Author: Dr Rajvinder Karda, University College London, 16 December 2021
Rare disease is defined by the European Commission on Public Health as life threatening or chronically debilitating conditions whose prevalence is less than 5 per 10,000 (1). NHS England published their Implementation Plan for the UK Strategy for Rare Diseases in 2018 (2) which stated “There are between 5,000 and 8,000 rare diseases that affect the lives of around three million of the UK population”. The three key objectives in this Implementation Plan are facilitating earlier diagnosis and intervention, improving care coordination and promoting research. Over 10,000 monogenic diseases have been identified of which 17% are neurological disorders. These are estimated to account for up to 40% of the workload in hospital paediatric facilities; more than 1% of children are affected at birth by monogenic neurological disease. It is recognised that, historically, attitudes to treatment of these diseases have been pessimistic. However more recently there is increased optimism that improvements in DNA sequencing, model generation and the advent of clinical gene therapy offer great hope for diagnosis and treatment of such diseases (3).
Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease caused by loss of function of the gene encoding survival motor neuron 1 (SMN1), resulting in degeneration of motor neurons and muscular atrophy. SMA1 is an early onset disease (median age of 1.2 months) resulting in premature death or the need of mechanical ventilation by 2 years of age.
In 2010 Foust and colleagues developed a pre-clinical gene therapy treatment for SMA1 with the use of adeno-associated virus serotype 9 (AAV9) (4). They demonstrated that by a single intravenous delivery of an self-complementary AAV9 vector containing the full sequence of SMN1 to new-born SMA knock-out mice, resulted in complete rescue of motor function and neuromuscular physiology (4).
The results from the pre-clinical study resulted in a clinical trial in the US where 15 patients with SMA1 received a single dose of the AAV9 gene therapy treatment (Zolgensma, developed by Novartis Pharmaceuticals) via intravenous delivery. 3 patients (mean age of 6.3 months) received a lower dose (6.7x1013vector genomes/kilogram; cohort 1) and 12 of these patients (mean age of 3.4 months) received the higher dose (2x1014 vector genomes/kilogram; cohort 2) (5).
Impressively all gene therapy patients reached month 20 without permanent mechanical ventilation. At 29 months one patients from cohort 1 required permanent mechanical ventilation due to hypersalivation. However, after salivary gland ligation the requirement of ventilation was reduced to 25%. Furthermore, strikingly all patients had an increase in motor function from baseline and 11/12 patients from cohort 2 were able to sit unassisted, achieve head control, roll over, stand independently and walk independently (5). Therefore, highlighting the tremendous success of this clinical trial especially in the cohort 1, who were treated with the higher dose of Zolgensma gene therapy.
This year the NHS approved the one-off Zolgensma gene therapy treatment. There are 4 center’s across the UK (Bristol, London, Manchester & Sheffield) approved for the use of Zolgensma for the treatment for Type-1 SMA.
This is a very exciting time for regenerative medicine and hopefully this will open doors for future gene therapy treatments for deliberating neurological disorders.
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England, N. H. S. "Implementation plan for the UK strategy for rare diseases; 2018."
Chen, Wan-Jin, et al. "Rethinking monogenic neurological diseases." bmj 371 (2020).
Foust, Kevin D., et al. "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN." Nature biotechnology 28.3 (2010): 271-274.
Mendell, Jerry R., et al. "Single-dose gene-replacement therapy for spinal muscular atrophy." New England Journal of Medicine 377.18 (2017): 1713-1722.