The DRIVE Program

St. Jude-led team received $28.5 million ARPA-H grant to advance precision genetic medicines.

Inherited bone marrow failure syndromes are rare genetic conditions characterized by hematopoietic stem cell dysfunction leading to cytopenia and immunodeficiency. Many of these conditions carry a high lifetime risk of myelodysplastic syndrome (MDS) and leukemia.

Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative option. HSCT carries risks including graft-versus-host disease, infertility, damage to various organs and a risk of second cancers. In addition, many patients have no available donors, are too ill or their organs are too fragile to safely tolerate the chemotherapy conditioning, and some have already developed complications that make transplant high risk.

The DRIVE Program is a research program that is developing a platform approach for therapeutic in vivo gene editing to increase treatment options for certain genetic diseases. The DRIVE Program unifies scientists and physicians who are experienced in genome editing, drug delivery, manufacturing and computational biology with the goal of developing precision gene editing treatments that correct the underlying genetic causes of several bone marrow failure syndromes. 

Our inaugural therapies target recurrent (“hotspot”) mutations shared by many patients, so a single medicine might be useful for more than one family.

GATA2 deficiency

GATA2 is a master hematopoietic transcription factor. A single heterozygous mutation can cause disease, with roughly 90% lifetime penetrance for MDS and immunodeficiency. Patients develop cytopenia and immune deficiency with loss of monocytes, B-cells, NK-cells, and CD4+ cells, susceptibility to warts, atypical mycobacterial and fungal infections and sometimes lymphedema or hearing loss. All patients with GATA2 mutations have a high lifetime risk of progression to MDS and acute myeloid leukemia. St. Jude investigators identified GATA2 deficiency as the most common genetic predisposition in pediatric MDS, accounting for about 15% of advanced cases, with a median onset around age 17 years old. Conventional lentiviral gene therapy (where a healthy copy of the gene is inserted into the genome) does not work here, because overexpression of GATA2 is toxic, which is precisely why we focus on correcting the patient’s own gene.

GATA2 mutations of current interest: 

• c.1084C>T (p.Arg362X) 
• c.1009C>T (p.Arg337X) 
• c.1081C>T (p.Arg361Cys) 
• c.1082G>A (p.Arg361His)
• other mutations with G>A or C>T change

Shwachman-Diamond syndrome (SBDS)

Shwachman-Diamond syndrome comes with very high risk for MDS and leukemia. Children usually come to attention with failure to thrive from exocrine pancreatic insufficiency together with low neutrophil counts and recurrent infections; low platelets, anemia, skeletal abnormalities and short stature are also common. Loss of SBDS function impairs the final step of 60S ribosomal subunit maturation, imposing chronic stress on the hematopoietic stem cells and conferring one of the highest rates of clonal evolution to MDS and leukemia among the inherited bone marrow failure syndromes. As with GATA2, overexpressing SBDS is itself harmful, so precise correction of the patient’s own gene is preferable to adding extra copies. Most patients carry the same recurrent splice-site mutation, which makes a single corrective gene editing broadly applicable.

SBDS mutation of current interest: 

• c.258+2T>C

Dyskeratosis congenita / telomere biology disorder

Germline DKC1 variants cause X-linked dyskeratosis congenita, among the most severe of the telomere biology disorders. Affected patients typically present within the first decade with progressive marrow failure and immunodeficiency, often accompanied by the mucocutaneous triad of reticulated hyperpigmentation, nail dystrophy and oral leukoplakia. Pulmonary fibrosis, hepatic disease and squamous cell malignancy can follow with age. This group illustrates the unmet need most starkly: transplant outcomes are poor, largely from treatment-related mortality as well as organ fragility that defines the disease. An approach that requires no conditioning chemotherapy would be especially valuable for these patients. 

DKC1 mutation of current interest: 

• c.1058C>T (p.Ala353Val)
• other mutations with G>A or C>T change

Other mutations

Base editing can correct many single-letter changes of the same type, and our platform is deliberately designed so that new mutations can be added. If your patient carries a variant in a different gene with C>T or G>A change, we would still like to hear from you, and we are glad to evaluate whether it may be correctable

Our overarching goal is to translate the therapeutics born from this platform into clinically relevant, effective treatments for inherited bone marrow failure syndromes. We welcome informal inquiries from hematologists, oncologists, immunologists, geneticists and genetic counselors caring for patients carrying the specific mutations listed above and patients carrying additional transitional mutations that may be amenable to adenine base editing. Although the DRIVE Program is not an open clinical trial, clinical providers are encouraged to contact us to learn about inclusion criteria for future studies. 

Email: DRIVE@stjude.org