An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0056
Progressive myoclonus epilepsies (PMEs) are genetic diseases that together account for about 1% of all epilepsies in childhood and adolescence. Even though the age of onset, symptom spectrum, and severity vary among different PMEs, all patients experience myoclonic seizures, generalized epilepsy, and progressive neurological decline, often intractable and fatal. Antisense oligonucleotides (ASOs) are synthetic single-stranded chemically modified nucleic acid polymers that target RNA to alter splicing, modulate translation, or promote/prevent mRNA degradation. Their gene-specific action and versatility has made ASO-based therapeutics one of the major pillars of drug development for genetic diseases with more than a dozen ASO drugs FDA-approved and many more in development and clinical trials. Advances in ASO technology already paved the way toward “N of 1” patient-customized therapies and hold great promise for personalized drug development that is much needed to treat rare genetic diseases such as PMEs. This chapter discusses the potential of ASO therapies for PMEs by giving an overview of the possible mechanisms of action employed to target disease genes and by reviewing ASO studies aimed to treat neuromuscular or neurodegenerative diseases, including PMEs.
Progressive myoclonus epilepsies (PMEs) are a group of clinically diverse disorders caused by mutations in specific genes. All PMEs are extremely rare, but together they account for about 1% of all epilepsies in children and adolescents and certainly belong to the most serious epileptic syndromes known (Orsini et al., 2019). Commonalities among PMEs include the occurrence of myoclonus and generalized epilepsy as well as progressive neurological decline, including dementia and ataxia. As the disease progresses, PMEs in many cases become intractable and often fatal. With no cures available, treatments usually aim to reduce symptoms such as seizures combined with palliative, supportive, and rehabilitative measures (Kälviäinen, 2015; Minassian et al., 2016; Orsini et al., 2019).
The most common PMEs are Unverricht-Lundborg disease (ULD), Lafora disease (LD), the group of neuronal ceroid lipofuscinoses (NCLs/CLNs), and myoclonus epilepsy and ragged-red fibers (MERFF) (Kälviäinen, 2015). In most cases ULD is caused by mutations in the CSTB gene, but in some instances mutations in SCARB2 or PRICKLE1 were found instead (Table 56–1). Most PMEs are autosomal recessive disorders, but there are examples of autosomal dominant inheritance, including dentatorubral-pallidoluysian atrophy (DRPLA), CLN4B, progressive myoclonus epilepsy 11 (EPM11), myoclonus epilepsy and ataxia due to pathogenic variants in the potassium [K] channel (MEAK/EPM7), and familial encephalopathy with neuroserpin inclusion bodies (FENIB). MERRF is caused by mutations in mitochondrial genes and inheritance is therefore maternal. Some of the diseases affect the lysosome and because of that are also classified as lysosomal storage disorders, including NCLs, sialidosis, Gaucher disease (GD), and Niemann-Pick type C (NPC). Details on the symptom spectrum of the different PMEs and their basic disease mechanism (if known) are reviewed elsewhere and beyond the scope of this book chapter.
Progressive Myoclonus Epilepsies with Preclinically or Clinically Tested ASO Strategies.
As mentioned above, there are no effective and curative therapies for most PME disorders. Exceptions are an FDA-approved enzyme replacement therapy for CLN2 (de Los Reyes et al., 2020) and gene therapy approaches that are in development or clinical trials for CLN1, CLN2, CLN3, CLN5, CLN6, and CLN7 (Brenner et al., 2020; Masten et al., 2020). In the following, different ways of utilizing antisense oligonucleotide technology to treat genetic diseases will be introduced and their potential as therapies for PMEs presented and discussed. References showing examples of ASO strategies for PMEs are also listed in Table 56–1.
