MFN2

RICHMOND, Calif.--(BUSINESS WIRE)-- Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, today announced that the American Society of Gene & Cell Therapy (ASGCT) has accepted 20 Sangamo abstracts for presentation at the 27th ASGCT Annual Meeting being held May 7-11, 2024, in-person in Baltimore, MD and in a virtual format. Presentations will focus on the progression of Sangamo’s neurology-focused pre-clinical pipeline, including data supporting innovations in zinc finger epigenetic regulation, advances in AAV capsid engineering, and discovery of next-generation integrase technology. “We are thrilled to be showcasing at ASGCT the strong depth of our neurology pipeline, including various applications for our zinc finger epigenetic regulation platform, exciting advances in our capsid delivery technology, and new, potentially transformative Modular Integrases (MInts), that together reflect our continued commitment to developing potential neurology genomic medicines for patients in need,” said Amy Pooler, Head of Research at Sangamo. “Potent epigenetic regulation in diseases such as prion disease and tauopathies are complemented by our exceptional AAV delivery capabilities, a combination that is essential to the development of effective potential genomic medicine treatments to treat devastating neurological conditions.” “These data showcase the deep expertise of our scientific team in engineering DNA-protein interactions and the broad potential reach of our innovative pre-clinical approaches, including exciting new discoveries for site-directed integration of large DNA sequences via engineered MInts,” said Greg Davis, Head of Technology at Sangamo. “Using compact, protein-guided integrases built from Bxb1 variants as a means of targeted integration expands our genome editing abilities and underscores our drive to develop technologies that enable potentially transformative new medicines.” Data presentations at the ASGCT Annual Meeting include three oral presentations, two of which detail Sangamo’s potent delivery capabilities developed through its AAV capsid engineering platform SIFTER, and one that will discuss a new breakthrough in programming Bxb1, a large serine recombinase, for the development of MInts to potentially enable large-scale genome engineering. These data will showcase a novel AAV capsid, STAC-BBB, that exhibited robust and widespread central nervous system transduction in cynomolgus macaques after intravenous delivery, as well as another novel AAV capsid, STAC-150, engineered to accelerate the discovery of potent and highly specific epigenetic regulators. Sangamo will also showcase data highlighting the use of MInts, derived from compact Bxb1 variants, to integrate large sequences of DNA into the genome with minimal double-stranded DNA breaks and without the need for assistance from ancillary genome editing or DNA-repair modulating cargo. Additional poster presentations at the ASGCT Annual Meeting will showcase the use of zinc finger activators and repressors for the potential treatment of neurological diseases such as prion disease, tauopathies, Charcot-Marie-Tooth disease type 1A (CMT1A), Dravet Syndrome, SOD1-mediated amyotrophic lateral sclerosis (ALS), Phelan-McDermid syndrome, Parkinson’s disease, Angelman syndrome, and other CNS disorders. Sangamo will also present additional data from its AAV capsid engineering platform SIFTER and its efforts for integrase evolution and utilization. ASGCT Annual Meeting Presentations and Invited Sessions Epigenetic Regulation for the Central Nervous System Restoration of Normal Gene and Protein Expression in Mouse and Human Disease Models of SCN2A Haploinsufficiency Using Zinc Finger Activators Abstract No. 636 Poster Presentation – May 8; 5:30-7:00 pm ET A Zinc Finger Activator Platform to Restore Normal Gene & Protein Expression in Cellular Models of Dravet Syndrome Abstract No. 642 Poster Presentation – May 8; 5:30-7:00 pm ET SNCA Gene Repression Mediated by Zinc Finger Repressors (ZFRs) as a Therapeutic Approach for Parkinson's Disease Abstract No. 1120 Poster Presentation – May 9; 5:30-7:00 pm ET UBE3A Gene Activation Mediated by Zinc Finger Activators (ZFAs) as a Therapeutic Approach for Angelman Syndrome Abstract No. 1121 Poster Presentation – May 9; 5:30-7:00 pm ET Whole CNS Human Tau Knockdown for the Potential Treatment of Alzheimer’s Disease and Other Tauopathies Abstract No. 1126 Poster Presentation – May 9; 5:30-7:00 pm ET SOD1 Gene Repression Mediated by Zinc Finger Repressors (ZFRs) as a Therapeutic Approach for SOD1-Mediated ALS Abstract No. 1597 Poster Presentation – May 10; 5:30-7:00 pm ET PMP22 Gene Repression Mediated by Zinc Finger Repressors (ZFRs) as a Therapeutic Approach for CMT1A Abstract No. 1600 Poster Presentation – May 10; 5:30-7:00 pm ET Shank3 Gene Activation Mediated by Zinc