Progress on Gene Therapy Against Muscular Spinal Atrophy
Most probably, one of the breakthroughs that is going to be most important in the gene therapeutic field is the one related to muscular spinal atrophy, the type that represents one of the main genetic causes of death in newborns. This is a result of a mutation of a gene that goes by the name SMN1, which, when in a defective form or a mutation, becomes deprived of the ability to synthesize enough of a key protein controlling the growth and survival of motor neuron proteins involved in the functionality of motor neurons. Traditionally, the prognosis for patients with SMA has been poor because of the rapid progression of the disease to severe muscle wasting and respiratory failure.
Gene therapy has been nothing short of transformational development in treating those with SMA. The breakthrough, in this case, was to develop an AAV9-based gene therapy including a functional copy of the SMN1 gene and deliver it directly inside the motor neurons. As per the clinical studies, patients treated for the same showed improvements in motor function and a remarkable rate of survival. For instance, most of these gene-treated patients were able to do some things that had not been done before, from sitting unaided and rolling over to walking. Gene therapy didn’t just give these patients a chance to live longer but enabled them to live better.
Real success under the canopy of treatment comes with substantial evidence that gene therapy can pack a punch at the very roots of these neurodegenerative diseases with a genetic basis. In the case of SMA patients, the functional gene inclusion acts as compensation for the defective one and has provided a template for the treatment of other similar disorders.
Gene Therapy for the Treatment of Tay-Sachs and Sandhoff Diseases
Tay-Sachs and Sandhoff diseases are two disastrous inherited neurodegenerative disorders classified under GM2 gangliosidoses. These two disorders are caused by a deficiency in the activity of the enzyme β-hexosaminidase A and result in an accumulation of GM2 ganglioside in neurons, bringing about progressive neurological damage. Patients in the infantile form of the disease usually do not survive early childhood.
Research into gene therapy for these disorders has had promising results in preclinical models. More specifically, AAV vectors have been used for the delivery of functional copies of the HEXA and HEXB genes encoding subunits of the β-hexosaminidase enzyme. Common among these studies was the feature that such an approach, similar to what was previously seen in gene therapy studies for lysosomal storage disorders in animal models, such as mice and sheep, showed that this type of approach diffused the enzyme far enough throughout the CNS to decrease GM2 accumulation and attenuate symptoms.
One study demonstrated dual AAV vectors, each carrying one of the necessary subunits of the enzyme. This gene therapy administered intracranially significantly reduced GM2 levels, improved motor function, and extended survival in animal models. The results thus set a basis for translating this approach into humans, provided further refinement of the technique takes place, offering for the first time an effective therapy for these devastating conditions.
Challenges of ALS: Intervention by Gene Therapy
Amyotrophic lateral sclerosis is a neurodegenerative, progressive disease that makes patients suffer from muscle weakness, develop paralytic disorders, and die. The genetic nature of ALS is multifactorial, and genes were described, including SOD1, C9orf72, and others. Although ALS is largely considered to be a multifactorial disease, some familiar forms of it are directly related to some specific genetic mutations, which might become the target for gene therapy.
Among gene therapy strategies for ALS was targeting the SOD1 gene, with mutations accounting for a subset of cases of familial ALS. Researchers used AAV vectors to develop approaches to knock down MN’s expression of the mutant SOD1, which has been demonstrated to attenuate neurotoxicity and extend survival in animal models of ALS.
More recently, gene editing technologies such as CRISPR-Cas9 are being explored for the correction of genetic mutations at the DNA level in ALS. These techniques involve a one-time treatment that could permanently alter the disease course. Challenges remain, especially in ensuring precise targeting and minimizing off-target effects.