Antisense oligonucleotides (ASOs) are synthetic single-stranded chemically modified nucleic acid (RNA or DNA) polymers. They target RNA via complementary Watson-Crick base pairing, which is the basis of their specificity and their capability to modulate RNA processing (Sharma and Watts, 2015). Their high specificity enables targeting of specific transcript isoforms (Han et al., 2020; Lim et al., 2020; Roberts et al., 2020) and disease alleles with only single base pair changes (Carroll et al., 2011; Southwell et al., 2018), without affecting the wild-type RNA, making even “undruggable” targets “druggable.” The therapeutic potential of ASOs is reflected by the recent approval of more than a dozen ASO drugs (Kuijper et al., 2021; Roberts et al., 2020; Xiong et al., 2021) and the high number of ASOs currently in clinical trials for genetic diseases (Bennett et al., 2017; Brenner et al., 2020; Roberts et al., 2020; Silva et al., 2020) and cancer (Xiong et al., 2021).
One major obstacle for ASO therapeutics to become even more widespread is the difficulty of efficient delivery, especially to extrahepatic tissues (Roberts et al., 2020). For central nervous system (CNS) diseases, direct injection of ASOs into the cerebrospinal fluid (CSF) leads to good distribution and therapeutic effects, as demonstrated with the ASO drug nusinersen for spinal muscular atrophy (Finkel et al., 2016). Active research is going into improving ASO drug delivery and stability by chemical modifications, tissue/cell-targeting or cell-penetrating covalent conjugates, and nanoparticle vehicles (Gagliardi and Ashizawa, 2021; Roberts et al., 2020).
ASO design is very flexible and allows for multiple mechanisms of action, depending on the specific ASO chemistry and on the target sequence (Chan et al., 2006; Scoles et al., 2019). The most widely used mechanisms either promote RNA degradation via RNase H or function without RNA degradation by steric hindrance, leading to translation arrest or splice modulation (Bennett et al., 2017). In the former case, protein knockdown is achieved by recruitment of endonuclease RNase H to the ASO-mRNA heteroduplex, which results in mRNA degradation, leaving the DNA-based ASO behind (Chan et al., 2006; Roberts et al., 2020). ASO-dependent protein knockdown is not only valuable for developing therapeutic approaches but has been utilized to generate PME disease models, for example, by targeting the ASAH1 ortholog in zebrafish for SMA-PME (Zhou et al., 2012) or murine Npc1 for Nieman-Pick type C (Rimkunas et al., 2008). Translation arrest and splice modulation are achieved by steric-block ASOs. In the case of splice modulation, the ASO targets the pre-mRNA to mask a specific sequence, for example, splice sites or exonic/intronic cis-regulatory elements. Altering splicing can either correct splicing defects due to mutations, or use exon skipping or inclusion to restore an open reading frame or to disrupt it, thereby causing mRNA degradation through nonsense-mediated mRNA decay (NMD). It can be used to remove exons with the disease-causing mutation or to induce isoform switching, for example, promoting the splicing of a beneficial alternatively spliced isoform (Kuijper et al., 2021; Roberts et al., 2020; Silva et al., 2020, 2014).
One mode of action of ASOs is the modulation of splicing. This can be advantageous for cases where (point) mutations cause splicing defects, or where deletions lead to frameshifts/premature termination codons (PTCs) and altering splicing restores the open reading frame, preventing NMD or the formation of strongly truncated proteins. Two well-known examples for ASO therapies targeting splicing are the FDA-approved drugs for the neuromuscular diseases spinal muscular atrophy (SMA, nusinersen; Finkel et al., 2017; Mercuri et al., 2018) and Duchenne muscular dystrophy (DMD, eteplirsen; Alfano et al., 2019; Mendell et al., 2016).
SMA is caused by mutations in SMN1 (Survival Motor Neuron 1). A paralogous gene, SMN2, exists and encodes a functional SMN protein. However, exon 7 is removed during splicing in about 90% of the SMN2 transcripts, resulting in truncated/nonfunctional proteins and leaving only about 10% of full-length mRNA and hence very low levels of functional SMN protein. Nusinersen binds to an intronic splicing silencer (ISS) element in intron 7 to prevent splicing, which leads to exon-7 inclusion and increased levels of functional SMN protein (Fig. 56–1A) (Chiriboga et al., 2016; Mercuri et al., 2020).
