Gene Therapy

• ALD is a severe neurodegenerative disorder characterized by demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids (VLCFAs) in tissues.

• 70% of males with the ALD gene will have cerebral degeneration.

• Males with cerebral ALD are generally clinically normal until they develop demyelination, destruction of the brain’s white matter (also called myelin), which leads to death within 3 to 5 years.

• Males that are spared from the fatal cerebral involvement (30%) experience adrenomyeloneuropathy (AMN) that over years leads to physical handicap of the extremities, often of a severe nature.

• ALD is much more common than originally reported.  Current estimates are 1:17,000, an incidence more frequent than ALS (Lou Gehrig’s Disease).

• Bone marrow transplantation (BMT) benefits some males with early cerebral involvement; however, this procedure is accompanied by very high risk, with a morbidity and mortality rate approaching 50%.

In the context of gene therapy as an effective treatment for ALD, the procedure will ultimately involve removing some of the affected person’s bone marrow type cells (also called “stem cells”) that carry defective genetic material, inserting the proper genetic code into those cells, and transplanting those same cells back into the ALD male.  Each male provides his own cells for gene transfer and transplant, and thus this type of gene therapy BMT is termed “autologous.”

Why a Gene Therapy BMT vs. a Traditional BMT or a Traditional Umbilical Cord Blood Transplant (UCBT)?

Problems with a Traditional BMT	Solutions with a Gene Therapy BMT
Bone marrow or umbilical cord blood donor matches can't always be found for ALD patients who desperately need a BMT.	Each patient will serve as his own donor, and thus there will ALWAYS be a perfect match.
Weakening the patient’s immune system via "conditioning" (ablation / chemotherapy / radiation treatment) to prepare the patient to receive donor cells is a horrible invasive process that leaves the patient extremely vulnerable as he is then left with a severely compromised immune system that may not be strong enough to fight off a common cold (which could actually kill him).	"Conditioning" is expected to be much less severe since a gene therapy BMT will correct that patient’s marrow (i.e., no foreign cells will be introduced).  As a result, the patient will be better equipped to successfully face everyday immune challenges (i.e. colds, stomach “bugs”, ubiquitous viruses).
Cyclosporine, a medication commonly used in BMT and UCBT patients, further damages the myelin (white matter).  Therefore, Cyclosporine compounds the ALD’s devastation that is already attacking the myelin and destroying the brain.	Cyclosporine will not be used since each patient will be his own donor, as a gene therapy BMT will correct that patient’s marrow.  Thus, no further myelin destruction is anticipated.
Graft versus host (GVH) disease is a common and potentially lethal complication following BMT or UCBT.  This occurs as the donated cells may attack the recipient’s tissues and organs.	Graft versus host (GVH) disease is eliminated, since each patient will be his own donor.
Adults with cerebral ALD are typically not candidates for BMT or UCBT.  For these males, in particular, GVH is a common and lethal complication, and thus precludes adults from qualifying for this treatment in the vast majority of cases.	If the patient requires therapy as an adult, instead of dying from advanced demyelination lesions, gene therapy BMTs will offer a solution.  GVH will not be an issue.
Procedure is effective approximately 50% of the time, and has a mortality rate of up to 40%	A significantly higher success rate and considerably lower morbidity rate is anticipated with gene therapy.

• As a result of the dedication, drive, and desire to help on the part of many key individuals and related institutions, the world’s leading experts in ALD, gene therapy, and bone marrow transplants have come together to work on what is deemed the most promising and near term therapy for stopping ALD.  The Stop ALD Foundation has been an active force in facilitating this interdisciplinary approach.

• Dr. Hugo Moser, the world's leading expert in ALD with over three decades of experience, believes a gene therapy approach MUST be taken.  He is now intricately involved in The Stop ALD Foundation’s gene therapy research process.

• Dr. Inder Verma is President of the American Society of Gene Therapy (the ASGT is the largest and most prestigious professional organization for gene therapists in the world).  He is the world’s leading expert in gene therapy vector technology.   He has assigned one of his Ph.D. postdoctoral candidates to work under him on this project.

• Dr. Don Kohn, a pioneer and leading expert on gene therapy bone marrow transplants, has agreed to perform the pre-clinical work necessary to get to an FDA Phase I Clinical Trial.

• Because the FDA and the NIH hold Drs. Moser, Verma, and Kohn in the highest regard, gene therapy BMT Clinical Trails for ALD have a strong probability of FDA approval.

Steps to be Performed

• The Stop ALD Foundation has received agreement from Dr. Moser that he will be the principal investigator (PI) during clinical trial work necessary for the FDA.

• The pre-clinical experiments that previously produced excellent results in tissue cultures and in mice need to be duplicated using Good Manufacturing Practices (GMPs – an FDA-specific term that means that certain regulatory conditions are followed).  Drs. Verma, Kohn, and Moser have agreed to do this.

• A vector (a vector is the “delivery vehicle” that is used to transport a gene therapy treatment to the proper cells in the body) must be created under Good Manufacturing Practices. 

• A protocol describing how the trial will be run needs to be written (e.g. How would patients be selected/prepped/monitored? How would success be measured?).  Dr. Moser has committed to address and complete this complex task.

• The protocol needs to be approved by the Institutions' Review Board (IRB) and the FDA (Dr. Moser will work with others to do this).

• A clinical trial involving ALD patients must be conducted.

• The data from the clinical trial must be collected, analyzed, and reported.  Dr. Moser has committed to do this.

Pre-Clinical Experiments to be Conducted Include

• Bone marrow from an ALD patient needs to be "put in a dish" (ex vivo, meaning, “outside the body”) and have gene therapy "applied.”  The bone marrow then needs to be tested to ensure that the cells were corrected.

• SCID/NOD mice (mice that can take human cells and grow them) need to receive the corrected human cells and then be tested to see if the cells stay corrected, and that they still maintain their progenitor abilities to differentiate into various types of cells.

• ALD mice (the current animal disease model) need to be treated with a traditional BMT with varying amounts of "good" marrow to see how many "good" cells are required to have an impact on the disease.  The information collected from this traditional BMT experiment will provide a hypothesis for what will be needed by a gene therapy bone marrow transplant.

• ALD mice then need to have gene therapy BMTs performed to determine the therapy’s efficacy.

• Immunological studies must be completed at the cellular and murine (mouse) level to ensure safety of the future gene product and vector in patients.

• Toxicological studies must be completed to ensure patient safety.  This may include the study of the proposed vector in non-human primates.

Funding

• Although much of the work initiated is being done by scientists generously donating their time, talent, and resources (i.e., after meeting with Stop ALD representatives, they have agreed to do the necessary work without the Stop ALD Foundation providing any funding), immediate funding is needed for implementation.

• Dr. Patrick Aubourg (Paris, France), who was first to look at gene therapy for ALD, requires funding to continue his research.  He is the most advanced in looking at gene therapy BMTs in mice. 

• The Stop ALD Foundation working with its Scientific Board of Advisors also needs to consider other potential therapies that should be explored with vigor.

 

 

The Stop ALD Foundation has initiated gene therapy BMT research for ALD with the world’s leading experts.  Collectively, a gene therapy BMT is considered the number one hope for effectively treating ALD.