes says these iPSCs are unique in that after forced aging, they spontaneously show aging reversal. “iPSCs self-rejuvenate within days, meaning that the cellular hallmarks of aging disappeared. Given that these hallmarks are cellular phenotypes of age-related disease, our hypothesis is that understanding this self-rejuvenation process should yield therapeutically translatable insights.”
Company scientists have systematically identified genetic factors involved in this aging process using genome-wide CRISPR screening that selectively knocks out or activates all individual genes across the genome. Baranes reports, “This unbiased approach allows us to determine the role of each gene in rejuvenation. If knocking out a gene impairs rejuvenation, it suggests that the gene is essential for the process. Conversely, if knocking out a gene accelerates rejuvenation, it may function as an aging-promoting factor.”
Employing this strategy, the company has identified more than 150 genes so far. “We collectively call this the ‘Atlas of Rejuvenation Factors.’ Our early findings suggest that approximately 25% of these genes are ‘rejuvenation genes’ (whose loss inhibits rejuvenation), while around 75% are ‘aging genes’ (whose loss enhances rejuvenation). Therefore, we have sufficient degrees of freedom to potentially operate with classic modalities of protein inhibition.”
Scientists at Rejuvenate Biomed utilize AI to identify synergistic drug combinations that can target multiple pathways simultaneously for the treatment of age-related diseases.
Clock Bio scientists have tested more than 300 drugs, with over 100 that target their hits using a proprietary pre-clinical drug discovery assay. Baranes summarizes, “This allows us to validate the effect of our identified genes in somatic cells and prioritize them for clinical application in the near future. We started with validation in fibroblasts and will move to neuronal models and immune cells from there.”
The post Scientists Are Turning Back the Clock appeared first on GEN - Genetic Engineering and Biotechnology News.
GEN spoke to several leaders in the field about their regenerative medicine programs and the applications they are pursuing. One approach utilizes the massive computing power of AI to identify safe drug combinations that can simultaneously target and treat multiple age-related biological pathways. Cells can be rejuvenated by harnessing the directorial capabilities (on/off switch) of epigenetics with engineered adeno-associated viruses (AAV) carrying transcription factors. An implantable bio-hybrid organ bearing healthy human pancreatic cells has shown promise in correcting type 1 diabetes (T1D). Parkinson’s disease may be treatable by transplanting precursor stem cells that can differentiate into function-restoring mature cells. While suitable aging models are still a challenge, one model system force-ages stem cells in a dish, couples this with CRISPR screenings, and has shown promise in identifying rejuvenation genes.
Targeting multiple pathways
“Age-related diseases are driven by interconnected biological changes that evolve with age, described as the hallmarks of aging,” explains Ann Beliën, PhD, founder and CEO of Rejuvenate Biomed. She continues, “Understanding this complexity is crucial for the development of targeted interventions that can effectively change the course of disease and enhance the quality of life for the aging population.”
Ann Beliën, PhD
Founder, CEO
Rejuvenate Biomed
One therapeutic challenge is that single-target drugs often do not fully address such complex multifactorial processes. According to Beliën, the company is addressing this need by pursuing synergistic combinations of therapeutics that can impact multiple pathways simultaneously to enhance clinical benefit. “We are using drug combinations with established safety profiles for derisking clinical development and shortening the development time. This approach thus presents an opportunity to address medical unmet needs in severe diseases of aging.”
The company identifies and assesses the combos using two synergistic platforms: the AI-enabled CombinAgeTM and in vivo CelegAgeTM platforms. “These enable a biology-first and disease-agnostic approach,” informs Beliën.
The CombinAge platform sifts through vast datasets of biomedical knowledge on hundreds of individual drugs already proven safe for older adults and “analyzes pathways linked to hallmarks of aging, such as mitochondrial dysfunction, epigenetic alterations, and intercellular communication, to uncover combinations of those individual drugs that can impact multiple aging pathways simultaneously.”
After an additional safety check on the identified drug combination, its impact on health span is assessed in vivo via CelegAge, a platform that employs C. elegans worms. Beliën summarizes, “This model focuses on outcomes like movement, speed, and overall mobility, key indicators of aging and vitality, to validate CombinAge’s predictions.”
Following these analyses, the company goes back to CombinAge, which contains disease-specific data, to predict which age-related disease the drug combination could most effectively treat. The combination is then ready for the typical preclinical process and suitable to be advanced in Phase II trials directly, after the proof of principle is demonstrated in animal models.