ASO strategies for neuromuscular and neurodegenerative diseases. (A) Exon inclusion by nusinersen for SMA. (B) Exon skipping by eteplirsen for DMD. (C) ASO-dependent exon skipping for CLN3. (D) Exclusion of cryptic exon by milasen for CLN7. (more...)
DMD is caused by mutations in the DMD gene, encoding dystrophin. Most of the DMD mutations are deletions. The most severe DMD phenotype results from out-of-frame mutations with no or negligible amounts of dystrophin. In contrast, in-frame mutations cause the milder dystrophinopathy Becker MD (BMD). The ASO strategy for DMD is to delete an exon (e.g., exon-51 skipping by eteplirsen; Fig. 56–1B) adjacent to the deletion to generate an in-frame deletion that results in a truncated but still functional variant of dystrophin, shifting the disease phenotype from severe DMD to milder BMD (Duan et al., 2021; Verma, 2018).
Similar to the ASO-dependent exon-51 skipping in DMD, an exon-skipping approach has been studied for CLN3 Batten disease (Centa et al., 2020). In most cases this disease is caused by deletions of exon 7 and 8, which results in a PTC in exon 9 (Cotman et al., 2002; Munroe et al., 1997). ASO-mediated skipping of exon 5 through steric hindrance restored the open reading frame (Fig. 56–1C), leading to the inclusion of the lysosomal-targeting sequence (LTS) containing C terminus (Centa et al., 2020), the loss of which invariably leads to more severe forms of the disease (Centa et al., 2020; Kousi et al., 2012). In the disease mouse model, ASO treatment resulted in improved motor coordination, reduced histopathology, and increased survival (Centa et al., 2020).
Intriguingly, an ASO-based “N of 1” therapy was developed for a patient with CLN7. A unique mutation was found in the MFSD8 gene of this patient where an SVA retrotransposon insertion generated a cryptic splice site that resulted in a PTC-containing transcript. Milasen, a splicing-altering steric-block ASO, was developed to enable proper splicing of intron 6 and hence an increase in correctly spliced MFSD8 transcripts (Fig. 56–1D). Administration to the patient reduced frequency and duration of seizures, a few other symptoms stabilized, but neurological assessment scores continued to decline (Kim et al., 2019). Even though the ASO was not able to restore lost function, this case is an exciting example of precision medicine and patient-customized treatment that is possible today.
Disease-causing missense mutations are commonly assumed to disrupt protein function. However, 22%–25% of exonic disease mutations are estimated to be splicing sensitive (Lim et al., 2011; Sterne-Weiler et al., 2011), with up to 50% for genes that are particularly sensitive toward mutation-induced aberrant splicing (e.g., DMD; Sterne-Weiler and Sanford, 2014). Splicing defects are not only caused by missense mutations but also by deletions, silent and nonsense mutations, and intronic mutations, inactivating or weakening 3′ or 5′ splice sites or disrupting/creating splicing enhancer/silencer elements (Daguenet et al., 2015; Ward and Cooper, 2010). Overall, it is estimated that approximately one-third of all disease-causing mutations are splicing mutations (Lim et al., 2011). Splicing defects have been described for PMEs such as Gaucher type 3 (Tonin et al., 2019), sialidosis (Caciotti et al., 2009; Penzel et al., 2001), CLN3 (Mirza et al., 2019), CLN13 (Di Fabio et al., 2014), AMRF/EPM4 (Dibbens et al., 2009; Yari et al., 2021), ULD (Matos et al., 2018), and NPC (Encarnação et al., 2020; Paron et al., 2020; Zech et al., 2013). ASO approaches have been tested for the latter two diseases (Matos et al., 2018; Rodriguez-Pascau et al., 2009), both as proof-of-principle studies in patient fibroblasts. Splicing mutations are more frequent than commonly thought, and it will be interesting to revisit known PME-causing mutations for their possible effect on splicing to potentially find suitable ASO therapies targeting the root of the problem.