Finger Transcriptional Activators (ZFA) as a Therapeutic Approach for Phelan-McDermid Syndrome Abstract No. 1605 Poster Presentation – May 10; 5:30-7:00 pm ET Development of a Robust Zinc Finger Activation Platform for Treatment of Neurological Disorders Abstract No. 1609 Poster Presentation – May 10; 5:30-7:00 pm ET Epigenetic Regulation of Human Prion Expression as a Potential One-Time Treatment for Prion Disease Abstract No. 1616 Poster Presentation – May 10; 5:30-7:00 pm ET Viral Engineering for the Central Nervous System Identification and Characterization of STAC-BBB, an Engineered AAV Capsid That Exhibits Widespread Transduction of the Central Nervous System in Cynomolgus Macaques Abstract No. 117 Oral Presentation – May 8; 4:00-4:15 pm ET A Highly Potent Engineered AAV Capsid, STAC-150, Enables High-Throughput AAV Production and Arrayed Epigenetic Regulator Screening Directly in Cultured Neurons Abstract No. 351 Oral Presentation – May 10; 5:15-5:30 pm ET Optimal Drug Product Presentation and Container Closure Selection for AAV-Based Genomic Medicines Abstract No. 547 Poster Presentation – May 8; 5:30-7:00 pm ET Development of Blood-Brain Barrier Penetrant AAVs through Receptor-Targeted Capsid Engineering Abstract No. 985 Poster Presentation – May 9; 5:30-7:00 pm ET Unraveling Impact of Manufacturing Process-Related Stresses on AAV Stability, Aggregation, and DNA Release Abstract No. 1032 Poster Presentation – May 9; 5:30-7:00 pm ET Process and Formulation Development for a Novel Blood-Brain Barrier Penetrant AAV Capsid Abstract No. 1052 Poster Presentation – May 9; 5:30-7:00 pm ET Next-Generation Genome Engineering Directed Evolution of Bxb1 for the Development of Modular Integrases (MInts) Abstract No. 192 Oral Presentation – May 9; 4:00-4:15 pm ET Zinc Finger Mediated Repression and Replacement of MFN2 Leads to the Rescue of Cellular Disease Phenotype in CMT2A Patient-Derived Cells Abstract No. 637 Poster Presentation – May 8; 5:30-7:00 pm ET Highly Specific Zinc Finger Proteins with Synthetic Target Sites Enable Self-Regulated Expression of Dosage-Sensitive Transgenes Abstract No. 722 Poster Presentation – May 8; 5:30-7:00 pm ET Site-directed integration of large DNA sequences into endogenous sites in the human genome using engineered Modular Integrases (MInts) Abstract No. 1680 Poster Presentation – May 10; 5:30-7:00 pm ET All abstracts for the ASGCT Annual Meeting are available on ASGCT’s website. About Sangamo Therapeutics Sangamo Therapeutics is a genomic medicine company dedicated to translating ground-breaking science into medicines that transform the lives of patients and families afflicted with serious neurological diseases who do not have adequate or any treatment options. Sangamo’s zinc finger epigenetic regulators are ideally suited to potentially address devastating neurological disorders and Sangamo’s capsid discovery platform is expanding delivery beyond currently available intrathecal delivery capsids, including in the central nervous system. Sangamo’s pipeline also includes multiple partnered programs and programs with opportunities for partnership and investment. To learn more, visit and connect with us on LinkedIn and Twitter/X. Sangamo Forward Looking Statements This press release contains forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, statements relating to Sangamo’s technologies, the presentation of data from various therapeutic and research programs and the potential of these programs to demonstrate therapeutic benefit and transform the lives of patients. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, the research and development process, including the results of clinical trials; the regulatory approval process for product candidates; and the potential for technological developments that obviate technologies used by Sangamo. Actual results may differ from those projected in forward-looking statements due to risks and uncertainties that exist in Sangamo's operations and business. These risks and uncertainties are described more fully in our Securities and Exchange Commission filings and reports, including in our Annual Report on Form 10-K for the year ended December 31, 2023. Forward-looking statements contained in this announcement are made as of this date, and Sangamo undertakes no duty to update such information except as required under applicable law. View source version on businesswire.com: Contacts Investor Relations & Media Inquiries Louise Wilkie ir@sangamo.com media@sangamo.com Source: Sangamo Therapeutics, Inc. View this news release online at:

