Two different gene therapies have been used to mitigate a mechanism underlying development of sickle cell disease (SCD) and transfusion-dependent -thalassemia (TDT), and both have demonstrated clinical success in separate, concurrently published trials.
The hemoglobinopathies manifest after fetal hemoglobin synthesis is replaced by adult hemoglobin in individuals who have inherited a mutation in the hemoglobin subunit gene (HBB).Identifying factors in the conversion from fetal to adult hemoglobin synthesis, however, has provided potential targets for therapeutic intervention.
Gene therapy that can safely arrest or reduce the conversion offers the potential for a one-time treatment to obviate the need for lifetime transfusions and iron chelation for patients with TDT, and the pain management, transfusions and hydroxyurea administration for those with SCD.
Two groups of investigators have now reported in The New England Journal of Medicine that, using different gene therapy techniques that target the transcription factor, BCL11a, involved in the globin switching, they have improved clinical outcomes in patients with TDT and with SCD.
In an editorial in the issue featuring the 2 studies, Mark Walters, MD, Blood and Marrow Transplant Program, University of California, San Francisco-Benioff Children's Hospital, welcomed the breakthroughs.
"These trials herald a new generation of broadly applicable curative treatments for hemoglobinopathies," Walters wrote.
In one clinical trial with 2 patients, one with TDT and the other with SCD, Haydar Frangoul, MD, MS, Medical Director, Pediatric Hematology/Oncology, Sarah Cannon Center for Blood Cancer at the Children's Hospital at Tristar Centennial, and colleagues administered CRISPR-Cas9 gene edited hematopoietic stem and progenitor cells (HSPCs) with reduced BCL11A expression in the erythroid lineage.
The product, CTX001, had been shown in preclinical study to restore -globulin synthesis and reactivate production of fetal hemoglobin. Both patients underwent busulfan-induced myeloablation prior to receiving the treatment.
The investigators suggested that the CRISPR-Cas9-based gene-edited product could change the paradigm for patients with these conditions, if it was found to successfully and durably graft, produce no "off-target" editing products, and, importantly, improve clinical course.
"Recently approved therapies, including luspatercept and crizanlizumab, have reduced transfusion requirements in patients with TDT and the incidence of vaso-occlusive episodes in those with SCD, respectively, but neither treatment addressed the underlying cause of the disease nor fully ameliorates disease manifestations," Frangoul and colleagues wrote.
The investigators reported that both patients had "early, substantial, and sustained increases" in pancellularly distributed fetal hemoglobin levels during the 12-month study period. Further, the patients no longer required transfusions, and the patient with SCD no longer experienced vaso-occlusive episodes after the treatment.
In commentary accompanying the report, Harry Malech, MD, Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD, described the investigators' application of the gene-editing technology as a "remarkable level of functional correction of the disease phenotype."
"With tangible results for their patients, Frangoul et al have provided a proof of principle of the emerging clinical potential for gene-editing treatments to ameliorate the burden of human disease," Malech pronounced.
In the other published trial, with 6 patients with SCD, Erica Esrick MD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, and colleagues described results with infusion of gene-modified cells derived from lentivirus insertion of a gene that knocks down BCL11a by encoding an erythroid-specific, inhibitory short-hairpin RNA (shRNA).
The severity of SCD that qualified patients for enrollment included history of stroke (n = 3), frequent vaso-occlusive events (n = 2) and frequent episodes of priapism (1).Patients were followed for 2 years, and offered enrollment in a 13-year long-term follow-up study.The infusion of the experimental drug BCH-BB694, from the short hairpin RNA embedded within an endogeonous micro RNA scaffold (termed a shmiR vector), was initiated after myeloablation with busulfan.
Esrick and colleagues reported that, at median follow-up of 18 months (range, 7-29), all patients had engraftment and a robust and stable HbF induction broadly distributed in red cells.Clinical manifestations of SCD were reduced or absent during the follow-up period; with no patient having a vaso-occlusive crisis, acute chest syndrome, or stoke subsequent to the gene therapy infusion.Adverse events were consistent with effects of the preparative chemotherapy.
"The field of autologous gene therapies for hemoglobinopathies is advancing rapidly," Esrick and colleagues reported, "including lentiviral trials of gene addition in which the nonsickling hemoglobin is formed from an exogenous -globin or modified -globin gene."
Walters agreed that gene therapy is rapidly progressing, but expressed concern about the large gap that looms between laboratory bench and clinical bedside, particularly for this affected population.
"Access to and delivery of these highly technical therapies in patients with sickle cell disease will be challenging and probably limited to resource-rich nations, at least in the short term," Walters commented.
The studies, CRISPR-Cas9 Gene Editing for Sickle Cell Disease and -Thalassemia, as well as, Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease, were published online in The New England Journal of Medicine.
