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Gene therapy: would ALS and SMA be the next candidates?

Spinal muscular atrophy and amyotrophic lateral sclerosis are two devastating neurological conditions with the common pathological sign of motor neuron degeneration, which eventually leads to muscle wasting and death. While the etiology, age of onset, progression and survival outcomes may differ drastically among diseases, they share a number of mechanistic parallels; therefore, the experimental and clinical insights on the only disorder may prove useful to the other. It is an exciting time for the SMA community because the first treatment, an ASO gene therapy called nusinersen, was approved in the United States by the FDA on December 23, 2016. Nusinersen subsequently received marketing authorization in the EU from ‘EMA in June 2017 This in stark contrast to the situation of ALS, where clinically valid gene therapies are currently non-existent, while recent studies on chemically different drugs have failed to meet the expectations raised by the experiments on mice. Although there are numerous complications in the treatment of ALS that do not relate to SMA, some key lessons have been learned from the range of preclinical research and clinical studies on SMA gene therapies that may prove useful for galvanizing an SLA gene targeted design and development of therapy.

Spinal muscular atrophy

Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease that affects 1 in 8,500-12,500 newborns and is the most common genetic cause of infant mortality (Verhaart et al., 2017a, b). Patients have severe muscle weakness and atrophy, predominantly in the proximal muscles (eg trunk), due to the degeneration of the ventral horn of the spinal cord. Pathology in further cells and tissues can be observed in more severe manifestations of the disease, which has significant implications for treatment (Hamilton and Gillingwater, 2013). SMA is caused by reduced levels of SMN protein, which is found in the nucleus and cytoplasm of almost all cells, and plays a vital role of cleaning in the assembly of spliceosomes. The protein is encoded by two almost identical genes, SMN1 and its parallel SMN2. A single functioning SMN1 allele produces enough protein for the motor neuron to remain healthy, as demonstrated by 1 person in 40-60 with a functional copy of SMN1 (ie SMA carriers) that do not have a clinical phenotype. Therefore, when the production of proteins from SMN1 is compromised, SMN2 can only partially compensate.

The SMN protein is highly conserved during evolution, allowing the modeling of SMN function reduced in different organisms. By manifesting at 6 months or earlier and radically limiting life expectancy (<2 years), type I SMA (Werdnig-Hoffmann’s disease) is the most severe and frequently diagnosed form of SMA and prevents children from being able to sit without Help. Child death is usually caused by respiratory complications, although with specialized care, lifespan can be artificially prolonged for long periods. Type II SMA (Intermediate / Dubowitz Syndrome) occurs between 7 and 18 months, allows a session without help but not to walk with a chance of survival of 93% and 52%, respectively, at 20 and 40 years ( Farrar et al., 2013). Type III SMA (Kugelberg-Welander disease) limits motor function and begins> 18 months, but before adolescence, whereas type IV SMA (onset in adults) typically occurs in the second or third decade of life with mild to moderate muscle weakness, but generally without respiratory problems.

Amyotrophic lateral sclerosis

ALS has traditionally been classified into sporadic clinically indistinguishable (sALS) and familial forms (fALS); sALS occurs without family history of the disease and represents the majority of cases (90%), whereas fALS contributes to 10% of patients and is genetically inherited, predominantly in an autosomal dominant manner. The pathological and clinical variability of the disease has led to the idea that, in addition to being in a continuum with FTD, the same SLA may not be a single disorder, but a syndrome (Turner et al., 2013). Consistently with this, aberrations in over 25 genetic loci have been reproducibly linked to the ALS phenotype (Brown and Al-Chalabi, 2017), with new genes constantly identified. The four most common mutations are large expansions (G4C2) on chromosome 9 of the C9orf72 gene, and dominant mutations in superoxide dismutase 1 (SOD1), TDP-43 protein and FUS / TLS gene.