Mutations in a disease gene often result in loss of function, in which case further downregulation of gene expression is not meaningful. There are, however, instances where downregulation of gene expression is beneficial. That is the case for autosomal dominant diseases with mutations causing dominant-negative effects. Another example could be a disease where a target can be identified, and the downregulation of which prevents or slows down disease progression.
The ASO strategy for Lafora disease, proven to be successful in a preclinical study, is a great example for the latter case (Ahonen et al., 2021). Lafora disease is caused by loss-of-function mutations in either EPM2A or NHLRC1/EPM2B, encoding the glycogen phosphatase laforin and E3 ubiquitin ligase malin, respectively (Chan et al., 2003; Minassian et al., 1998). Both proteins form a functional complex that is crucial for maintaining proper glycogen structure that ensures glycogen solubility. In Lafora disease, glycogen molecules are formed that have longer than normal glucan chains and fewer branch points, respectively, which can render the molecule insoluble. Over time, insoluble glycogen molecules accumulate and form pathognomonic, pathogenic polyglucosan bodies (better known as Lafora bodies [LBs]) in the brain and other organs (Nitschke et al., 2018; Sullivan et al., 2017). Inhibiting or slowing down glycogen synthesis has been proven to correct the neuropathological bases of Lafora disease in the disease’s mouse models (Duran et al., 2014; Gumusgoz et al., 2021; Israelian et al., 2020; Nitschke et al., 2021; Pederson et al., 2013; Turnbull et al., 2011, 2014; Varea et al., 2021). Glycogen synthase (GYS) is the rate-limiting enzyme during glycogen synthesis and therefore a valuable/promising therapeutic target in Lafora disease. ASO-mediated downregulation of Gys1 transcripts (Fig. 56–1E) efficiently prevents further disease progression in Lafora disease mice, including the halt of LB formation, glycogen accumulation, and neuroinflammation (Ahonen et al., 2021).
Although most PMEs are autosomal recessive disorders, there are a few that are autosomal dominant with dominant-negative effects caused by only one mutant allele such as CLN4B (Naseri et al., 2021), MEAK/EPM7 (Muona et al., 2015), EPM11 (Hamanaka et al., 2020), FENIB (Roussel et al., 2016), and DRPLA (Tsuji, 2012). Using ASOs that lead to RNase H-dependent degradation of the target mRNA can be beneficial for these diseases. DRPLA, for example, belongs to a group of nine neurodegenerative diseases that are caused by CAG repeat expansions, leading to expanded polyglutamine (polyQ) tracts in the resulting proteins, hence called polyQ disorders (Lieberman et al., 2019; Riley and Orr, 2006). Well-known examples of polyQ disorders are Huntington’s disease (HD) or spinocerebellar ataxias (SCA) for which several preclinical ASO trials showed promising results, with ASO drugs for HD even progressing to clinical trials (Silva et al., 2020), with some trials terminated but a new one launched that is still recruiting. Non-allele-specific ASO approaches targeting both wild-type and mutant huntingtin (HTT) mRNA (Kordasiewicz et al., 2012) as well as allele-specific strategies targeting only the mutant mRNA (Carroll et al., 2011; Datson et al., 2017; Southwell et al., 2018) (Fig. 56–1F) showed success in preclinical studies. It needs to be evaluated for each of the autosomal dominant disorders individually if a non-allele-specific ASO strategy is an option, depending on how essential the (wild-type) protein’s function is for cellular processes or even survival.
