Gene Therapy for ALD

January 31st, 2017 |

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.

Bone-marrow cells were extracted from the patients. Before therapy, no ALD protein was detectable in the patients’ blood cells. In the laboratory, a normal copy of the ALD gene was inserted in the bone marrow cells using a virus derived from HIV. The patients underwent chemotherapy to eradicate their bone marrow to stop it from producing further stem cells. They then received an infusion of their own genetically corrected stem cells carrying the normal gene.

Movie explaning 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. 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) is a Phase 2/3 investigational gene therapy study to determine the safety and tolerability of Lenti-D while determining if the one-time treatment can stop the progression of cerebral ALD. As of March 2016, 17 boys, aged 17 and younger, with a diagnosis of cerebral ALD but for whom a matched donor (to perform HSCT) was not available, had been treated with Lenti-D drug product. In December 2016, enrollment in the study was expanded to 25 total patients (8 additional patients).

The primary efficacy endpoint for the Starbeam Study is the proportion of patients with no Major Functional Disabilities (MFDs) at 24 months post treatment. If present, these MFDs would have a profound effect on a patient’s ability to function independently: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence and complete loss of voluntary movement. The secondary endpoints of the study include progression of the cerebral disease as evaluated by brain MRI, Neurologic Function Score (NFS, which is a scoring system used to evaluate the severity of clinical deficits by scoring 15 symptoms across multiple domains), gadolinium enhancement on brain MRI (which is an indicator of neuroinflammation), and safety (side-effects and genome integration analysis of the gene).

In April 2016, interim clinical data from 17 patients treated in the Starbeam Study were presented at the American Academy of Neurology (AAN) Annual Meeting. All data presented at the AAN Annual Meeting and summarized below are as of the data cut-off date of March 31, 2016.

After completing Study ALD-102 (approximately 2 years), the patients will be enrolled in a new study (LTF-304) for an additional 13 years to evaluate long-term safety and efficacy.


Figure: Starbeam treatment protocol overview. Image courtesy of bluebird bio.

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

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