Loading
What changed between revision 1 and revision 2, compared over the article's markdown source with its frontmatter — so a change to status, evidence or reversibility shows up as the edit it is.
Older · revision 1
Import· initial corpus import, not an edit
Initial import of content/casgevy.md — the filesystem corpus, unchanged. Not an edit.
12.5 kB
Revision 1
Revision 2
lines 8–14 → 8–147 unchanged lines not shown
categories: ["genetics"]categories: ["genetics"]tags: ["crispr", "sickle cell disease", "gene therapy", "haemoglobin", "drug pricing", "clinical trials"]tags: ["crispr", "sickle cell disease", "gene therapy", "haemoglobin", "drug pricing", "clinical trials"]summary: "The first approved CRISPR-based medicine, which disrupts a fetal-haemoglobin repressor in a patient's own blood stem cells to treat sickle cell disease and beta thalassaemia."summary: "The first approved CRISPR-based medicine, which disrupts a fetal-haemoglobin repressor in a patient's own blood stem cells to treat sickle cell disease and beta thalassaemia."updated: "2026-07-27"updated: "2026-10-29"humanEvidence: "In single-arm trials with no control group, most sickle cell recipients went at least twelve months without a vaso-occlusive crisis and most thalassaemia recipients stopped transfusions; follow-up is short."humanEvidence: "In single-arm trials with no control group, most sickle cell recipients went at least twelve months without a vaso-occlusive crisis and most thalassaemia recipients stopped transfusions; follow-up is short."access: "Approved in the United Kingdom in November 2023 and the United States shortly after; the US list price is about 2.2 million dollars, delivery is confined to authorised transplant centres, and early uptake was slow."access: "Approved in the United Kingdom in November 2023 and the United States shortly after; the US list price is about 2.2 million dollars, delivery is confined to authorised transplant centres, and early uptake was slow."reversibility: "irreversible"reversibility: "irreversible"lines 35–60 → 35–6020 unchanged lines not shown
## How it works## How it works Casgevy does not repair the mutation that causes either disease. It works around it.Casgevy does not repair the mutation that causes either disease; it works around it. Human beings make two different beta-like globin chains over a lifetime. Fetal haemoglobin, containing gamma-globin, dominates before birth and is switched off in the months afterwards, when adult beta-globin takes over. People who carry a beta-globin mutation are therefore healthy in utero and become ill only once the switch completes. A minority of people carry variants that keep fetal haemoglobin switched on into adulthood — hereditary persistence of fetal haemoglobin — and if they also inherit sickle mutations, their disease is markedly milder. That natural experiment defined the therapeutic target.Human beings make two different beta-like globin chains over a lifetime. Fetal haemoglobin, containing gamma-globin, dominates before birth and is switched off in the months afterwards, when adult beta-globin takes over. People who carry a beta-globin mutation are therefore healthy in utero and become ill only once the switch completes. A minority of people carry variants that keep fetal haemoglobin switched on into adulthood (hereditary persistence of fetal haemoglobin), and if they also inherit sickle mutations, their disease is markedly milder. That natural experiment defined the therapeutic target. The switch is enforced by the transcription factor BCL11A, identified as the repressor of fetal haemoglobin by Stuart Orkin's group in 2008.[^sankaran2008] Knocking out BCL11A entirely is unacceptable — it is needed in B cells and in the brain — but the gene carries an enhancer, active only in the erythroid lineage, whose disruption lowers BCL11A in red cell precursors and nowhere else.[^bauer2013] A saturating mutagenesis screen mapped the critical bases within that enhancer, giving a small target that a single guide RNA can hit.[^canver2015]The switch is enforced by the transcription factor BCL11A, identified as the repressor of fetal haemoglobin by Stuart Orkin's group in 2008.[^sankaran2008] Knocking out BCL11A entirely is unacceptable, since it is needed in B cells and in the brain, but the gene carries an enhancer, active only in the erythroid lineage, whose disruption lowers BCL11A in red cell precursors and nowhere else.[^bauer2013] A saturating mutagenesis screen mapped the critical bases within that enhancer, giving a small target that a single guide RNA can hit.