For DRPLA, a CAG repeat targeting ASO was tested in patient fibroblasts and led to a 98% downregulation of mutant atrophin-1 (ATN1), while the wild-type ATN1 mRNA was only reduced by 30% (Evers et al., 2011). Even though CAG repeat targeting ASO approaches can be allele-specific, it depends on the ASO and the disease allele how selectively the mutant mRNA is reduced because even the wild-type alleles contain CAG repeats only much less than the mutant alleles in polyQ disorders (for CAG repeat numbers, see Riley and Orr, 2006; and Lieberman et al., 2019). Another concern could be the nonspecific reduction of other genes containing CAG repeats. For DRPLA, ASO studies in mice have not been done, and it is unclear what consequences an additional reduction of the wild-type Atn1 mRNA would have. Interestingly, Atn1–/– null mice are viable and fertile (Shen et al., 2007) and mice expressing a truncated ATN1 protein lacking both the polyQ repeat and the following C-terminal peptides (Atn1t/t) display growth retardation and progressive male infertility, but no obvious signs of neurodegeneration (Yu et al., 2009). Other studies have used ASOs, targeting SNPs that are tightly linked to CAG expansion in the mutant HTT gene, which successfully and selectively silenced the latter and reduced cognitive and behavioral impairments (Carroll et al., 2011; Southwell et al., 2018).
The fact that ASO technology is so advanced that ASOs can be designed that selectively target a mutant allele with a single base pair difference from the wild-type allele holds great promise for the other autosomal dominant PMEs with dominant negative effects of the mutant allele. However, this approach may be impractical for diseases where ASOs need to be designed for multiple different mutations, and in these cases a combination of a non-allele-specific ASO drug with an enzyme or gene replacement therapy could be an alternative solution. Other RNase H-independent ASO strategies such as translation inhibition or exon skipping could be considered as well (Silva et al., 2020); specifically, proof-of-concept studies using ASOs that cause exon skipping have shown potential for HD (Evers et al., 2014) and SCA3 (Evers et al., 2013).
For some diseases it would be beneficial to upregulate gene expression or promote translation of a certain gene product. One example would be haploinsufficiencies, one type of autosomal dominant diseases where the remaining intact allele is not sufficiently expressed to compensate for loss of function of the other allele. Increasing the gene output could also help in cases where the disease-causing mutation did not result in a complete loss of function (hypomorphic alleles), or where only protein levels and not functionality of the protein are affected. A third example would be to promote expression of another target (not the disease gene) which, once upregulated, helps slowing or preventing disease progression. In sialidosis (caused by NEU1 mutations), such a target would be protective protein cathepsin A (PPCA, encoded by the CTSA gene), the natural chaperone of NEU1. Mutations in CTSA lead to galactosialidosis, involving secondary deficiency of NEU1. Proper folding, lysosomal localization, and catalytic activation of NEU1 depend on PPCA (d’Azzo et al., 2015; Mosca et al., 2020).
Even though ASOs are more commonly known for modulating splicing, promoting RNA degradation, or causing translation arrest, there are ways to increase protein production utilizing ASO technology. Antagonizing microRNAs which otherwise suppress protein production has been shown as one possible mode of action (Esau et al., 2006; Lima et al., 2018; Rotllan et al., 2013). Another possibility to increase levels of therapeutic proteins would be for the ASO to bind to upstream ORFs (uORFs) or other translation inhibitory elements in the 5′ UTR, thereby blocking inhibition of translation initiation and hence promoting translation (Liang et al., 2016, 2017). A third way to upregulate protein levels is to prevent nonproductive alternative splicing (AS) events that induce NMD due to the presence of PTCs in the resulting transcript isoforms (Lim et al., 2020). This approach is called TANGO (Targeted Augmentation of Nuclear Gene Output) and basically utilizes the capability of ASOs to alter splicing in a gene-specific and AS type-dependent fashion.
