Rare neurodegenerative diseases are low-prevalent, life-threatening, or chronically debilitating disorders, caused by pathogenic mutations in a single gene or by particular environmental insults (e.g., pesticides, metals, air pollution, endotoxins, and prions, among others), triggering progressive neuronal dysfunction and loss of specific groups of neurons (Matilla-Duenas et al., 2017). Depending on the disease etiology, distinct parts of the central nervous system may be affected, resulting in impaired motor and cognitive function with a significant impact on the quality of life of the affected individuals (Matilla-Duenas et al., 2017). The prevalence threshold defining a disease as rare largely varies between countries, but disorders with a prevalence of five cases or less per 10,000 individuals according to the European Union (EU) are designated as such (Nguengang Wakap et al., 2020). In the last few years, the advances in next-generation sequencing (NGS) have importantly accelerated the identification of disease-causing genes. Indeed, the Online Mendelian Inheritance in Man database (https://omim.org/statistics/geneMap) of July 2021 reports 4473 genes with phenotype-causing mutations resulting in neurological and non-neurological disorders. Despite the advances in next generation sequencing (NGS), data analysis, and other technologies that importantly contribute to identify the mutated genes and understand the biology of rare diseases and their underlying pathogenic mechanisms, the diagnosis, treatment, and availability of therapeutics for these pathologies are still very limited (Fernandez-Marmiesse et al., 2018; Pogue et al., 2018). Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Most of the patients with rare diseases receive treatments intended to alleviate the disease-derived complications and improve their quality of life, but without tackling the underlying disease cause. Indeed, for most rare pathologies, including the neurodegenerative ones, there is no treatment to prevent, delay, or cure the disease (Kaufmann et al., 2018), in particular in children (Raïs Ali and Tubeuf, 2019). There is then an urgent necessity to find therapeutic opportunities to fulfill these unmet needs. Recently, gene therapies were authorized for the treatment of neurodegenerative disorders. This is the case of onasemnogene abeparvovec (Zolgensma^®), which, if administered early in life seems to cure spinal muscular atrophy (Hoy, 2019). However, these technologies, even if very promising, might be very costly and time-consuming in some cases. Because of that, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high investment compared to the low market return that may get from the developed product (Pogue et al., 2018). According to the EU, 10% of orphan drug designations have a neurological indication (Morel et al., 2016). Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases (Pushpakom et al., 2019). In this article, we discuss the scientific, regulatory, and economic aspects of the repurposed drugs proposed for the treatment of rare neurodegenerative disorders using as example the approaches taken for the treatment of Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis, four rare neurodegenerative disorders (Matilla-Duenas et al., 2017). The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation is also discussed.

Drug repurposing or repositioning implies the use of approved drugs or previously evaluated but unapproved active pharmaceutical compounds for the treatment of diseases or conditions different from their original medical indication (Pushpakom et al., 2019; Fetro and Scherman, 2020). In the past, this approach was only based on serendipitous findings in which a drug was found to have an additional on-target or off-target effect that could be eventually exploited for the treatment of other diseases (Ashburn and Thor, 2004). In recent years, the identification of repurposed drug candidates is based on systematic, computational, and/or experimental (patient-centered or drug-centered) approaches based on understanding the underlying pathophysiological disease mechanisms or having a better knowledge on the mechanism of the action of a given drug (Park, 2019; Pushpakom et al., 2019). The different strategies currently used for the identification of new therapeutic indications for existing drugs have been extensively reviewed by Pushpakom et al., 2019.

Compared to “de novo” drug discovery, drug repurposing constitutes a very attractive option to save time and money and reduce the risk of failure. Indeed, while some estimates find that the development of new drugs might take around 13–15 years with an overall investment of around US$ 1.3–3 billion to bring one drug to the market, it has been proposed that drug repurposing might allow to save 5–7 years, reduce the cost to around US$ 300 million per molecule, and the risk of failure from more than 95% for newly-designed drugs to around 45% for a repurposed one (Ashburn and Thor, 2004; Nosengo, 2016; Cha et al., 2018; Wouters et al., 2020). This is because the repurposed drugs have already passed preclinical testing, safety, and pharmacokinetic profiles from early-stage clinical trials, and often their formulation has already been developed (Ashburn and Thor, 2004; Nosengo, 2016; Cha et al., 2018). However, if the route of administration is changed, early phase I clinical trials need to be performed. The regulatory and phase III costs, however, are about the same as for newly developed drugs (Pushpakom et al., 2019). Even if drug repurposing offers very good advantages for the treatment of rare diseases, this approach does not always succeed. Indeed, the risk of late-stage failure is analogous to the one-off newly developed drugs, and sometimes the need for drug reformulations may be as costly as that for de novo drug development (Pushpakom et al., 2019; Fetro and Scherman, 2020).