The company has built a pipeline of five unique combination drugs targeting neuromuscular, musculoskeletal, metabolic, cardiovascular, nephrological, and neurodegenerative diseases. Beliën asserts that its lead Phase II-ready asset, RJx-01, has already demonstrated significant potential in treating sarcopenia. “We look forward to initiating a Phase II trial to evaluate sarcopenia in patients with chronic obstructive pulmonary disease this year.”
Epigenetic focus
Aging has historically been viewed to result from random wear and tear on the body that accumulates throughout a person’s life. Life Biosciences says that these biological aging processes are modifiable. Sharon Rosenzweig-Lipson, PhD, CSO, provides a perspective: “As we age, the epigenetic code that regulates gene expression drifts, leading to altered patterns of gene expression. This shift is associated with changes in epigenetic markers called methyl groups that may lead to dysfunction.”
Sharon Rosenzweig-Lipson, PhD
CSO, Life Biosciences
The company is focusing on partial epigenetic programming based on the Nobel-Prize-winning discovery of Yamanaka factors. These four transcription factors can completely dial back and reprogram mature cells to become pluripotent. Rosenzweig-Lipson explains, “Life Bio is leveraging our partial epigenetic reprogramming platform using three factors, OSK (Oct4, Sox2, Klf4), to reset the epigenetic code and reverse age-related epigenetic changes. This allows for cellular rejuvenation to a younger state, without the loss of cell identity, to prevent or reverse age-related diseases. This approach targets a key root cause of aging at the epigenetic level, thereby offering the potential to address a wide range of age-related diseases with significant unmet medical needs.”
Life Biosciences’ lead candidate is ER-100. Rosenzweig-Lipson elaborates, “ER-100 utilizes a dual vector AAV2 tet-on system containing an AAV2 with a transactivator and an AAV2 that can express OSK in the presence of oral doxycycline. This permits the expression of OSK within target cells to reprogram the epigenome in a controlled manner.”
ER-100 is currently in late-stage preclinical development for both chronic and acute optic neuropathies including glaucoma and the rare eye disease non-arteritic anterior ischemic optic neuropathy (NAION). Rosenzweig-Lipson reveals, “ER-100 has demonstrated safety and efficacy in multiple pre-clinical animal models of disease. We are aiming to initiate the first human clinical studies evaluating ER-100 for optic neuropathies within a year.”
Bio-hybrid organ
Regenerative medicine also provides a promising avenue for treating chronic diseases such as T1D, an autoimmune disorder that destroys the insulin-producing cells of the pancreas. Sernova is focusing on restoring the body’s natural ability to regulate insulin by combining its implantable Cell PouchTM bio-hybrid organ with therapeutic human cells.
Jonathan Rigby
CEO, Sernova
CEO Jonathan Rigby explains, “In the case of T1D, the therapeutic cells that are transplanted into the Cell Pouch chambers are pancreatic islets. Islets are clusters of alpha, beta, and delta cells, which create vital hormones called glucagon, insulin, and somatostatin. These hormones regulate blood glucose. By transplanting islets into the chambers of the Cell Pouch bio-hybrid organ, we aim to provide a location within the body for the long-term survival and function of the therapeutic cells.”
According to Rigby, the Cell Pouch is a small, chambered structure made from nontoxic, medical-grade, biocompatible materials previously approved by the FDA for permanent use in the body. “It is surgically implanted under the skin against the abdominal muscles, where it seamlessly integrates within the body to create an ideal vascularized tissue environment. The cells are transplanted into chambers of the Cell Pouch bio-hybrid organ.”
One of the hallmarks of T1D is destruction of insulin-producing pancreatic cells. Sernova is pioneering the use of an implantable Cell Pouch that houses healthy donor islet cells to create a bio-hybrid organ.
Rigby says the company is currently conducting Phase I/II clinical trials in combination with human donor islets. “The Cell Pouch has shown the ability to support the survival and function of transplanted islets for over five years. In addition, it has demonstrated complete retrievability with no evidence of fibrosis, while also showing promising signs of efficacy.”
However, Rigby believes that utilizing donor islets is not a commercially viable option for the future. He reports, “We have partnered with Evotec, a company that has developed induced pluripotent stem cell (iPSC)-derived islet-like clusters, which can be manufactured in nearly unlimited quantities. Notably, in preclinical studies, Evotec’s islet-like clusters have performed comparably to human islets when implanted within the chambers of a pre-vascularized Cell Pouch.”