-- Future clinical trials to determine if combination chloroquine and venetoclax addresses disease comeback NEW YORK, April 24, 2023 /PRNewswire/ -- Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs' effects within a year. Now, new research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions. This process of "programmed cell death" often goes wrong in cancer. Damaged mitochondria can also undergo a form of "self-eating" termed mitophagy that prevents them from sending "death signals." Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells to evade the killing effects of venetoclax, a drug in a class of medications known as BH3 mimetics. Publishing in the journal Cancer Discovery online April 24, researchers found that the levels of several genes associated with mitophagy were increased in 20 leukemia patient samples compared with normal controls. The level of these genes was even higher in samples from leukemia patients with drug resistance than in those leukemic patients who were not. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane. Further experiments using mice into which bone marrow from acute myeloid leukemia patients was transplanted showed that the drug chloroquine, a known mitophagy inhibitor, restored the ability of venetoclax to kill the cancer cells. "Overcoming resistance to BH3 mimetic drugs like venetoclax is of unique clinical significance because these medications are often used for treating people with acute myeloid leukemia," said study co-lead investigator Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now an assistant professor at Rutgers University. "Acute myeloid leukemia is notoriously difficult to treat, with fewer than a third of those affected living longer than five years after their diagnosis, so it is important to maximize the impact of existing therapies," said study co-lead investigator Xufeng Chen, PhD, an instructor in the Department of Pathology at NYU Grossman. "Our preclinical findings suggest that combining BH3 mimetics like venetoclax with either MFN2 or general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia, as current drug treatments are stalled due to drug resistance," said study senior investigator Iannis Aifantis, PhD. Aifantis, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Grossman and Perlmutter, says the research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance in people with acute myeloid leukemia. Speaking about other study results, the researchers say they not only found that MFN2 was overly active in people with drug-resistant disease, but also that cancer cells exposed to similar cell-death-inducing compounds demonstrated a doubling in mitophagy rates. Additional testing in cancer cells engineered to lack MFN2 showed increased sensitivity to drugs similar to venetoclax compared with cells that had functional MFN2. The new study and previous research by the team showing misshapen mitochondria in drug-resistant leukemic cells confirmed that increased mitophagy was the source of the problem. Acute myeloid leukemia, the most common form of adult leukemia, originates in the bone marrow cells and involves the rapid buildup of abnormal blood cells. The blood cancer results in the deaths of more than 11,500 Americans annually. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail. Funding support for the study was provided by National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602. Additional funding support was provided by the Leukemia & Lymphoma Society and by AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments. Aifantis has received additional research funding from AstraZeneca. This arrangement is being managed in accordance with the policies and practices of NYU Langone Health. Besides Glytsou, Chen, and Aifantis, other NYU Langone study investigators are Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos. Other study co-investigators are Emmanouil Zacharioudakis and Evripidis Gavathiotis, at Albert Einstein College of Medicine in New York, who have filed a patent on mitofusin inhibition based on this research; Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff, at the University of Texas MD Anderson Cancer Center in Houston; and Raoul Tibes, at AstraZeneca in Cambridge, the United Kingdom. Media Inquiries David March 212-404-3528 [email protected] STUDY LINK SOURCE NYU Grossman School of Medicine and NYU Langone Health

