Neurodegenerative and Movement Disorders

Neurodegenerative diseases encompass a spectrum of disorders, which are characterized by progressive degeneration of neurons - electrically excitable cells that transmit information. Symptoms are variable and include problems with movement, sensation, memory and intellect. Certain neurodegenerative diseases start in childhood, while others develop later in life. Most cells, in the central nervous system, including neurons, are non-dividing cells and cannot regenerate to form new cells. Moreover, they are separated from the rest of the body by certain barriers, the most well-known of which is the blood-brain barrier (BBB). These aspects of the nervous system necessitate the application of special delivery vehicles (vectors) that can cross barriers and are able to target non-dividing cells, such as neurons. 

Diseases of the central nervous system can be caused by both genetic and environmental factors. Monogenic diseases are characterized by mutations in specific genes, often leading to the development of a disease even without environmental influence. A mutation can result in loss-of-function of the protein encoded in the gene. Most of these diseases are termed as recessive diseases, as the child inherits a mutant copy of the gene from both the mother and father. In this case, a gene therapy strategy aims at restoring the normal protein to deficient cells. In contrast, if the mutation generates a toxic protein (in this case usually one copy is sufficient to cause disease, thus these diseases are termed dominant), silencing or inhibiting this abnormal gene or protein is desired. Polygenic diseases, such as Alzheimer's disease and Parkinson's disease, stem from the constellation of many genes and environmental factors. It is often challenging to pinpoint the exact cause and selecting a therapeutic target is often difficult. 

“Given the promise of gene and cell therapy to treat uncurable diseases, investigators, patient advocates and patients have dedicated tireless efforts to this cause, with several recent successes and more to come.”

- Xandra Breakefield, past president of ASGCT

Most gene therapy trials targeting the central nervous system take advantage of adeno-associated viral (AAV) vectors. AAVs are non-pathogenic viruses and vector uptake results in long-term expression of the transgene in non-dividing cells. One type of AAV, AAV9 (Figure 1) can actually cross the blood-brain barrier and thus the nervous system can be targeted after introduction of the vector into the bloodstream. Other types of AAVs that do not cross the blood-brain barrier, can be injected locally: into the brain itself, into the ventricles of the brain or into the cerebrospinal fluid ('brain fluid' that fills the ventricles and surrounds the brain and spinal cord) (Figure 2). Since neurons do not regenerate, the primary aim for many gene therapy strategies is to prevent further loss of neurons and stabilize the disease.

Stem cell therapy also holds significant promise for the treatment of various neurological conditions. Stem cells can be differentiated into neurons or other cells that support neurons in the brain. These cells can be obtained from many different tissues and changed into pluripotent stem cells, therefore, the patient can be treated with their own cells in a personalized manner. 

Parkinson's Disease (PD)

PD is characterized by the loss of a specific neuron population, which is found in the so-called substantia nigra (black substance), a part of the midbrain responsible for movement coordination. These neurons produce an important neurotransmitter, dopamine, which signals between neurons. The selective loss of these dopaminergic neurons leads to shaking of the hands and slowness of movements, decreased facial expression and difficulty with walking.  Gene and cell therapy strategies are underway. AAV-gene therapy focuses either on trying to inhibit the loss of neurons by conferring on cells in the brain the ability to produce neuroprotective agents, called neurotrophins (GDNF, glial cell line-derived neurotrophic factor (AAV2-GDNF for Advanced Parkinson's Disease) and neurturin (Safety and Efficacy of CERE-120 in Subjects With Parkinson's Disease).  Another strategy is to increase the production of the aromatic L-amino acid decarboxylase (AADC) enzyme, which is responsible for the production of dopamine from its precursor, L-Dopa. Clinical trials using AAV encoding for AADC are underway (Safety Study of AADC Gene Therapy (VY-AADC01) for Parkinson's Disease (AADC), AADC Gene Therapy for Parkinson's Disease). Several cell therapies are also underway, some of them aim at restoring dopaminergic neurons (A Study to Evaluate the Safety of Neural Stem Cells in Patients With Parkinson's Disease), while others attempt to ameliorate the disease through supportive cell-cell interactions (Outcomes Data of Adipose Stem Cells to Treat Parkinson's Disease). 

Alzheimer's Disease (AD)

AD is the most common cause of dementia in the elderly, resulting from loss of neurons in the brain. The neuron loss is thought to be a consequence of the deposition of certain proteins (amyloid beta and tau), however it is not well known how exactly this deposition leads to pathology. Similarly, to other neurodegenerative diseases, cell survival can be augmented using neurotrophins delivered by vectors (Randomized, Controlled Study Evaluating CERE-110 in Subjects With Mild to Moderate Alzheimer's Disease). However, treatment of AD remains very challenging due to the large affected brain area and the lack of reliable animal models. 