Replace-restore-reimagine
In degenerative illnesses, such as Parkinson’s disease, cells undergo progressive deterioration and dysfunction, potentially leading to cell death. BlueRock Therapeutics is focusing on regenerative pluripotent stem cells (PSCs) that can differentiate into specific cell types that have the potential to replace the cells lost or damaged by disease.
Amit Rakhit, MD
Chief Medical Officer
BlueRock Therapeutics
Amit Rakhit, MD, chief medical officer, discusses, “Typically, by the time a person is diagnosed with Parkinson’s disease, approximately 80% of their dopamine-producing neurons are gone. This impacts a person’s cognitive, motor, and non-motor functions. Current standard of care, using small molecules or deep brain stimulation, can help mimic this loss of dopamine and provide symptomatic relief, but over time, their effectiveness declines.”
According to Rakhit, BlueRock Therapeutics is taking a different approach. They aim to replace the dopamine-producing neurons that are lost in Parkinson’s disease by administering PSCs differentiated into dopamine-producing neuron progenitors. “In a one-time surgical procedure, the dopamine-producing neuronal precursors are transplanted into a part of the brain called the putamen. When transplanted, these precursors have the potential to halt disease progression, by further developing into mature brain cells after implantation and reforming the neural networks that have been severely affected by Parkinson’s–restoring motor and non-motor function to patients.”
Last year, the company’s candidate therapy, named bemdaneprocel, completed an open-label Phase I clinical trial in 12 participants. Rakhit reports, “Based on the data from this trial and conversations with the FDA under a Regenerative Medicine Advanced Therapy designation, BlueRock plans to advance bemdaneprocel to a Phase III pivotal trial that is expected to start later this year. This will be the first registrational Phase III clinical trial for an investigational allogeneic stem cell-derived therapy for treating Parkinson’s disease.”
BlueRock also plans to initiate a Phase I clinical trial for an investigational iPSC-derived therapy, OpCT-001, for the treatment of primary photoreceptor diseases that cause irreversible vision loss in children and adults.
Rakhit believes that such allogeneic cell therapies offer the potential of achieving a global impact. “We look forward to continuing to work with our colleagues in cell therapy to advance the field and bring these cutting-edge treatment options forward, and aspire to transform medical practice of the future.”
Aging in a dish
Koby Baranes, PhD, head of science at Clock Bio, cautions, “Aging is not yet fully understood and existing models often fail to fully replicate the complexity of human aging, making it difficult to conduct high-throughput screening and accurately predict the efficacy and safety of potential interventions.”
Koby Baranes, PhD
Science Head, Clock Bio
Thus, the company is working to “reset the clock” by utilizing a stem cell model. Baranes elaborates, “We have developed a proprietary aging model–an aging intervention–that enables us to force age human iPSCs. By applying this intervention, we can faithfully recreate all known cellular hallmarks of aging.”
Baranes says these iPSCs are unique in that after forced aging, they spontaneously show aging reversal. “iPSCs self-rejuvenate within days, meaning that the cellular hallmarks of aging disappeared. Given that these hallmarks are cellular phenotypes of age-related disease, our hypothesis is that understanding this self-rejuvenation process should yield therapeutically translatable insights.”
Company scientists have systematically identified genetic factors involved in this aging process using genome-wide CRISPR screening that selectively knocks out or activates all individual genes across the genome. Baranes reports, “This unbiased approach allows us to determine the role of each gene in rejuvenation. If knocking out a gene impairs rejuvenation, it suggests that the gene is essential for the process. Conversely, if knocking out a gene accelerates rejuvenation, it may function as an aging-promoting factor.”
Employing this strategy, the company has identified more than 150 genes so far. “We collectively call this the ‘Atlas of Rejuvenation Factors.’ Our early findings suggest that approximately 25% of these genes are ‘rejuvenation genes’ (whose loss inhibits rejuvenation), while around 75% are ‘aging genes’ (whose loss enhances rejuvenation). Therefore, we have sufficient degrees of freedom to potentially operate with classic modalities of protein inhibition.”
Scientists at Rejuvenate Biomed utilize AI to identify synergistic drug combinations that can target multiple pathways simultaneously for the treatment of age-related diseases.
Clock Bio scientists have tested more than 300 drugs, with over 100 that target their hits using a proprietary pre-clinical drug discovery assay. Baranes summarizes, “This allows us to validate the effect of our identified genes in somatic cells and prioritize them for clinical application in the near future. We started with validation in fibroblasts and will move to neuronal models and immune cells from there.”
The post Scientists Are Turning Back the Clock appeared first on GEN - Genetic Engineering and Biotechnology News.