Genetic Neurodegenerative Disorders: Close to a Symptom-Free Life?

NeurologyLive, February 2022, Volume 5, Issue 1

Although we have entered the age of genetically targeted therapies in the neuromuscular clinic, there are many unresolved clinical, economic, and ethical questions that require extensive further research.

BREAKTHROUGHS IN targeted genetic treatment have transformed medicine in recent years, with specialties such as neuromuscular neurology in the vanguard. In this issue of NeurologyLive®, Crystal M. Proud, MD, expertly outlines recent advances in neuromuscular care—with more promising approaches on the near horizon—and reviews some of the unanswered questions requiring further research now that it has become standard of care to alter genetic expression in our patients in the clinic.

Spinal muscular atrophy (SMA) is the first disease with an approved systemic in vivo gene therapy in the US, available since 2019. With onasemnogene abeparvovec-xioi (Zolgensma; Novartis) for survival motor neuron (SMN) gene transfer, as well as nusinersen (Spinraza; Biogen) in 2016 and risdiplam (Evrysdi; Genentech) in 2020 as RNA-based therapies, there has been a transformative impact on SMA disease course over the past 5 years. Currently in the clinic, discussions that were once primarily of a palliative nature are focused rather on potential for at minimum disease stabilization and often improved function with treatment. Real-world data on short- and long-term impact of all 3 approved SMA treatments continue to be collected.

Duchenne muscular dystrophy (DMD) also has had several recent genetically targeted therapy approvals. The conditional approval of eteplirsen (Exondys 51; Sarepta), an antisense oligonucleotide targeting skipping of exon 51, by the FDA in 2016 marked the first DMD-targeted therapy to receive a conditional approval in the US; after subsequent approval of exon 53 skipping with golodirsen (Vyondys 53; Sarepta) and viltolarsen (Viltepso; NS Pharma) and exon 45 skipping with casimersen (Amondys 45; Sarepta) in 2021, approximately 25% to 30% of patients are eligible for exon-skipping treatments.1 As the size of the dystrophin gene precludes gene transfer with existing viral vector technology, programs are under way utilizing tailor-made versions incorporating the most critical regions for DMD protein function within the muscle fiber. A rise in genetically targeted treatment trials continues to hold promise for rarer and/or more heterogenous genotypes and phenotypes; this powerful therapeutic option still has many unknowns about ideal timing of intervention, short- and long-term toxicities, and durability in the context of optimization.

Early diagnosis and referral for treatment are key in neurodegenerative disorders, as most reach an irreversible stage in affected tissues.2 The pace of decline can be highly variable across the phenotypic spectrum, and approaches such as newborn screening, now in place for SMA in the majority of US births as well as in several other countries, lead to considerations about optimal timing of intervention based on available biomarkers; in SMA, genotype is the most well established, and debate continues over timing of intervention for those with more than 4 SMN2 copies.3 Some who receive a diagnosis via screening and are seen immediately postnatally are symptomatic and do not have as robust a response to treatment, suggesting a wider spectrum of prenatal onset of motor neuron loss than had been appreciated in natural history studies. Prenatal therapies are also being studied preclinically. Precise and reliable biomarkers of disease onset and rate of progression in neurodegenerative disorders significantly aid treatment decisions but must be interpreted in the context of the phenotypic complexity and other challenges of rare disease research.

Genetically based therapies increase, decrease, or otherwise modify expression of a gene via DNA- or RNA-based techniques, which can lead to both short- and long-term toxicities.4,5 Currently, all commercially available genetic therapies alter gene expression in some way, and affect only the proband receiving therapy and should be paired with appropriate genetic counseling as it relates to family planning and risk for future generational inheritance, as well as impact on carrier relatives if relevant. Genome editing, either somatic or germline, is currently present only in the research setting; as it targets the proband’s DNA permanently by removing or correcting a pathogenic variant, it may also affect the germline and subsequent generations. Several potential concerns remain regarding gene therapy: Cellular immunity as well as complement activation have been identified in tolerability concerns that have arisen in multiple programs.4 Individuals with preexisting immunity to the viral vector are also not candidates for gene therapy with current technology, except for neonates who can show clearance of passively transferred maternal antibodies over weeks; some investigators have begun to study plasmapheresis and other measures to attenuate this issue and it may also allow for repeat dosing if optimized. In the DMD programs, the microdystrophin protein expressed is not fully functional and thus disease expression over time is expected but hoped to be ameliorated compared with natural history; in any gene transfer, penetrance and efficacy may vary across tissues because of tropism and other factors.4 Durability is also a concern. As an example, in DMD, since the genome of adeno-associated viruses (AAVs) generally does not integrate into the host genome, the micro/ minidystrophin transgene would persist in host cells as episome and would not be replicated during mitosis. Thus, in any tissue with cell division or turnover, the transgene may eventually become diluted or lost—although satellite cells may harbor some reserve. Alternatively, some have raised the possibility of the rare occurrence of AAV vector integration; if this happens at any significant frequency, it raises the concern of altering the expression of endogenous genes and potential issues such as oncogenicity over the life span.6

