CRISPR For Sickle Cell Disease Shows Promise In Early Test
Scientists are reporting the first evidence that genetically edited cells could be safely helping a patient with sickle cell disease. The cells are producing a crucial oxygen-carrying protein.
Sickle cell disease (SCD) is the most common inherited hemoglobin disorder affecting approximately 100,000 people in the United States (U.S.). Allogeneic hematopoietic cell transplantation (alloHCT) is currently the only curative option for SCD. However, alloHCT is an optional benefit under Medicaid, the largest health program in the US. This means that individual state Medicaid programs can chose to cover alloHCT, define the indications, clinical trial coverage, and/or determine the scope of key health benefits, including donor search, cell procurement, medication, travel and lodging.
Allogeneic hematopoietic stem cell (HSC) transplantation (allo-HSCT) is a treatment option for several monogenic diseases; however, its use is limited by the need for a matched donor and risk of HSCT-related complications. Autologous HSC gene addition does not have some of these limitations and may have similar efficacy with an improved safety profile. Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion-dependent β-thalassemia (TDT) using betibeglogene autotemcel (beti-cel, LentiGlobin for TDT) in the HGB-204, -205, -207, and -212 studies, sickle cell disease (S...
Patients with severe sickle cell disease (SCD) experience organ damage, poor quality of life and premature mortality. Hematopoietic cell transplantation (HCT) is curative in SCD. Excellent outcomes have been achieved in young children with HLA matched related donors (MRD), with low rates of acute and chronic graft versus host disease (GVHD). Adolescent patients with SCD receiving MRD HCT and patients with SCD receiving matched unrelated donor (MUD) HCT, remain at highest risk for GVHD and resulting morbidity and mortality.
LentiGlobin for SCD GT contains autologous CD34+ hematopoietic stems cells (HSCs) encoding β-globin with the anti-sickling T87Q mutation (βA-T87Q) and is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554) in patients with SCD. Levels of GT-derived hemoglobin (HbAT87Q) in 7 initial patients (Group A) were suboptimal but were maintained for ≥ 30 months of follow-up pos t-treatment, suggesting durable transgene expression. To increase HbAT87Q production, protocol and manufacturing changes were made (Group B; N=2).
G-CSF mobilization of hematopoietic stem cells (HSCs) requires 4-7 days of injections that provide unreliable collections. G-CSF is associated with significant side effects and potential for fatal complications in some patient populations (e.g. sickle cell disease, multiple sclerosis). MGTA-145 is an analog of the chemokine GRO β that activates CXCR2 and with plerixafor rapidly mobilizes HSCs in mice and non-human primates. The combination promises to be a same-day mobilization regimen that does not require G-CSF.
This study aims to describe organ function in transplant recipients followed for one or more years after HSCT for SCD.
The cognitive and neurological impairments associated with SCD that are due to cerebral vascular injury have been well documented (DeBaun et al, Blood, 2012). Brain abnormalities are evident on neuroimaging and cognitive domains in the areas of attention, memory, processing speed, executive functioning, and lower general intellectual functioning. Processing speed in particular is a vulnerable domain, with deficits mediating difficulties across other domains and is independently decreased in SCD patients unrelated to overt or silent infarctions (Stotesbury et al, Neurology, 2018).
We reported a very low incidence of GVHD in pediatric recipients receiving CD34 enriched HPC products with PBMNC addback from MUD donors (Geyer/Cairo et al, BJH, 2012). Rapid NK cell reconstitution after AlloSCT is associated with a significant improvement in 1yr OS (Pical-Izard, BBMT, 2015).
Red blood cell (RBC) rheology is markedly abnormal in sickle cell disease (SCD) and is associated with clinical complications. Even fully oxygenated, sickle RBC are less deformable than those of HbAA or HbAS individuals; upon deoxygenation, deformability further declines. The goal of any cell-based therapy of curative intent should be to normalize SCD RBC rheology. We propose to functionally assess a series of post-allogeneic hematopoietic cell transplant (alloHCT) patients (pts) with SCD using rheological biomarker measurements of deformability and sickling to determine if the rheology has been normalized.
Sickle cell disease (SCD) is prevalent in Saudi Arabia. We reviewed transplant outcome among SCD patients who underwent HLA-matched related donor HSCT at our institution using either myeloablative or reduced intensity conditioning (RIC)