Bluebird bio, Inc., recently announced that interim data
from an initial cohort of 17 patients in the ongoing Phase 2/3 Starbeam Study (ALD-102) evaluating Lenti-D investigational gene therapy in boys with cerebral adrenoleukodystrophy (CALD) were published in the New England Journal of Medicine
CALD, the cerebral form of ALD, affects an estimated 21,000 male births around the world, and can cause permanent damage to the nerve cells in the brain due to a breakdown of the myelin sheath.
Rare Disease Report (RDR)
recently spoke with Mohammed Asmal, Vice President, Clinical Development at bluebird bio about the data and what the future holds for the gene therapy as a potential treatment option.
Can you explain the presentation of CALD?
The ALDP protein is involved in the metabolism of very long chain fatty acids. Certain individuals that have certain mutations that make this protein dysfunctional end up with the inability to process very long chain fatty acids, and that generally has 2 major consequences: 1 is adrenal insufficiency, which can relatively be taken care of with supplemental steroids taken daily. The other more problematic consequences are neurologic and are often recognized too late. One is an inflammatory neuropathy – a cerebral neuropathy – and it’s a demyelinating process, so, basically, it’s the deposition of very long-chain fatty acids and the inability to metabolize them results in an inflammatory response in the central nervous system, which results in demyelination. There’s no certain action for this; it can develop in some individuals when they’re young, but most experience it by the time they hit adolescence.
Is CALD difficult to diagnose?
It’s a very difficult disease to diagnose because symptoms are typically non-specific, and are usually behavioral. For instance, it’s not uncommon for these individuals to have ADHD (attention deficit hyperactivity disorder). Later on, patients will develop motor disorders, bladder dysfunction, etc., and it becomes obvious that something worse is happening. Even then, it can take a while for it to be properly diagnosed. One of the most common ways for someone to be diagnosed is that one sibling will die of the progressive disease, so the next sibling will get screened.
How has CALD being treated in the past?
In individuals that develop this disease, the therapy that has been involved over the last 20 years as standard of care has been bone marrow transplantation before really substantial neurologic progression. The mechanism as to why this works is obviously not intuitive; it’s actually very complicated. With bone marrow transplantation, it’s hoped that by giving donor cells from someone who has a normal ALDP expression, the individuals’ monocyte lineages are reconstituted with normal ALDP-expressing monocytes. It then migrates to the central nervous system where they differentiate into microglial, and these produce the ALDP protein, and are then able to metabolize the long-chain fatty acids that accumulate in the brain. These are then able to substitute for what was lacking. That’s theoretically how transplant therapy works.
What are some of the concerns with stem cell transplant therapy?
There are a couple of problems with that: number one is that the disease is already advanced if there’s already a significant enough injury observed on an MRI for neurologic progression. You would really have to get patients at the very early stages of diagnosis, which usually requires either a patient having been diagnosed with idiopathic adrenal insufficiency and then someone doing a genetic test discovering that this person has ALD. More recently, there are some states that have newborn screening programs in place for ALD, and patients may be diagnosed that way.
The other major problem with stem cell transplantation is that, unless there is a very good match between the donor and recipient, graft versus host disease is a problem, and graft projection is a problem. For patients who have sibling donors who are a match – which is about 20-25% of the general population – they can get reasonable treatment. Other patients have to rely on matched, unrelated donors, and the outcomes are just not as good. Our therapy seeks to step in to this void where patients seem to have suboptimal outcomes.
How is bluebird bio approaching therapy for CALD?
Our therapy is called Lenti-D, and it uses fragments of HIV and another virus called VSV (vesicular stomatitis virus) to deliver an additional copy of the ALD protein – actually, the functional gene that will then produce the protein. The treatment methodology involves personal stem cell mobilization in young boys that have been diagnosed in the early stages of this disease. The stem cells are harvested, then transduced, and tested to verify that they were correctly treated, and then the cells get sent back while the patient undergoes mild-grade chemotherapy to get rid of the existing microglia and then they’re infused with the gene-corrected stem cells. These repopulate the microglia and theoretically, the expression of the ALD protein should correct the problem.
What was the impetus behind bluebird initiating this study?
The initial impetus of the start of the study came from the patients who don’t have matching donors; they don’t have good outcomes. We needed to find an alternative, and the theory that gene therapy can correct something like this was certainly out there. The mechanism by which this would work is very much like how stem cell therapy transplantation is able to correct the disease. The theory was certainly there, it just relied on someone, essentially, being willing to develop the vector and then try it on patients who did not have any other feasible options for transplant, and who had poor predicted outcomes for transplant survival. The original studies done on ancestors to our vectors – either 8 or 9 years ago – showed that in these initial subjects, progression of neurologic compromise due to ALD was stalled. That initial data, that showed that in an academic setting, somebody could develop a successful therapy to treat a disease with a very poor prognosis, was actually what led to the founding of bluebird. Bluebird’s vision was to take that kind of therapy, turn it into something that could be realized outside of the academic setting, and bring it to patients around the world.
What’s next for bluebird bio?
The goal right now is to continue to follow these boys, to accrue more data, and ultimately to achieve a product that we can get approval for and treat boys around the world with. The questions of “Can you go to additional populations” or “Can you treat boys that have later disease or similar diseases?” all need to be considered. We need to evaluate our next strategies in CALD. Certainly, we believe that what we currently have is an excellent option for patients with early stages of the disease. Generally, I think the feeling is that the way that we can effectively treat more patients is to make sure that patients are diagnosed at an early age. We need wider-spread newborn screening for this disease to allow for preemptive diagnoses of these patients and appropriate early management.
For more from bluebird bio and other studies evaluating gene therapies as treatments for rare diseases, follow Rare Disease Report