Abstract Body

Childhood neuromuscular disorders are devastating conditions associated with major disability and shortened life span. They encompass common muscular dystrophies such as Duchenne muscular dystrophy (DMD); motorneuron diseases such as spinal muscular atrophy (SMA), and less common limb girdle muscular dystrophies and congenital myopathies.

Each of these conditions presents its own therapeutic challenges. The major hurdle in muscular dystrophies is the abundance of the target organ (skeletal muscle is ~40% of the body weight), the need to target the heart and, in DMD, the large size of its cDNA that precludes its packaging in commonly used viral vectors. For SMA1, one of the challenges is the need to target all motorneurons, and the short window for therapeutic intervention in this rapidly progressive condition. In myotubular myopathy, the profound severity and rarity of affected children complicates the design and execution of clinical trials.

The therapeutic landscape is however changing very rapidly, following landmark studies and global approval of one AAV for SMA, and several ongoing trials on DMD.
In SMA, a AAV9 viral vector carrying the defective gene achieved efficient motorneurons targeting following intravenous administration. A range of AAV vectors has also been engineered to deliver highly internally deleted “minidystrophin” in DMD and 4 studies are ongoing.

These early successes also bring the need for future developments, from further improvement in delivery to the need to better understand safety of the very high doses of AAV required in these studies, as highlighted by 3 treatment related fatalities in myotubular myopathy.

Abstract Body

SMN1 gene is missing in SMA, however only a 5 nucleotid different, homologus, and centromeric gene called SMN2 is maintained. In RNA based therapies the main aim is to be able to obtain more SMN protein transcripts from SMN2. There is a rough inverse correlation between SMN2 copy number and clinical severity. Currently, we have two options. The first one is nusinersen, a molecule that prevents alternative splicing out of exon 7 of the SMN2 gene at the mRNA level so that more transcript is yielded. So, this is an exon inclusion. This molecule has been in practice since the end of 2016, and is recognized globally. So far more than 11,000 patients from all types of SMA has recevied or actively ongoing as a regimen. In SMA I, babies younger than 6 months old are expected to benefit better. The second one is a ‘small modifier molecule’ again hitting the same area in the gene ending with no exclusion of the exon 7, called risdiplam. There are several active studies in different forms of SMA. An initial approval by the FDA has recently become real: SMA I babies older than 2 months based on survival and ventillation prevention facts in the subjects. New and clear data is expected.

Abstract Body

Hereditary ATTR amyloidosis is a progressive and fatal disorder caused by variant transthyretin (TTR) deposition as amyloid. A progressive axonal neuropathy with autonomic involvement is a common presentation associated with variable heart involvement.

Liver transplant was the first treatment available, but its benefits were limited. In the last decade three drugs were approved for the treatment of ATTR amyloidosis with polyneuropathy.

Tafamidis is a TTR stabilizer presented as a 20mg capsule for daily oral intake. The best treatment results are seen in female patients with early disease. No safety issues were detected.

Patisiran is an interference RNA preventing the synthesis of wild and variant TTR in the liver. A dose of 300 µg/Kg is infused every three weeks after pre-medication with a low dose steroid. The phase 3 clinical trial showed a highly significant difference between treatment arms, with some degree of improvement in a large percentage of patients. Some mild infusion reactions may occur, but they are easily controlled.

Inotersen is an antisense oligonucleotide that also prevents TTR synthesis. It is formulated for weekly subcutaneous injection. The pilot trial showed a highly statistically significant difference between treatment arms. The drug may cause severe thrombocytopenia and renal disease. Monitoring rules with frequent blood and urine analysis are needed.

There are other drugs under development, addressing some unmet needs. Anyway, the approval of these three new drugs is changing a devastating and life-threatening disease into a chronic condition with better quality of life and prolonged survival.