[^canver2015] The manufacturing sequence is that of a stem cell transplant with an editing step inserted. Stem cells are mobilised from the marrow with plerixafor and collected by apheresis, often over several cycles. In the factory, CD34+ cells are electroporated with a Cas9 ribonucleoprotein complex carrying the guide; the protein enters as a preassembled complex rather than being encoded on a viral genome, so it acts within hours and is then degraded. Nothing persists in the cell, which is why no [[aav-vectors|viral vector]] is involved and why immunity to a capsid is not a consideration. The edited cells are frozen and tested. The patient then receives myeloablative busulfan to empty the marrow niche, and the edited cells are infused.The manufacturing sequence is that of a stem cell transplant with an editing step inserted. Stem cells are mobilised from the marrow with plerixafor and collected by apheresis, often over several cycles. In the factory, CD34+ cells are electroporated with a Cas9 ribonucleoprotein complex carrying the guide; the protein enters as a preassembled complex rather than being encoded on a viral genome, so it acts within hours and is then degraded. Nothing persists in the cell, which is why no [[aav-vectors|viral vector]] is involved and why immunity to a capsid is not a consideration. The edited cells are frozen and tested. The patient then receives myeloablative busulfan to empty the marrow niche, and the edited cells are infused. The edit itself is a blunt one — a double-strand break repaired by error-prone end joining, producing small insertions and deletions that happen to destroy an enhancer motif. Competing programmes aim at the same biology with gentler chemistry: [[base-editing]] can install the exact single-base changes found in people with naturally persistent fetal haemoglobin, and [[epigenome-editing]] could in principle silence the enhancer without breaking DNA at all. Correcting the sickle mutation directly, which [[prime-editing]] makes conceivable, would be the more complete solution and is further from the clinic.The edit itself is a blunt one: a double-strand break repaired by error-prone end joining, producing small insertions and deletions that happen to destroy an enhancer motif. Competing programmes aim at the same biology with gentler chemistry: [[base-editing]] can install the exact single-base changes found in people with naturally persistent fetal haemoglobin, and [[epigenome-editing]] could in principle silence the enhancer without breaking DNA at all. Correcting the sickle mutation directly, which [[prime-editing]] makes conceivable, would be the more complete solution and is further from the clinic. ## Development history## Development history ```timeline```timeline[[ { "year": "2008", "title": "BCL11A identified", "text": "Orkin's laboratory shows that BCL11A is the developmental-stage repressor that silences fetal haemoglobin after birth." }, { "year": "2008", "title": "BCL11A identified", "text": "Orkin's laboratory shows that BCL11A is the developmental-stage repressor that silences fetal haemoglobin after birth." }, { "year": "2013–2015", "title": "The enhancer as a target", "text": "The erythroid-specific BCL11A enhancer is characterised and then dissected base by base with Cas9, defining a narrow, lineage-restricted target." }, { "year": "2013-2015", "title": "The enhancer as a target", "text": "The erythroid-specific BCL11A enhancer is characterised and then dissected base by base with Cas9, defining a narrow, lineage-restricted target." }, { "year": "2019", "title": "First patients dosed", "text": "Victoria Gray in the United States and a beta thalassaemia patient in Germany receive edited cells in the CLIMB trials." }, { "year": "2019", "title": "First patients dosed", "text": "Victoria Gray in the United States and a beta thalassaemia patient in Germany receive edited cells in the CLIMB trials." }, { "year": "2021", "title": "First results published", "text": "The New England Journal of Medicine reports elimination of vaso-occlusive crises and transfusion independence in the first treated patients." }, { "year": "2021", "title": "First results published", "text": "The New England Journal of Medicine reports elimination of vaso-occlusive crises and transfusion independence in the first treated patients." }, { "year": "2023", "title": "Approval", "text": "The UK MHRA authorises the therapy in November; the FDA follows in December for sickle cell disease, and in January 2024 for beta thalassaemia." }, { "year": "2023", "title": "Approval", "text": "The UK MHRA authorises the therapy in November; the FDA follows in December for sickle cell disease, and in January 2024 for beta thalassaemia." }, { "year": "2024–2025", "title": "Reimbursement fights", "text": "European and UK health-technology bodies negotiate managed-access arrangements; uptake remains slow and confined to authorised transplant centres." } { "year": "2024-2025", "title": "Reimbursement fights", "text": "European and UK health-technology bodies negotiate managed-access arrangements; uptake remains slow and confined to authorised transplant centres." }]]`````` lines 69–88 → 69–868 unchanged lines not shown
## The conditioning burden## The conditioning burden The editing is the easy part. The hard part is busulfan.The editing is the easy part; the hard part is busulfan. To make room for edited cells, the existing marrow must be