Novartis and the Bill and Melinda Gates Foundation are joining forces to discover and develop a gene therapy to cure sickle cell disease with a one-step, one-time treatment that is affordable and simple enough to treat patients anywhere in the world, especially in sub-Saharan Africa where resources may be scarce but disease prevalence is high.

The three-year collaboration, announced Wednesday, has initial funding of $7.28 million.

Current gene therapy approaches being developed for sickle cell disease are complex, enormously expensive, and bespoke, crafting treatments for individual patients one at a time. The collaboration aims to instead create an off-the-shelf treatment that bypasses many of the steps of current approaches, in which cells are removed and processed outside the body before being returned to patients.

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Sickle cells cause is understood. The people it affects are known. But its cure has been elusive, Jay Bradner, president of the Novartis Institutes for BioMedical Research, told STAT.

We understand perfectly the disease pathway and the patient, but we dont know what it would take to have a single-administration, in vivo gene therapy for sickle cell disease that you could deploy in a low-resource setting with the requisite safety and data to support its use, he said. Im a hematologist and can assure you that in my experience in the clinic, it was extremely frustrating to understand a disease so perfectly but have so little to offer.

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Sickle cell disease is a life-threatening inherited blood disorder that affects millions around the world, with about 80% of affected people in sub-Saharan Africa and more than 100,000 in the U.S. The mutation that causes the disease emerged in Africa, where it protects against malaria. While most patients with sickle cell share African ancestry, those with ancestry from South America, Central America, and India, as well as Italy and Turkey, can also have the hereditary disease.

The genetic mutation does its damage by changing the structure of hemoglobin, hampering the ability of red blood cells to carry oxygen and damaging blood vessels when the misshapen cells get stuck and block blood flow. Patients frequently suffer painful crises that can be fatal if not promptly treated with fluids, medication, and oxygen. Longer term, organs starved of oxygen eventually give out. In the U.S., that pain and suffering is amplified when systemic and individual instances of racism deny Black people the care they need.

Delivering gene therapy for other diseases has been costly and difficult even in the best financed, most sophisticated medical settings. Challenges include removing patients cells so they can be altered in a lab, manufacturing the new cells in high volume, reinfusing them, and managing sometimes severe responses to the corrected cells. Patients also are given chemotherapy to clear space in their bone marrow for the new cells.

Ideally, many of those steps could be skipped if there were an off-the-shelf gene therapy. That means, among other challenges, inventing a way to eliminate the step where each patients cells are manipulated outside the body and given back the in vivo part of the plan to correct the genetic mutation.

Thats not the only obstacle. For a sickle cell therapy to be successful, Bradner said, it must be delivered only to its targets, which are blood stem cells. The genetic material carrying corrected DNA must be safely transferred so it does not become randomly inserted into the genome and create the risk of cancer, a possibility that halted a Bluebird Bio clinical trial on Tuesday. The payload itself mustnt cause such problems as the cytokine storm of immune overreaction. And the intended response has to be both durable and corrective.

In a way, the gene delivery is the easy part because we know that expressing a normal hemoglobin, correcting the mutated hemoglobin, or reengineering the switches that once turned off normal fetal hemoglobin to turn it back on, all can work, Bradner said. The payload is less a concern to me than the safe, specific, and durable delivery of that payload.

For each of these four challenges delivery, gene transfer, tolerability, durability there could be a bespoke technical solution, Bradner said. The goal is to create an ensemble form of gene therapy.

Novartis has an existing sickle-cell project using CRISPR with the genome-editing company Intellia, now in early human trials, whose lessons may inform this new project. CRISPR may not be the method used; all choices are still on the table, Bradner said.

Vertex Pharmaceuticals has seen encouraging early signs with its candidate therapy developed with CRISPR Therapeutics. Other companies, including Beam Therapeutics, have also embarked on gene therapy development.

The Novartis-Gates collaboration is different in its ambition to create a cure that does not rely on an expensive, complicated framework. Novartis has worked with the Gates Foundation on making malaria treatment accessible in Africa. And in October 2019, the Gates Foundation and the National Institutes of Health said together they would invest at least $200 million over the next four years to develop gene-based cures for sickle cell disease and HIV that would be affordable and available in the resource-poor countries hit hardest by the two diseases, particularly in Africa.

Gene therapies might help end the threat of diseases like sickle cell, but only if we can make them far more affordable and practical for low-resource settings, Trevor Mundel, president of global health at the Gates Foundation, said in a statement about the Novartis collaboration. Its about treating the needs of people in lower-income countries as a driver of scientific and medical progress, not an afterthought.

Asked which is the harder problem to solve: one-time, in vivo gene therapy, or making it accessible around the world, David Williams, chief of hematology/oncology at Boston Childrens Hospital, said: Both are going to be difficult to solve. The first will likely occur before the therapy is practically accessible to the large number of patients suffering the disease around the world.

Williams is also working with the Gates Foundation, as well as the Koch Institute for Integrative Cancer Research at MIT, Dana-Farber Cancer Institute, and Massachusetts General Hospital, on another approach in which a single injection of a reagent changes the DNA of blood stem cells. But there are obstacles to overcome there, too, that may be solved by advances in both the technology to modify genes and the biological understanding of blood cells.

Bradner expects further funding to come to reach patients around the world, once the science progresses more.

There is no plug-and-play solution for this project in the way that mRNA vaccines were perfectly set up for SARS-CoV-2. We have no such technology to immediately redeploy here, he said. Were going to have to reimagine what it means to be a gene therapy for this project.

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Novartis, Gates Foundation pursue a simpler gene therapy for sickle cell - STAT

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