Continue reading here:
- UC Davis Health's partnership in telegenomics improves accessibility to genetic medicine with telemedicine robots - The Aggie - The Aggie - September 5th, 2021
- Could gene therapies be used to cure more people with HIV? - aidsmap - September 5th, 2021
- What to expect at the FDA's two-day meeting on gene therapy safety - BioPharma Dive - September 5th, 2021
- Global DNA Sequencing Report 2021: There is a Move Toward a More Consumer-Focused Model - Yahoo Finance - September 5th, 2021
- Agathos Biologics Receives $900,000 from the North Dakota Bioscience Innovation Grant Program - Yahoo Finance - September 5th, 2021
- New gene therapies may soon treat dozens of rare diseases, but million-dollar price tags will put them out of reach for many - The Conversation US - September 5th, 2021
- An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and s... - Physician's Weekly - September 5th, 2021
- Intense exercise could trigger ALS in those with genetic risk - Livescience.com - September 5th, 2021
- UT Southwestern selected top health care employer in Texas by Forbes - UT Southwestern - September 5th, 2021
- Opinion: Gene editing can be leveraged for the greater good with appropriate regulations - Varsity - September 5th, 2021
- Beefing up livestock disaster assistance | Farm & Ranch | willistonherald.com - Williston Daily Herald - September 5th, 2021
- Precision Medicine Platform Aims to Advance Cancer Gene Therapies - HealthITAnalytics.com - February 11th, 2021
- Celebrate the Third Annual Medical Genetics Awareness Week April 13-16, 2021 - PRNewswire - February 11th, 2021
- The race to treat a rare, fatal syndrome may help others with common disorders like diabetes - Science Magazine - February 11th, 2021
- Myriad Genetics to Participate in Multiple Upcoming Health and Technology Conferences - GlobeNewswire - February 11th, 2021
- Neurons from patient blood cells enable researchers to test treatments for genetic brain disease - Brown University - February 11th, 2021
- The science behind those afternoon naps Harvard Gazette - Harvard Gazette - February 11th, 2021
- Ensoma Launches to Pioneer Next-Generation In Vivo Approach to Deliver First Off-the-shelf Genomic Medicines - Business Wire - February 11th, 2021
- Im 28 and I Dont Know My Family HistoryHeres How That Affects My Health - Well+Good - February 11th, 2021
- Ensoma Launches with $70 Million Series A and Takeda Licensing Deal - BioSpace - February 11th, 2021
- Response to Cancer Immunotherapy May Be Affected by Genes We Carry from Birth - UCSF News Services - February 11th, 2021
- NeuBase Therapeutics Reports Financial Results for the First Quarter of Fiscal Year 2021 - GlobeNewswire - February 11th, 2021
- PM Modi Waives off Rs 6 Crore Tax on Imported Medicine for 6-month-old Baby Girl from Mumbai - News18 - February 11th, 2021
- GeneSight Psychotropic Test's Combinatorial Approach Proves Better than Single-Gene Testing at Predicting Patient Outcomes and Medication Blood Levels... - February 11th, 2021
- Reflections on the 20th Anniversary of the First Publication of the Human Genome - Scientific American - February 11th, 2021
- Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder - Newswise - February 1st, 2021
- Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them - CNN - February 1st, 2021
- Decibel Therapeutics and Invitae Announce Launch of Amplify Genetic Testing Program - BioSpace - February 1st, 2021
- CCMB team identifies variants of genes that metabolise drugs - BusinessLine - February 1st, 2021
- Digbi Health's gut-microbiome and genetic-based obesity management program now allows 60,000 Doctors and Providers in Blue Shield of California's... - February 1st, 2021
- Copy number variations linked to autism have diverse but overlapping effects - Spectrum - February 1st, 2021
- Are Gene Therapies the Medicine of the Future? - BioSpace - February 1st, 2021
- Exploring the Relationship Between the Microbiome, Precision Medicine and Cancer - Technology Networks - February 1st, 2021
- Press Registration Is Now Open for the 2021 ACMG Annual Clinical Genetics Meeting - A Virtual Experience - PRNewswire - February 1st, 2021
- 4 New Life Sciences Licensing Deals and Investments to Watch - BioSpace - February 1st, 2021
- CRISPR Mutants - The Dawn of CRISPR Mutants - SAPIENS - SAPIENS - February 1st, 2021
- SMART Study Finds 22q11.2 Microdeletion Prevalence Much Higher than Expected - PRNewswire - February 1st, 2021
- Genomes, Maps, And How They Affect You - IFLScience - February 1st, 2021
- Are Phages Overlooked Mediators of Health and Disease? - The Scientist - February 1st, 2021
- The First Targeted Therapy For Lung Cancer Patients With The KRAS Gene MutationExtraordinary Results With Sotorasib - SurvivorNet - February 1st, 2021
- Atsena Therapeutics Raises $55 Million Series A Financing to Advance LCA1 Gene Therapy Clinical Program, Two Preclinical Assets, and Novel Capsid... - December 17th, 2020
- Locanabio Announces $100 Million Series B Financing to Advance Portfolio of Novel RNA-Targeted Gene Therapies for Neurodegenerative, Neuromuscular and... - December 17th, 2020
