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 successfully treatment of two 7-year old boys with early signs of cerebral ALD using gene therapy (Cartier et al. Science). These boys were candidate for allogeneic hematopoietic stem cell transplantation (HSCT), but a matched donor was not available.

Gene therapy is based on correcting the patients’ own bone-marrow stem cells:

• Bone-marrow stem cells were extracted from the patients. This procedure is called “apheresis”.
• In the laboratory, a normal copy of the ALD gene was inserted in the bone marrow stem cells using a virus derived from HIV.
• The patients underwent chemotherapy to eradicate their bone marrow to stop it from producing further stem cells. This procedure is called “conditioning”.
• They then received an intravenous infusion of their own genetically corrected stem cells carrying the normal ALD gene.

Movie explaining the basics of a stem cell transplant

Produced by bluebird bio, Inc.

The two patients were followed for 24 and 30 months. Over this period, 15% of their blood cells demonstrated expression of the normal ALD protein, while before therapy, no ALD protein was detectable in the patients’ blood cells. The VLCFA were reduced by 38% in the plasma of the patients.

Brain MRI scans and cognitive tests showed that progression of the cerebral disease stopped after 14-16 months. The patients 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 that is comparable with the clinical outcome of HSCT.

Starbeam Study

The Starbeam Study (ALD-102, NCT01896102) is a Phase 2/3 investigational gene therapy study. The goals are to determine the safety and tolerability of the one-time gene therapy treatment “Lenti-D”, and to determine if it can stop 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 have been treated with Lenti-D and the median follow-up for all treated patients was 34 months (0.4 – 54 months).

The primary efficacy endpoint for the Starbeam Study is the absence of Major Functional Disabilities (MFDs) at 24 months after transplantation. MFDs correspond to severe disabilities thought to have a profound impact on a patient’s ability to function independently: loss of ability to communicate, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement. The secondary efficacy endpoint of the study is the progression of the cerebral disease. This is evaluated by gadolinium enhancement on brain MRI (which is an indicator of neuroinflammation) and by the Neurologic Function Score. The NFS is a scoring system that is used to evaluate the severity of clinical deficits by scoring 15 symptoms across multiple domains. The safety profile of Lenti-D was also evaluated (side-effects and genome integration analysis of the gene).

In October 2017, the results of the 17 patients treated with Lenti-D who completed the 24 months 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 from disease progression during pre-transplantation conditioning, and
  • 1 patient was withdrawn from the study and died from complications of a subsequent allogeneic transplantation.
• In the 15 remaining patients no graft-versus-host disease was seen (which is when the transplanted cells “attack” the patient’s cells).
• Fourteen of these 15 patients had a score on the NFS of 0 or 1, which indicates 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 at baseline in all the patients, was absent in all 15 patients by month six post-transplant. A few patients experienced reemergence of gadolinium enhancement at various time points (including 2 patients at Month 24), but the enhancement was less extensive than the gadolinium enhancement that was present at baseline.

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

After completing Study ALD-102 (approximately 2 years), the 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 study, bluebird bio, is a biotechnology company based in Cambridge, MA, USA

Last modified | 2019-03-12