A base editing approach for Shwachman-Diamond-Syndrome
Background
Shwachman-Diamond-Syndrome (SDS), is life threatening genetic condition caused in 90% of cases by a mutation in the SBDS-gene, which leads to defective splicing and loss of protein expression. Patients may develop many symptoms such as frequent infections due to low white blood cell counts, excessive bleeding, chronic diarrhea, poor growth, and skeletal abnormalities. The most serious symptom, however, is bone marrow failure. Additionally, about 30% patients develop myelodysplastic syndrome and acute myeloid leukemia (AML). Currently the only curative treatment for SDS is bone marrow transplantation from a matched donor, a risky procedure that carries significant risks to the patient such as infection, organ damage and graft-versus-host disease.
Technology Overview
Researchers at Boston Children’s Hospital have developed an in-vitro cell line system and performed extensive screening of many available base editing enzymes and several dozen sgRNAs. By reverting the mutation in the SBDS-gene to its original sequence, the group observed improvements of SDS specific molecular and cellular phenotypes, such as recovery of correct splicing, recovery of SBDS protein expression, improvements in cell proliferation, ribosome maturation, and protein synthesis. The potency of the approach was confirmed in 3 separate SDS-patient-derived bone marrow samples which showed a high-efficacy with 70-80% of alleles being corrected by the treatment. This base-editing approach, which provides an advantage over alternative correction strategies due to the absence of DNA double strand breaks and reduced activation of cellular defense mechanisms, is particularly safe, which is especially important given the inherent risks of SDS. The approach also may represent the first real therapeutic treatment for SDS which does not require surgery.
Applications
Treatment of Shwachman-Diamond-Syndrome
Advantages
- Easier recovery for patients with fewer side-effects and risks of complications than with bone marrow transplant
- First potential non-surgical treatment for SDS
- Does not require transplant and donors
- Lower cost compared to surgery
