More than 10,000 diseases have a known genetic etiology. From haematological disorders to gastrointestinal disturbances and ophthalmic dysfunction, few organ systems are untouched by diseases of genetic origin. The nervous system is not exempt.
Biologic products have long been thought of as drugs with the potential to have curative effects on genetic pathologies and some of the earliest known biopharmaceuticals include the diptheria antitoxin and porcine insulin.
Originally, developments in the field of gene therapy were primarily based on combating disorders such as adenosine deaminase deficiency, an inheritable cause of severe combined immunodeficiency, known as ADA-SCID. The first genetic therapy for ADA-SCID was approved by the European Medicines Agency (EMA) in 2016. Strimvelis is a fraction of hematopoietic stem cells (HSCs) that express cluster of differentiation 34 (CD34), a membrane-spanning phosphoglycoprotein that facilitates cell adhesion. The HSCs which have been extracted from the patient are grown under controlled conditions and treated with cytokines and growth factors. A gammaretrovirus containing the human adenosine deaminase gene is the vector that is used to transfect the cells and these modified HSCs are delivered to patients via the intravenous route of administration. In the bone marrow, the cells replicate and mature which restores the function of the adenosine deaminase protein and has a life-long curative effect on ADA-SCID patients.
Four central strategies are explored in the field of developing genetic therapeutics:
The substitution of a mutated gene with a healthy variant is known as gene replacement therapy.
Introducing a new gene into the body to supplement a targeted therapeutic agent as an adjunctive treatment is known as gene addition there. This form of therapy is currently being explored in clinical trials.
Inactivating a mutated gene by using RNA-silencing techniques is known as gene inhibition and this is mostly being investigated as a strategy to treat toxic gain-of-function pathologies.
Making a targeted alteration to a known genetic sequence is referred to as gene editing.
In a talk at the European Academy of Neurology conference in Oslo, the benefits and drawbacks of potential vectors for gene therapy were discussed. In particular, retroviruses can potentially induce oncogenesis and can only transfer genetic material into actively dividing cells. Although adenoviruses are effective as transducing vectors, capsid proteins are likely to trigger an inflammatory response. As a vector, the herpes simplex type 1 virus (HSV-1) has a large packaging capacity and tropism for neurons. A major factor that must be taken into consideration during the process of developing a vector delivery system is the risk of inducing an inflammatory response. It is for this reason that patients who are preparing for therapy are given courses of corticosteroids such as prednisolone or dexamethasone.
Adeno-associated virus (AAV) is an infectious, non-pathogenic micro-organism that is under investigation as a potential vector for the treatment of systemic central nervous system (CNS) indications. Single-stranded AAV vectors are made by deleting viral genes which are replaced by a transgene cassette. Nucleic acid sequences are placed between inverted terminal repeats, a promoter, the gene of interest and a termination signal.
Despite the limitation of AAV is the small packaging capacity and reduced range of therapeutic genes that can be used in this delivery system, the lack of inflammatory response makes this potential therapy an attractive prospect for researchers in the field.
In indications such as amyotrophic lateral sclerosis (ALS), the use of AAV is being investigated as a strategy to downregulate the expression of mutated superoxide dismutase (SOD1), an enzyme that catalyzes the disproportionation of superoxide oxygen radicals into oxygen or hydrogen peroxide. SOD1 is a biomarker associated with a poor prognosis for ALS patients.
There are still challenges for the use of gene therapy in treating neuropathic diseases. Physiological obstacles include the difficulty of penetrating the blood-brain-barrier and safety measures such as protective equipment are needed to ensure that biologic drugs are appropriately handled in the clinical setting. There is currently no standardised consensus on the management of genetically modified organisms although it is postulated that the biosafety levels established by the World Health Organization (WHO) could be used to inform future practices concerning these treatments.
Even with the promise of continued research efforts in gene therapy, the risk of unforeseen outcomes cannot be underestimated which is certainly one of the lessons learned from the death of Jessie Gelsinger, the first patient to die from a clinical trial for gene therapy. The immunological reaction that ensued after Gelsinger was infused with a viral vector containing a gene intended to cure his X-linked genetic hepatopathology serves as a constant reminder of the ability of the body to unpredictably, yet decidedly, thwart attempts to override the biological mechanisms that are the foundation of the neuropathologies that continue to increase in incidence, prevalence, expensiveness and deadliness.
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