Consistently, the overwhelming majority of SALS and FALS patients have cytoplasmic depositions of aggregated proteins, the main component of which is TDP-43, albeit with various cellular distributions (Al-Sarraj et al., 2011). However, these inclusions clearly lack TDP-43 in the SOD1-dependent and FUS-dependent forms. Further defects in several cellular processes have been implicated in ALS, including excitotoxicity, oxidative stress, impaired oligodendrocyte function, axonal transport defects, mitochondrial malfunction, and neurotrophic factor deficiency (Kiernan et al., 2011, Taylor et al., 2016 ). It is not clear which of these phenomena, if any, has a primary role in the pathogenesis of the disease, rather than simply being the non-specific consequences of a dysfunctional system.

The new gene therapies

Nusinersen (Spinraza, IONIS-SMNRx and ASO-10-27) is an antisense oligo-nucleotide (ASO) developed by the work of numerous laboratories and a collaboration between Biogen Idec and Ionis Pharmaceuticals. ASOs are synthetic, single-stranded RNA sequences (15-25 nucleotides) that specifically bind to pre-mRNA or mRNA target sequences, affecting gene expression. ASOs that specifically modulate splicing are also called SSOs. Especially for diseases affecting the nervous system, ASOs are widely distributed when injected into the cerebrospinal fluid, do not require carrier molecules and have relatively long half-lives (Geary et al., 2015). A significant amount of work in SMA mice has provided substantial evidence of the in vivo efficacy of nusinersen (Singh NN et al., 2017), leading to a series of stratified clinical studies (Chiriboga et al., 2016; Finkel et al., 2016, 2017). There is a pre-specified provisional analysis from a randomized double-blind phase III trial in type I SMA patients called ENDEAR.

A second gene therapy called AVXS-101 (scAAV9.CB.SMN and ChariSMA), which carries the SMN1 gene using the non-recurrent adenovirus serovar 9 (scAAV9), has also shown a significant pre-clinical potential. One of the main advantages of this therapy compared to nusinersen is that AAV9 can cross the brain barrier in mice, cats and non-human primates, allowing intravenous administration. Furthermore, AAV9 shows predilection for neurons and can mediate a long-term stable expression with a single administration, which is important given the immunogenicity problems associated with viruses. This contrasts with multiple and invasive intrathecal injections of nusinersen, which may have adverse side effects (Haché et al., 2016). Commercialized by AveXis, AVXS-101 completed the tests in SMA type I patients in a phase I clinical trial with open dose-escalation (NCT02122952). The treatment is safe and well tolerated and has led to improvements in survival, in the achievement of motor functions also with respect to the historical cohorts of SMA patients (Mendell et al., 2017). Two further phase III open-label studies are planned with type I patients in the United States and Europe. The expression of SMN1 is driven by a hybrid promoter of the beta-actin chicken gene with one of the cytomegalovirus and the AVXS-101 can be injected intravenously.

To judge from the steps forward and with a good omen, hope is great.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Bartus RT, Johnson, EM (2017a).  Neurobiol. Dis. 97, 156–168. 

Bartus RT, Johnson, EM (2017b).  Neurobiol. Dis. 97, 169–178.

Becker LA et al. (2017). Nature 544, 367–371.

Bevan AK et al. (2011). Mol. Ther. 19, 1971–1980.

Biferi M et al. (2017). Mol. Ther. 25, 2038–2052.

Borel, F et al. (2016). Hum. Gene Ther. 27, 19–31.

Chan KY et al. (2017). Nat. Neurosci. 20, 1172–1179. 

Chen L et al. (2017). Front. Neurosci. 11:476.

Evers MM et al. (2015). Drug Deliv. Rev. 87, 90–103.

Hammond SM et al. (2016). PNAS U.S.A. 113, 10962–967.

Jiang J et al. (2016). Neuron 90, 535–550.

Raoul C et al. (2005). Nat. Med. 11, 423–428.

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