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Sickle cell disease (SCD) is a group of genetic disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disease inherit two copies of a gene, each with a single letter misspelling. This misspelling causes production of atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent, shape, blocking the flow of blood and oxygen throughout the body. The characteristic features of SCD begin in childhood and may include anemia, repeated infections, and episodes of pain. The severity of symptoms varies from person to person and throughout life. The diminished oxygen delivery to tissues and organs can lead to life-threatening complications, such as stroke and organ damage. Chronic organ damage is the leading cause of death in adults with SCD.

Beam is advancing multiple base editing programs for sickle cell disease, led by Beam-101, an ex vivo cell therapy in which cells are collected from a patient, edited, and then infused back into the patient. To create space for the edited cells to take hold in the bone marrow, patients undergo a conditioning regimen, such as treatment with busulfan, the standard of care in hematopoietic stem cell (HSC) transplantation today.

Today’s conditioning regimens are associated with significant toxic effects. Future improved conditioning regimens that produce fewer toxic effects could potentially be paired with BEAM-101 and with other future programs.  Beam’s ESCAPE program uses base editing to enable a potentially new non-genotoxic conditioning option for patients with sickle cell disease.

Beam is also exploring the potential for in vivo base editing programs for SCD, in which base editors would be delivered to a patient through an infusion of lipid nanoparticles (LNPs) targeted to HSCs, eliminating the need for transplantation. This approach has the potential to provide a more accessible option for patients, particularly in regions where ex vivo treatment and transplantation are not widely accessible.

Chimeric antigen receptor T-cell (CAR-T) therapies have the potential to address a number of T-cell cancers, but their therapeutic potential is often hindered by technological limitations in their development and application. For example, approved CAR-T therapies are created from a patient’s own cells, which creates both technical and logistical challenges. To address these limitations, we are using multiplex base editing to create donor-derived CAR-T cells by simultaneously silencing multiple target genes, thereby potentially enabling universal compatibility and resistance to host rejection, fratricide, and immunosuppression.

Glycogen storage disease type 1a (GSD1a) is a serious, potentially life-threatening genetic disease with no approved disease-modifying treatments available to date. In patients who have GSD1a, glycogen accumulates in organs and tissues such as the liver, kidneys, and small intestine. The accumulation of glycogen (and sometimes fat) and inability to generate glucose during fasting can lead to severe and life-threatening hypoglycemia, seizures, metabolic dysfunction in lipids, short stature, liver adenoma, and renal disease.

Alpha-1 antitrypsin deficiency (AATD) is a potentially life-limiting genetic disorder that may cause disease in both lung and liver function. AATD is caused by changes in the SERPINA1 gene, leading to lower levels of circulating Alpha-1 antitrypsin protein in the blood (needed to protect the lungs from damage) and the build-up of toxic mutant protein in the liver. The vast majority of AATD diagnoses are in individuals with two copies of the PiZ variant (PiZZ), a single letter misspelling in the SERPINA1 gene. People with AATD usually develop symptoms of lung disease between 20 and 50 years old. Many individuals with AATD remain undiagnosed, specifically people with obstructive pulmonary disease (COPD) or emphysema. Liver disease can develop from infancy through adulthood. The severity, signs, and symptoms of the disease as well as the age at which they appear vary among individuals even within the same family.