Spinal Muscular Atrophy (SMA)

SMA is a relatively rare genetic disease, which is caused by a mutation in the SMN1 gene. The mutation results in degeneration of the spinal cord neurons that control movement of the body, leading to muscle wasting and early death. Recently, gene replacement therapy demonstrated success in the treatment of this particularly devastating disease; the results of a Phase I clinical trial using AAV9 vectors carrying the SMN1 gene have been published in November 2017. AAV9 vectors are capable of crossing the blood-brain barrier and thus reach neurons in the spinal cord after intravenous injection. In this study, all 15 injected children were alive and event-free at 20 months of age. Most patients who received high dose AAV9 vector were able to speak and sit unassisted at 20 months of age (note: median survival of this disease is only around 18 months).

Another, somewhat different strategy in SMA is to increase the expression of a similar gene, SNM2, using antisense oligonucleotides (ASOs). ASOs change how the final messenger RNA for a protein is made by altering splicing, a process necessary for RNA maturation and functionality. Nusinersen (Spinraza), an approved drug for SMA in the United States and European Union, is an ASO indicated for the treatment of SMA. 


Figure 1. AAV9 - a vector that can cross the blood-brain barrier and deliver therapeutic cargo to the central nervous system, transmission electron micrograph, 40,000x magnification, scale bar: 100nm. Courtesy of: Casey A. Maguire, and Bence Gyorgy, Massachusetts General Hospital. Image acquired by Maria Ericsson, Harvard Electron Microscopy Facility. 

Huntington's Disease (HD)

HD is a genetic disease with dominant inheritance (i.e. only one mutated copy of the gene is needed for the individual to be affected). The mutation itself is a so-called trinucleotide repeat expansion, which means a certain amino acid is incorporated into the Huntingtin protein multiple times and this repeat number is higher in patients than normal individuals. It has been technically challenging to develop a gene therapy strategy for HD, but gene therapy strategies that are focusing on silencing or inhibiting the mutant gene are being evaluated. There is no current human gene therapy clinical trial for Huntington's disease, however clinical trials based on expressing small inhibitory RNAs and microRNAs (inhibitory molecules that inhibit the mutant gene), as well as genome editing vectors to disrupt the repeat expansion are expected to begin soon. 

Amyotrophic Lateral Sclerosis (ALS)

ALS, commonly called Lou Gehrig's disease, is a progressive neurodegenerative disease affecting the motor neurons in the spinal cord and in the brain. About one fifth of ALS is known to be caused by a mutation in a single gene: superoxide-dismutase 1 (SOD1). Gene therapy approaches to replace this mutated gene are underway, including small inhibitory RNAs and antisense RNA to alter splicing to decrease expression of the mutant protein, as well as gene editing. Several other genes have been associated with ALS, including an expansion repeat in the C9orf72 gene which results in generation of toxic peptides which can be neutralized by expression of a heat shock protein. The first human clinical trial using neural stem cells (CNS10-NPC-GDNF) programmed to become a type of supporting cell (astrocyte) has been launched (CNS10-NPC-GDNF for the Treatment of ALS). These cells are expected to produce glial cell line-derived neurotrophic factor (GDNF, see above at the Parkinson's disease section) in the spinal cord that promotes the survival of motor neurons. 

X-Linked Adrenoleukodystrophy (X-ALD)

X-ALD is one of the most common inherited diseases of the central nervous system. It affects primarily the white matter, the part of the brain, which insulates the processes of neurons. The disease is caused by mutations in the ABCD1 gene, which impairs fatty acid metabolism in neurons leading to myelin sheath destruction. Interestingly, hematopoietic stem cell transplantation is an effective therapy, as certain hematopoietic cells can migrate into the brain, turn into microglia-like cells and ameliorate the metabolism. If a bone marrow transplant donor is not available, these patients can successfully be treated with their own bone marrow stem cells which are genetically modified with a lentivirus vector encoding the normal protein and then re-infused into the patient.


Figure 2. Routes of administration for gene and cell therapy agents targeting the central nervous system. Vectors can be directly injected into the brain (intraparenchymal), into the ventricles (intracerebroventricular) and intro the cerebrospinal fluid spaces surrounding the central nervous system (intrathecal). Courtesy of: Hocquemiller Michaël, Giersch Laura, Audrain Mickael, Parker Samantha, and Cartier Nathalie. Human Gene Therapy. June 2016, 27(7): 478-496.

22nd Annual Meeting
April 29 – May 2 | Washington D.C.