NEW YORK, April 24, 2023. Despite the promise of new medications that promote cancer cell death in people with acute myeloid leukemia, leukemic cells often adopt features that let them evade the drugs' effects within a year. Now, new research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions. This process of "programmed cell death" often goes wrong in cancer. Damaged mitochondria can also undergo a form of "self-eating" termed mitophagy that prevents them from sending "death signals." Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells to evade the killing effects of venetoclax, a drug in a class of medications known as BH3 mimetics. Publishing in the journal Cancer Discovery online April 24, researchers found that the levels of several genes associated with mitophagy were increased in 20 leukemia patient samples compared with normal controls. The level of these genes was even higher in samples from leukemia patients with drug resistance than in those leukemic patients who were not. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane. Further experiments using mice into which bone marrow from acute myeloid leukemia patients was transplanted showed that the drug chloroquine, a known mitophagy inhibitor, restored the ability of venetoclax to kill the cancer cells. "Overcoming resistance to BH3 mimetic drugs like venetoclax is of unique clinical significance because these medications are often used for treating people with acute myeloid leukemia," said study co-lead investigator Christina Glytsou, PhD, a former postdoctoral researcher at NYU Grossman School of Medicine and now an assistant professor at Rutgers University. "Acute myeloid leukemia is notoriously difficult to treat, with fewer than a third of those affected living longer than five years after their diagnosis, so it is important to maximize the impact of existing therapies," said study co-lead investigator Xufeng Chen, PhD, an instructor in the Department of Pathology at NYU Grossman. "Our preclinical findings suggest that combining BH3 mimetics like venetoclax with either MFN2 or general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia, as current drug treatments are stalled due to drug resistance," said study senior investigator Iannis Aifantis, PhD. Aifantis, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Grossman and Perlmutter, says the research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance in people with acute myeloid leukemia. Speaking about other study results, the researchers say they not only found that MFN2 was overly active in people with drug-resistant disease, but also that cancer cells exposed to similar cell-death-inducing compounds demonstrated a doubling in mitophagy rates. Additional testing in cancer cells engineered to lack MFN2 showed increased sensitivity to drugs similar to venetoclax compared with cells that had functional MFN2. The new study and previous research by the team showing misshapen mitochondria in drug-resistant leukemic cells confirmed that increased mitophagy was the source of the problem. Acute myeloid leukemia, the most common form of adult leukemia, originates in the bone marrow cells and involves the rapid buildup of abnormal blood cells. The blood cancer results in the deaths of more than 11,500 Americans annually. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail. Funding support for the study was provided by National Institutes of Health grants P30CA016087, P30CA013330, R01CA178394, R01CA173636, R01CA228135, R01CA229086, R01CA242020, and K99CA252602. Additional funding support was provided by the Leukemia & Lymphoma Society and by AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments. Aifantis has received additional research funding from AstraZeneca. This arrangement is being managed in accordance with the policies and practices of NYU Langone Health. Besides Glytsou, Chen, and Aifantis, other NYU Langone study investigators are Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, and Aristotelis Tsirigos. Other study co-investigators are Emmanouil Zacharioudakis and Evripidis Gavathiotis, at Albert Einstein College of Medicine in New York, who have filed a patent on mitofusin inhibition based on this research; Tomasz Zal, Malgorzata Anna Zal, Bing Carter, Jo Ishizawa, and Michael Andreeff, at the University of Texas MD Anderson Cancer Center in Houston; and Raoul Tibes, at AstraZeneca in Cambridge, the United Kingdom. SOURCE NYU Grossman School of Medicine and NYU Langone Health Posted: April 2023 Related articles Genentech Announces Full FDA Approval for Venclexta Combinations for Acute Myeloid Leukemia - October 16, 2020 AbbVie Announces US FDA Approval of Venclexta (venetoclax) as a Chemotherapy-Free Combination Regimen for Previously Untreated Chronic Lymphocytic Leukemia Patients - May 15, 2019 Genentech Announces FDA Grants Venclexta Accelerated Approval for People With Newly-Diagnosed Acute Myeloid Leukemia or Those Who Are Ineligible For Intensive Induction Chemotherapy - November 21, 2018 Genentech Announces FDA Approval for Venclexta Plus Rituxan for People With Previously Treated Chronic Lymphocytic Leukemia - June 8, 2018 FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion - April 11, 2016 FDA Grants Priority Review for Venetoclax New Drug Application - January 12, 2016 Pivotal Phase II Study Showed Nearly 80 Percent of People with Hard-to-treat Type of Chronic Lymphocytic Leukemia Responded to Investigational Medicine Venetoclax - December 6, 2015 Venclexta (venetoclax) FDA Approval History