Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

Abstract

Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. As a result, there has been an increasing interest in the use of these therapies to treat motor neuron diseases (MNDs), for which many potential molecular targets have been discovered. MNDs are neurodegenerative disorders that, in their most severe forms, can lead to respiratory failure and death, for instance, spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). Despite the fact that SMA has been known for many years, it is still one of the most common genetic diseases causing infant mortality. The introduction of drugs based on ASOs—nusinersen; small molecules—risdiplam; and replacement therapy (GRT)—Zolgensma has shown a significant improvement in both event-free survival and the quality of life of patients after using these therapies in the available trial results. Although there is still no drug that would effectively alleviate the course of the disease in ALS, the experience gained from SMA gene therapy gives hope for a positive outcome of the efforts to produce an effective and safe drug. The aim of this review is to present current progress and prospects for the use of gene therapy in the treatment of both SMA and ALS.

Analysis on the effect of genes on amyotrophic lateral sclerosis

“…After systemic delivery of AAV9, high expression is seen in the cervical spinal cord, hippocampus, motor cortex, and cerebellum. This strongly suggests that this method shows promise in the treatment of neurological diseases [11].…”

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy

“…In other motor neuron diseases, spinal muscular atrophy (SMA), and several gene therapeutic approaches, such as Nusinersen, Zolgensma, or Risdiplam, have been approved, which could lead to improved life quality of patients. The gene therapy strategy may also be promising for ALS drug development [258,259]. Antisense molecule delivery, which targets genetic mutations in SOD1, FUS, TARDBP, or c9orf72, was suggested to be helpful in disease therapy.…”

Spinal muscular atrophy – the effectiveness of treatment and new therapeutic possibilities for selected groups of patients in Poland

“…SMN2 różni się występowaniem substytucji cytozyna -tymina (C-T) w pozycji 6 w eksonie 7, która prowadzi do alternatywnego splicingu i wykluczenia eksonu 7. Skutkiem tego w translacji transkryptu SMN2 powstaje niestabilne i częściowo niefunkcjonalne białko SMNΔ7 [8]. Mechanizmy polegające na włączeniu eksonu 7 do transkryptu matrycowego RNA (mRNA) SMN2, a także dostarczeniu genu SMN1, są celem terapii stosowanej w leczeniu SMA.…”

“…Food and Drug Administration, FDA) oraz Europejską Agencję Leków (ang. European Medicines Agency, EMA) odpowiednio w 2016 i 2017 roku [8]. Lek ten to antysensowny oligonukleotyd (ASO), który prowadzi do włączenia eksonu 7 do prekursora mRNA (pre-mRNA) SMN2 poprzez wiązanie się do miejsca intronowego wyciszacza splicingu (ISS-N1) znajdującego się w intronie 7 pre-mRNA, a więc wypierając czynniki splicingowe, powoduje supresję splicingu i utrzymanie eksonu 7 w mRNA SMN2.…”