TANGO has been further tested, and an ASO (STK-001) has been selected and is currently undergoing a phase 1/2 clinical trial for Dravet syndrome (DS) (Han et al., 2020; Hill and Meisler, 2021). Dravet syndrome (OMIM # 607208) is classified as developmental and epileptic encephalopathy (DEE) and involves, very similar to PMEs, severe epilepsy (including myoclonic seizures) resistant to antiepileptic drugs and cognitive decline. In most cases, the disease is caused by mutations in one of the two SCN1A alleles, encoding the type I voltage-gated Na2+ channel Nav1.1, leading to haploinsufficiency (Depienne et al., 2009; Dravet and Oguni, 2013; Holmes, 2020). The steric-block ASO prevents the naturally occurring alternative splicing event, characterized by inclusion of an alternative (poison) exon (part of intron 20; Fig. 56–1G), thereby increasing the levels of productive full-length Scn1a transcripts and Nav1.1 protein in a DS mouse model. In this haploinsufficient DS mouse model, seizures were reduced and sudden unexpected death in epilepsy (SUDEP) prevented for up to 90 days upon ASO treatment (Han et al., 2020).
Interestingly, around 90% of the human genes undergo alternative splicing (McGlincy and Smith, 2008; Wang et al., 2008). This is not just a noise in the splicing process, but it generates distinct protein isoforms that either have different functions or regulate each other post-translationally. Approximately a third of all AS events in humans lead to nonproductive mRNAs, which are part of an important post-transcriptional mechanism (called AS-NMD), that is tightly regulated, to control gene expression (Hillman et al., 2004; McGlincy and Smith, 2008). Lim et al. analyzed 83 publicly available RNA-sequencing datasets from different human tissues and discovered 7757 genes undergoing at least one nonproductive AS event, 1246 of which are potentially disease-associated (Lim et al., 2020). According to these results, a significant number of PME-causing disease genes such as SCARB2 (ULD, AMRF/EPM4), EPM2A (LD), PPT1 (CLN1), TPP1 (CLN2), CLN3 (CLN3), DNAJC5 (CLN4B), CLN5 (CLN5), CLN6 (CLN6), MFSD8 (CLN7), CLN8 (CLN8), CTSD (CLN10), and KCNC1 (MEAK/EPM7), as well as CTSA, which could be beneficial to upregulate in sialidosis as described above, were found to be subjected to at least 1, and up to 13 different, nonproductive AS events. Together, this means there is an opportunity to possibly develop TANGO approaches for specific PMEs.
Approximately 10%–12% of monogenic diseases are caused by nonsense mutations (Bidou et al., 2012; Mort et al., 2008), and there are several PMEs for which nonsense mutations have been described, including LD (Singh and Ganesh, 2009), sialidosis (Pattison et al., 2004), GD (Hruska et al., 2008), AMRF/EPM4 (Balreira et al., 2008), and NCL (Kousi et al., 2012). Interestingly, around 50% of infantile NCL-causing PPT1 mutations are nonsense mutations (Miller et al., 2015), and hence compounds called nonsense suppression or readthrough drugs that override PTCs to enable translation of full-length proteins (Bidou et al., 2012; Dabrowski et al., 2018) could be beneficial for CLN1 patients with these mutations. Readthrough drugs such as ataluren (PTC-124) or gentamicin have been tested in CLN1 patient cell lines (Miller et al., 2013; Sarkar et al., 2011; Sleat et al., 2001) and a CLN1 mouse model that carries the most common nonsense mutation in CLN1 patients (p.R151X) (Miller et al., 2015; Thada et al., 2016). Even though the results showed significant increase in full-length PPT1 protein and PPT1 activity, the overall efficacy of readthrough drugs is limited by NMD (Dabrowski et al., 2018).
NMD not only regulates gene expression through AS-NMD (as explained above) but also serves as a mRNA surveillance mechanism that degrades mRNAs with PTCs, resulting from nonsense mutations, frameshift mutations, deletions, splicing-altering mutations, or nonproductive alternative splicing, to prevent production of aberrant/truncated proteins (Brogna and Wen, 2009). Therefore, it reduces the amount of mRNA that can be targeted by readthrough drugs, and a combination of readthrough drugs with NMD-inhibiting drugs could be promising (Geraets et al., 2016; Keeling and Bedwell, 2011; Nickless et al., 2017). This strategy has been successfully applied in a mouse model of Hurler’s syndrome (Keeling et al., 2013) and in cancer cells (Martin et al., 2014) using NMD-attenuating small molecules. Intriguingly, ASOs can also act as NMD suppressors and improve efficacy of readthrough drugs (Keenan et al., 2019; Nomakuchi et al., 2016). ASOs that target translation termination even had synergistic effects in combination with the readthrough drug geneticin in a mouse model of hemophilia (Huang et al., 2019). A similar approach could be envisioned for PTC-containing pathogenic variants that cause PMEs such as in CLN1 patients (Fig. 56–1H).
