The Promise of Gene Therapy in Brain Disorders


The neurones of our brains communicate via electrical impulses called action potentials. A portion of these neurones are wrapped in a fatty substance called myelin, which helps to insulate them and increase the rate at which action potentials are passed from neurone to neurone. Similar to the way an electrical wire is covered with insulating materials, such as plastic, the portion of the neurone (called the axon) is also covered with insulating material, which is the myelin. The axon in this case is said to be myelinated.

In some neurological disorders, such as multiple sclerosis (MS), the myelin becomes damaged or destroyed; a process referred to as demyelination. Demyelination causes the action potentials to slow down or stop, causing neurological problems. If the myelin is severely damaged, the neurone it’s meant to cover can die.

X-linked adrenoleukodystrophy (ALD) is a fatal, demyelinating disease of the central nervous system. It’s caused by mutations of a particular gene, called the ABCD1 gene, which normally encodes the ALD protein. The ALD protein plays a part in breaking down very-long-chain fatty acids (VLCFAs) in certain types of neuronal cells called oligodendrocytes and microglia. The deficiency of the ALD protein disrupts myelin maintenance by these cells.

Image 1: Labelled diagram of a myelinated neurone

ALD is a X-linked recessive disorder, meaning it only affects boys. In affected boys, demyelination occurs between 6-8 years of age, with most dying before reaching adolescence.

Prior to the results of this paper, allogeneic haematopoietic cell transplantation (HCT) was the only effective therapy. HCT is a blood and marrow transplantation in which the haematopoietic stem cells of a donor are injected into the patient in the hope of reconstitution of the patient’s haematopoietic system. It must be undertaken at an early stage of brain lesions for it to for it to have a chance of success. After a certain stage, demyelination cannot be halted. However, HCT is also limited by donor-related constraints and carries a substantial risk of mortality. For which reasons, the researchers of this paper investigated novel routes. Their findings suggest that haematopoietic stem cell (HSC) gene therapy could be a suitable therapeutic alternative.

Image 2: Description of the process of allogeneic HCT

This study was focussed on using lentiviral vectors. In gene therapy, lentiviral vectors are a research tool used to insert certain genes into organisms. These vectors make use of the lentivirus; a family of viruses that are responsible for diseases such as HIV. They inserting their DNA into their host cells’ DNA machinery, causing infection. Further, these viruses are unique in their ability to become a permanent part of the host cells’ DNA machinery, meaning their genes can permanently become part of an organism’s genome (that is an organism’s complete set of genes).

Lentiviral vectors, such as those derived from HIV, can also transduce nondividing cells (such as neuronal cells) and allow for a more efficient gene transfer into HSCs, compared to other types of vectors. This increased efficiency of lentiviral vectors in HSC transduction suggests that gene correction might be successful in a high percentage of HSCs. It could therefore cause long-term expression of the wanted therapeutic gene in all haematopoietic cell lineages of treated patients. Importantly, these vectors are created by removing the pathogenic genes of the lentivirus and inserting the wanted therapeutic genes, which is the non-mutated functioning ABCD1 gene.

Image 3: Diagram showing how a lentiviral vector integrates into the host cell’s genome. The genetic material of the viral vector joins with the genetic material of the host cell, and from that point on every protein expressed by the host cell will have part of the virus’ genetics in it

Two ALD patients with progressive brain demyelination and no matched donor for allogeneic HCT took part in this study. These two patients, ages 7.5 years (P1) and 7 years (P2), had ABCD1 gene mutations, which traditionally leads to a lack of ALD protein. Ex vivo infection of a sample of the boys’ HSCs was undertaken. This meant that a sample of cells from the boys’ bone marrow was taken, and the lentiviral vector (with the non-mutated functioning ABCD1 gene added) was inserted into these defective bone marrow cells. These cells were then grown in culture at the lab.

The boys also underwent full myeloablative conditioning, which is a procedure to destroy the diseased bone marrow cells, while allowing the gene-corrected bone marrow cells to become the dominant component in the bone marrow space of these patients, when returned. There was then reinfusion of the corrected bone marrow cells into the boys. The treated boys were then followed-up for 24-30 months post-treatment.

Image 4: Description of the process of ex vivo gene therapy.

From the results of the study (shown below by image 5) we learn that beginning 14-16 months post-treatment, progressive brain demyelination in the 2 boys had stopped and the clinical outcome was comparable to that achieved by allogeneic HCT. In 40% of ALD patients treated with allogeneic HCT, an initial decline of performance abilities without changes in verbal abilities is followed by stabilisation.

In this study, with P1, the lesions had progressed up to 14 months after HSC gene therapy, and then did not show progression in the following months. With P2, the lesions had progressed up to 16 months after gene therapy, having then stabilise with no further progression.

Image 5: Brain MRIs from P1 (A) and P2 (B) before and after gene therapy, and also shown is the progression of brain demyelinating lesions in an untreated 8-year-old ALD patient (C).

The results of this study are promising. The neurological benefits of this type of gene therapy, similar to those seen with allogeneic HCT, supports further testing of this treatment with more ALD patients with demyelination. Additionally, HSC gene therapy might also be considered as a therapeutic option for adult ALD patients who develop brain demyelination, as the mortality risk of allogeneic HCT is around 40%. Finally, this study may also provide a new avenue for cell-based gene therapy in other genetic and multifactorial diseases affecting the brain.

Some relevant sources: 

Original Paper:

Cartier N, Hacein-Bey-Abina S, Bartholomae C.C, et. Al., (2009). Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy. AAAS. DOI: 10.1126/science.1171242
Original Link:

Image Sources:

Image 1

Image 2

Image 3

Image 4

Image 5

Featured Image – Pexels by Pixabay

Edited by Malavika

Leave a Reply

Your email address will not be published. Required fields are marked *