Gene Therapy for ALD

Authors: Virginie Bonnamain, Ph.D. and Stephan Kemp, Ph.D.

In 2009, Drs. Nathalie Cartier and Patrick Aubourg and colleagues (Saint Vincent de Paul Hospital, Paris, France) reported the successfull treatment of two 7-year-old boys with early signs of cerebral ALD using gene therapy (Cartier et al. Science). These boys were candidates for allogeneic hematopoietic stem cell transplantation (HSCT), but a matched donor was not available.

The gene therapy is based on correcting the patients’ own bone marrow stem cells:

• Bone marrow stem cells are taken from the patient. This process is called “apheresis”.
• In the laboratory, a normal copy of the ALD gene was inserted into the bone marrow stem cells using a virus derived from HIV.
• The patients underwent chemotherapy to destroy their bone marrow and stop it from producing more stem cells. This is called “conditioning”.
• They then received an intravenous infusion of their own genetically corrected stem cells carrying the normal ALD gene.

The two patients were followed for 24 and 30 months, respectively. During this time, 15% of their blood cells showed expression of the normal ALD protein, compared to no detectable ALD protein in the patients’ blood cells before therapy. VLCFA were reduced by 38% in the patients’ plasma.

Brain MRI scans and cognitive tests showed that progression of brain disease was halted after 14-16 months. Patients have remained stable since then. The demyelinating lesion observed in the auditory pathway of one patient was reversed. The arrest of progressive cerebral demyelination in these two children represents a clinical outcome comparable to the clinical outcome of HSCT.

Starbeam Study

The Starbeam Study (ALD-102, NCT01896102) is a Phase 2/3 investigational gene therapy trial. The aim is to determine the safety and tolerability of the single gene therapy treatment with “Lenti-D”, and whether it can halt the progression of cerebral ALD. As of April 2018, a total of 31 patients have been enrolled in the study. Of these 31 patients, 29 were treated with Lenti-D and the median follow-up for all treated patients was 34 months (0.4 to 54 months).

The primary efficacy endpoint of the Starbeam study was the absence of major functional disabilities (MFD) at 24 months post-transplant. MFDs are severe disabilities that are considered to have a profound impact on a patient’s ability to function independently: loss of communication, cortical blindness, need for tube feeding, total incontinence, wheelchair dependency, and complete loss of voluntary movement. The secondary efficacy endpoint of the study is progression of brain disease. This was assessed using gadolinium enhancement on brain MRI (an indicator of neuroinflammation) and the Neurological Function Score (NFS). The NFS is a scoring system that evaluates the severity of clinical deficits by assessing 15 symptoms across multiple domains. The safety profile of Lenti-D was also evaluated (side effects and genomic integration analysis of the gene).

In October 2017, the results of the 17 patients treated with Lenti-D who completed 24 months of follow-up were published (Eichler et al. 2017). At the time of data analysis for this initial group of 17 patients, the median follow-up was 29.4 months (21.6 – 42.0 months).

• Fifteen (88%) of 17 patients were alive with minimal clinical symptoms.
  • 1 patient died due to disease progression during pre-transplant conditioning, and
  • 1 patient was withdrawn from the study and died from complications of a subsequent allogeneic transplant.
• The remaining 15 patients did not experience graft-versus-host disease (when the transplanted cells “attack” the patient’s cells).
• Fourteen of these 15 patients had a NFS score of 0 or 1, indicating no or minimal clinical symptoms.
• Twelve of the 15 patients had a stable Loes score, indicating no progression of the lesion.
• Gadolinium enhancement, which was present in all patients at baseline, was absent in all 15 patients at six months post-transplant. In a few patients gadolinium enhancement reappeared at various time points (including 2 patients at month 24), but the enhancement was less extensive than the gadolinium enhancement present at baseline.

These initial results suggest that gene therapy with Lenti-D for the treatment of cerebral ALD is at least as effective as conventional allogeneic transplantation. The absence of graft-versus-host disease suggests that it may be safer.

After completion of the ALD-102 study (approximately 2 years), patients were enrolled in a new study (LTF-304, NCT02698579) for an additional 13 years to evaluate long-term safety and efficacy.
Figure: Starbeam treatment protocol overview. Image courtesy of bluebird bio.

The sponsor of the Starbeam trial, bluebird bio, is a biotechnology company based in Cambridge, MA, USA.

Last modified | 2024-06-24