- NeuBase Therapeutics Announces Positive Preclinical In Vivo Data for PATrOL-enabled Anti-gene for the Treatment of Myotonic Dystrophy Type 1 -... - December 17th, 2020
- Genetic Analysis Services Market: Uptake of Next-generation Sequencing and Multi-gene Tests to Drive Market - BioSpace - December 17th, 2020
- FDA Clears Genetic Modification in Pigs for Biomedicine and Food - The Scientist - December 17th, 2020
- Key Genes Related to Severe COVID-19 Infection Identified - The Scientist - December 17th, 2020
- UNLV Researcher on the Curious Case of COVID-19 Reinfection - UNLV NewsCenter - December 17th, 2020
- Genomics and medicine it's complicated | Health | willistonherald.com - Williston Daily Herald - December 17th, 2020
- Emedgene collaborates with Illumina to scale the interpretation of genomic data for rare diseases - PRNewswire - December 17th, 2020
- Polymerase Chain Reaction Market | Increased Outbreak of Infectious Diseases to Accentuate Demand in the Market - BioSpace - December 17th, 2020
- LogicBio Therapeutics names Daphne Karydas and Jeff Goater to Board of Directors - BioSpace - December 17th, 2020
- rBIO Achieves Crucial Milestone on Mission to Lower the Cost of Insulin by 30% - BioSpace - December 17th, 2020
- Report: More than 1,300 Medicines and Vaccines in Development to Help Fight Cancer - PRNewswire - December 17th, 2020
- San Diego's Locanabio raises $100 million for treatments aimed at degenerative diseases - The San Diego Union-Tribune - December 17th, 2020
- Worldwide SNP Genotyping Industry to 2025 - Pharmacogenomics Led the End-user Segment of the SNP Genotyping Market - ResearchAndMarkets.com - Business... - December 17th, 2020
- Potential Weakness in SARS-CoV-2 Discovered Single Protein Needed for COVID-19 Virus to Reproduce and Spread - SciTechDaily - December 17th, 2020
- Landing of $75M expansion of Texas-based Taysha adds to Triangle's growing gene therapy hub - WRAL Tech Wire - December 17th, 2020
- Track the Vax: What Do We Need to Know About the New Vaccines? - Everyday Health - December 17th, 2020
- Medical history from the year you were born - Quad City Times - December 5th, 2020
- Sarepta Therapeutics to Share Clinical Update for SRP-5051, its Investigational PPMO for the Treatment of Duchenne Muscular Dystrophy - GlobeNewswire - December 5th, 2020
- Biochip Market | Increased Popularity of Personalized Medicine to Boost the Market Growth | Technavio - Business Wire - December 5th, 2020
- December: Baby birth weight research | News and features - University of Bristol - December 5th, 2020
- Global Next Generation Sequencing Market (2020 to 2026) - Growth, Trends, Competitive Landscape, and Forecasts - GlobeNewswire - December 5th, 2020
- NIH researchers link cases of ALS and FTD to a mutation associated with Huntington's disease - National Institute on Aging - December 5th, 2020
- Precision Medicine Market Poised to Grow at 11.5% By 20227 - GlobeNewswire - December 5th, 2020
- Fact check: mRNA vaccines kept at very cold temperatures so that they do not break apart; COVID-19 vaccines will not genetically modify humans -... - December 5th, 2020
- Stoke Therapeutics Announces Presentations Related to the Company's Work to Advance STK-001, the First Potential New Medicine to Target the Underlying... - December 5th, 2020
- King George III's illness debunked as symptom 'caused by medicine prescribed to him' - Express - December 5th, 2020
- Stoke Therapeutics to Present at the Needham Virtual Epilepsy & Pain Specialty CNS Therapeutics Conference - Business Wire - December 5th, 2020
- Following the science: the writers who have made sense of Covid - The Guardian - December 5th, 2020
- Gene experts claim they identified human genes that can protect against Covid-19 - CNBC - November 23rd, 2020
- Genome Medical Reaches 90 Million Covered Lives in US - PRNewswire - November 23rd, 2020
- Sarepta Therapeutics Named One of The Boston Globe's Top Places to Work 2020 - GlobeNewswire - November 23rd, 2020
- New Study Highlights the Importance of Genetic Testing for Pancreatic Cancer Patients - PRNewswire - November 23rd, 2020
- Baylor Genetics Launches Combination Test for COVID-19 and Influenza A and B; Multi-Panel Test Seeks to Address Dilemma of "Overlapping symptoms... - November 23rd, 2020
- CHOP Researchers Reverse Severe Lymphatic Disorder in Patient with Noonan Syndrome by Targeting Genetic Pathway - BioSpace - November 23rd, 2020
- Myriad Genetics Announces Global Expansion of Myriad myChoice Tumor Testing in Europe and China - GlobeNewswire - November 23rd, 2020
- Epigenetics and pulmonary diseases in the horizon of precision medicine: a review - DocWire News - November 23rd, 2020
- Four years after landing in US, graduating ISU senior is on his way to medical school - Iowa State University News Service - November 23rd, 2020
- Lethal brain infections in mice thwarted by decoy molecule - Washington University School of Medicine in St. Louis - November 23rd, 2020