With early diagnosis and intervention, hope is beginning to emerge for a subset of those with neurodegenerative genetic disorders to remain asymptomatic with treatment. Examples in nature occurred prior to having targeted treatments, such as families where a pediatric diagnosis of SMA led to testing of relatives and individuals with genetic SMA along with high SMN2 copy number received a diagnosis late in life and were asymptomatic.7 The standard of care for most inherited neurologic disorders includes interdisciplinary screening and management of neurologic and other systemic comorbidities; maximizing function and minimizing symptoms is the goal. It is important to reinforce with patients and their caregivers that this follow-up will continue to be required after receiving novel therapeutics. Currently available reviews and care consensus/care considerations guidelines often mention potential treatments on the horizon, but no guidelines that include targeted treatments are available to this point in 2022. The balance between target tissue expression—including the impact and durability of the protein expression achieved vs toxicity considerations with the medications themselves and potential off-target genetic and/or protein overexpression toxicities—requires extensive further research and long-term, real-world follow-up of those receiving treatment. Continuing to engage with a specialized care team throughout life is therefore important both for monitoring for potential disease manifestations in tissues not optimally rescued via targeted therapy, and for monitoring regarding short- and long-term adverse effects of the interventions.

In the neuromuscular field, gene transfer is actively being investigated in research trials or on the near horizon for genetic amyotrophic lateral sclerosis, limb-girdle muscular dystrophies, glycogen storage disease type II (Pompe disease), giant axonal and Charcot-Marie-Tooth inherited neuropathies, and congenital myopathies and myasthenic syndromes. 2021 also heralded the sobering announcement of multiple deaths at higher vector doses in a gene transfer trial for myotubular myopathy, and the rare incidence of thrombotic microangiopathy after SMN gene transfer.8 Combination therapy with multiple genetically targeted treatments is occurring in SMA; both research trial and real-world data will be critical for evaluating the efficacy and tolerability of combination treatment, informing the ethical and economic considerations of access to these high-cost treatments across the spectrum of SMA severity. Targeting the phenotype is also continuing in active study for many disorders, such as myostatin inhibition in SMA for those already on genetically targeted therapies. It is likely that eventually a cocktail approach will be tailored with optimized timing of intervention to the individual, based on genotype and age of diagnosis as well as symptom burden; this would ideally be informed by disease biomarkers. The important question of whether there is an end point where risk outweighs benefit in those whose disease has progressed also requires further investigation.

The quest for treatment optimization in genetic neurodegenerative disorders will not be complete until an affected patient has no detectable signs or symptoms of disease because of successful early identification and customized treatment with minimal adverse effects. Those affected will likely continue to require long-term follow-up by specialized interdisciplinary teams for both optimization of health and long-term monitoring of potential complications of targeted treatments. We have entered the age of genetically targeted therapies in the neuromuscular clinic; there are many unresolved clinical, economic, and ethical questions that require extensive further research.

1. Bladen CL, Salgado D, Monges S, et al. The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. 2015;36:395-402. doi:10.1002/humu.22758
2. Darras BT, Jones HR Jr, Ryan MM, Mathews KD, De Vivo DC, eds. Neuromuscular disorders of infancy, childhood, and adolescence: a clinician’s approach. 2nd ed. Academic Press; 2014.
3. Glascock J, Sampson J, Connolly AM, et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2.J Neuromuscul Dis. 2020;7(2):97-100.doi:10.3233/JND-190468
4. Tang R, Xu Z. Gene therapy: a double-edged sword with great powers. Mol Cell Biochem. 2020;474(1-2):73-81. doi:10.1007/s11010-020-03834-3
5. Bizot F, Vulin A, Goyenvalle A. Current statusof antisense oligonucleotide-based therapy in neuromuscular disorders. Drugs. 2020;80(14):1397-1415. doi:10.1007/s40265-020-01363-3
6. Shieh PB. Emergingstrategies in the treatment of Duchennemuscular dystrophy. Neurotherapeutics. 2018;15(4):840-848. doi:10.1007/s13311-018-00687-z
7. Jedrzejowska M, Borkowska J, Zimowsi J, et al. Unaffected patients with a homozygous absence of the SMN1 gene. Eur J Hum Genet. 2008;16(8):930-934. doi:10.1038/ejhg.2008.41
8. Chand DH, Zaidman C, Arya K, et al. Thrombotic microangiopathy following onasemnogeneabeparvovecfor spinal muscular atrophy: acase series. J Pediatr. 2021;231:265-268. doi:10.1016/j.jpeds.2020.11.054