In 2015, ASO-based therapeutics were predicted to become the third major pillar of drug development after small molecules and protein therapeutics (Sharma and Watts, 2015). Today, several ASO drugs are approved (Brenner et al., 2020; Kuijper et al., 2021; Xiong et al., 2021) and many are in development and clinical trials for diseases such as Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (Bennett et al., 2017; Brenner et al., 2020; Roberts et al., 2020; Silva et al., 2020). Using ASOs has become a prominent therapeutic strategy for the treatment of genetic diseases, including CNS disorders, and cancer (Brenner et al., 2020; Hill and Meisler, 2021; Schoch and Miller, 2017; Xiong et al., 2021).
One problem that medicine faces when treating CNS disorders is the delivery of the drug to the brain. ASOs, like many drugs, do not cross the blood–brain barrier (BBB) and therefore intrathecal injections into the CSF are necessary to target the brain sufficiently (Brenner et al., 2020; Roberts et al., 2020). Once in the CSF, ASOs distribute broadly and are quite stable (up to months) in the brain (Mazur et al., 2019; Rigo et al., 2014). CNS-specific application is an advantage because adverse effects in other organs due to systemic administration can be circumvented and lower doses are sufficient, which is more cost-effective. On the other hand, untreated tissues may become clinically relevant later in the disease course. Also, repeated lumbar punctures are not only inconvenient but are invasive, and ways to overcome the BBB are being actively investigated and will allow for easier and less invasive dosing in the future.
Another advantage of ASOs is that they are relatively short-lived and elicit limited or no immunogenicity or toxicity, while virus-mediated gene therapy is strongly immunogenic and long-lasting. In case of adverse effects of the ASO drug, the treatment can be stopped, while gene therapy is more permanent (Brenner et al., 2020). On the other hand, longer stability of ASOs could allow for less frequent dosing. Different ASO chemistries and modifications, conjugations, or packaging of ASOs into vehicles such as nanoparticles will help improving ASO stability and bioavailability, and potentially allow for delivery into selective tissues, including BBB crossing (Gagliardi and Ashizawa, 2021; Roberts et al., 2020).
ASO therapy is generally very safe and efficacious and most importantly immensely versatile because of the many different possible modes of action (Fig. 56–1). This allows for truly individualized drug development as seen with milasen for a CLN7 patient (Kim et al., 2019). In this case the precedent of nusinersen’s success made the rapid development of milasen possible. This is certainly a very exciting and encouraging example of today’s precision medicine. As discussed above, there are multiple ways to utilize ASO technology to tackle the genetic defects that cause PMEs. The small number of patients carrying a specific mutation, however, is undoubtedly an obstacle in terms of safety testing and cost. The hope, though, is that ASO strategies will be developed further and that with more experience and additional successes ASO platforms can be established which enable the rapid development of customized therapies, even for extremely rare diseases such as PMEs.
This work was funded by the National Institute of Neurological Disorders and Stroke under award number P01NS097197. Dr. Minassian holds the UT Southwestern Jimmy Elizabeth Westcott Chair in Pediatric Neurology and is Chief Medical Advisor to Taysha Gene Therapies.
This is an open access publication, available online and distributed under the terms of a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International licence (CC BY-NC-ND 4.0), a copy of which is available at https://creativecommons.org/licenses/by-nc-nd/4.0/. Subject to this license, all rights are reserved.
Your browsing activity is empty.
Activity recording is turned off.
See more...