destroyed with high-dose chemotherapy. That carries weeks of neutropenia and infection risk, mucositis, hospitalisation typically measured in a month or more, a high probability of permanent infertility, and a small long-term risk of secondary malignancy. Patients are advised to bank gametes beforehand, which links the therapy to the reproductive questions covered under [[embryo-selection]] and fertility preservation. For a young adult with severe disease the trade may be worth it; for a person with moderate disease it is not, and this is why eligibility is drawn narrowly. To make room for edited cells, the existing marrow must be destroyed with high-dose chemotherapy. That carries weeks of neutropenia and infection risk, mucositis, hospitalisation typically measured in a month or more, a high probability of permanent infertility, and a small long-term risk of secondary malignancy. Patients are advised to bank gametes beforehand, which links the therapy to the reproductive questions covered under [[embryo-selection]] and fertility preservation. For a young adult with severe disease the trade may be worth it; for a person with moderate disease it plainly is not, and this is why eligibility is drawn narrowly. Removing conditioning is the field's main objective. Antibody-based marrow clearance and, further out, editing haematopoietic stem cells directly inside the body using [[lipid-nanoparticles]] targeted to CD117-bearing cells would eliminate the chemotherapy step entirely. Both have shown promise in animals. Neither is an approved treatment as of 2026.Removing conditioning is the field's main objective. Antibody-based marrow clearance and, further out, editing haematopoietic stem cells directly inside the body using [[lipid-nanoparticles]] targeted to CD117-bearing cells would eliminate the chemotherapy step entirely. Both have shown promise in animals. Neither is an approved treatment as of 2026. ## Price and access## Price and access The US list price is about $2.2 million, alongside roughly $3.1 million for Lyfgenia, the lentiviral therapy approved the same day. Total cost of care — mobilisation, apheresis, conditioning, inpatient stay, and follow-up — is higher still. England's health-technology assessor initially declined to recommend the therapy on cost-effectiveness grounds and later agreed managed-access arrangements, first for beta thalassaemia and then for sickle cell disease.The US list price is about $2.2 million, alongside roughly $3.1 million for Lyfgenia, the lentiviral therapy approved the same day. Total cost of care, including mobilisation, apheresis, conditioning, inpatient stay and follow-up, is higher still. England's health-technology assessor initially declined to recommend the therapy on cost-effectiveness grounds and later agreed managed-access arrangements, first for beta thalassaemia and then for sickle cell disease. > [!stat] The mismatch> [!stat] The mismatch> Roughly 100,000 people in the United States live with sickle cell disease. Global prevalence is in the millions, and the overwhelming majority of affected births occur in sub-Saharan Africa and India, where apheresis and transplant infrastructure is scarce or absent.[^gbd2023]> Roughly 100,000 people in the United States live with sickle cell disease. Global prevalence is in the millions, and the overwhelming majority of affected births occur in sub-Saharan Africa and India, where apheresis and transplant infrastructure is scarce or absent.[^gbd2023] Uptake in the first two years after approval was slow. Patients must travel to an authorised centre, undergo mobilisation that can fail, and accept myeloablation; payers must find the money; and each course consumes scarce transplant-unit capacity. The result is a therapy that works and that almost nobody receives — an unusually stark instance of the pattern described in [[access-and-inequality]] and [[somatic-gene-therapy]] more generally. It has also sharpened arguments about the governance of who benefits from publicly funded discovery, since the biology underlying the target was worked out largely in academic laboratories.Uptake in the first two years after approval was slow. Patients must travel to an authorised centre, undergo mobilisation that can fail, and accept myeloablation; payers must find the money; and each course consumes scarce transplant-unit capacity. The result is a therapy that works and that almost nobody receives, an unusually stark instance of the pattern described in [[access-and-inequality]] and [[somatic-gene-therapy]] more generally. It has also sharpened arguments about the governance of who benefits from publicly funded discovery, since the biology underlying the target was worked out largely in academic laboratories. ## Outlook## Outlook removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
98 lines are the same in both revisions, and 57 of them are not shown. Neither revision here is necessarily the current article — read Casgevy for the text this wiki stands behind today.