Lenti-D, developed by Bluebird Bio, is an investigational gene therapy for the treatment of the childhood cerebral form of adrenoleukodystrophy (CALD).

As opposed to stem cell therapy that is the current standard of care for patients with CALD, which requires cells from a donor, Lenti-D involves genetically modified patient-derived stem cells. The use of patient-derived cells is associated with fewer complications such as graft-versus-host-disease.

How Lenti-D works

ALD is caused by mutations in the ABCD1 gene, which is located on the X-chromosome. The ABCD1 gene provides instructions to build the ALD protein, which is a transporter protein that mediates the transport of saturated, very long-chain fatty acids (VLCFAs) into the peroxisome. Peroxisomes are small compartments within the cell that play a crucial role in energy metabolism and the breakdown of many molecules, among them VLCFAs.

The inability to transport VLCFAs into the peroxisomes leads to their abnormal accumulation in the blood and tissues of the central nervous system and consequently to the damage of myelin, the protective sheath that insulates nerve cells.

Lenti-D therapy uses stem cells from the patient’s bone marrow, which are genetically modified with the help of a viral vector to include a functional copy of the ABCD1 gene. The cells are then transplanted back into the patient where they develop into different cell types, including brain cells. The inserted ABCD1 gene then produces ALD protein, allowing the transport of VLCFAs into peroxisomes. It takes six to 18 months for the transplanted cells to be fully engrafted and functional. During this time, the disease progresses.

Lenti-D in clinical trials

An ongoing Phase 2/3 clinical trial (NCT01896102) called STARBEAM is assessing the effectiveness and safety of transplanting patient-derived bone marrow stem cells that have been genetically modified with Lenti-D. A total of 17 boys with CALD under age 17 already received Lenti-D gene therapy. At the time of interim analysis, median follow-up was 29.4 months, and 15 of the 17 patients were alive and free of major functional disability. One patient died from disease progression, and another patient with disease progression withdrew from the study to undergo allogeneic stem cell transplant (transplanting stem cells from a donor). He later died from transplant-related complications.

The genetically modified cells and ALD protein could be detected in all patients.

No toxic effects related to the infusion of Lenti-D modified cells occurred. Most adverse side effects were observed two weeks after the infusion, and they were consistent with aside effects that usually occur with myeloablative chemotherapy. Myeloablative chemotherapy lowers the number of blood-forming cells in the bone marrow and increases successful transplant. No engraftment failure or graft-versus-host disease occurred.

Patients who completed the STARBEAM study can subsequently enroll in the LTF-304 study (NCT02698579) where they will be followed for an additional 13 years.

Based on the data of the STARBEAM study, the U. S. Food and Drug Administration (FDA) granted breakthrough therapy designation to Lenti-D in May 2018.

Lenti-D has been granted orphan drug status by the FDA and European Medicines Agency (EMA). Lenti-D also received a rare pediatric disease designation by the FDA.


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