In many European countries, the “off-label” use of repurposed drugs for rare diseases is relatively common, mostly in pediatric patients. This practice has some negative points; one is related with the liability with respect to the administration of medicinal products, since the marketing authorization holder is responsible for the adverse effects arising from the approved indication but not in the case of off-label use. In addition, the off-label administration of repurposed drugs prevents a proper documentation of their effects and safety. Therefore, it is much more advantageous and safer if the “off-label use” occurs within a clinical protocol as part of the repurposing process that will allow safe patient monitoring and a systematic data collection and analysis. For a good overview about the benefits and risks of the off-label use of repurposed medicinal products along with potential solutions to tackle the last issue, we suggest reading the study by Verbaanderd et al. (2019). According to the EU, the repurposing approval is frequently provided through a much simpler process than an initial marketing authorization. Indeed, a marketing authorization holder can apply for a type II variation of its authorized product for the addition of a new therapeutic indication under the same marketing approval (Verbaanderd et al., 2019). However, this fast procedure is only possible if no changes to the pharmaceutical form, strength, or route of the administration of the medicinal product were made. If alterations in one or more of the latter points are introduced, the marketing authorization of the repurposed drug will be considered an extension of the initial marketing authorization (Verbaanderd et al., 2019). In this case, the approval procedure will be the same as the one for newly designed drugs, and the market access for the new indication will be granted only if regulatory evidence of quality, efficacy, and safety is proven, and if the national criteria for coverage/reimbursement and pricing are satisfied (Fetro and Scherman, 2020). Regulatory approval is normally a requirement for inclusion in clinical guidelines and for reimbursement.

Additionally, even if one may think that repurposed drugs are cheaper (Chong and Sullivan, 2007), several repurposed medicinal products authorized by the European Medicines Agency (EMA) as orphan drugs are, for one reason or another, much more expensive than the original product for which the market price covered the cost for research and development. One example is mexiletine. Its price skyrocketed after receiving the European marketing authorization for the treatment of myotonia in patients with non-dystrophic myotonic disorders by the EMA. Naturally, this is only one example, and it does not imply that all drugs tend to follow the same price evolution. In fact, as described in more detail in the section “Incentives for R&D and new drug development for rare diseases”, there are several examples of drugs with a much cheaper price.

Academic research importantly contributes to the first steps of the discovery of “de novo” or repurposed drugs by elucidating underlying disease mechanisms and identifying therapeutic targets (Stevens et al., 2011). Indeed, a report aiming to evaluate the role of academia on the identification and development of “de novo” or repurposed transformative drugs with groundbreaking effects on patient care pointed to a key role of academic medical centers, often funded by the government and/or by patient associations or foundations, in conceptualizing therapeutic approaches based on preclinical research disease mechanisms, and providing the proof of concept for the utilization of a given molecule for a particular disease (Kesselheim et al., 2015). This study also highlighted the importance of collaborations between academia and pharmaceutical industries to perform the follow-up steps of drug development to ensure further clinical testing and formulation of the newly discovered or repurposed drug (Kesselheim et al., 2015). Besides the individual efforts taken by academic institutions or pharmaceutical companies, public–private collaborative initiatives also exist to promote the discovery of new indications for existing drugs, for example, the Medical Research Council (MRC)–AstraZeneca compound collaboration in United Kingdom (https://mrc.ukri.org/funding/browse/mrc-az-cld/mrc-astrazeneca-centre-for-lead-discovery/mrc-az-centre-for-lead-discovery-cld-faqs/), and “Discovering New Therapeutic Uses for Existing Molecules (New therapeutic uses)” program from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) in the United States (https://ncats.nih.gov/ntu/about). In both models, the MRC or the NIH provide funds to academic scientists to perform research in different disease areas, including rare disorders, and pharmaceutical companies such as AstraZeneca and NIH-industry partners grant access to their compound library, and their state-of-the-art high-throughput screening facilities (Rees et al., 2016). These public–private partnerships combining biological knowledge, financial support, and screening expertise contribute to accelerate the discovery of novel targets in a collaborative setting (Simpson and Reichman, 2014; Reichman and Simpson, 2016).

The Critical Path Institute (C-Path) is a non-profit, public-private partnership organization which has been working closely with experts from the pharmaceutical industry, academia, and the FDA in the context of collaborative approaches, where both sharing of data and expertise take place. Various programs are being conducted under the C-Path which include but are not limited to Critical Path to Therapeutics for Ataxia (CPTA), Huntington’s Disease Regulatory Science Consortium (HD-RSC), Critical Path for Alzheimer’s disease (CPAD), Critical Path for Parkinson’s (CPP), and Friedreich’s Ataxia-Integrated Clinical database (FA-ICD). In 2020, a public–private partnership dedicated to advance drug repurposing – CURE Drug Repurposing Collaboratory (CDRC, https://c-path.org/programs/cdrc) has been initiated by the C-Path and the FDA in collaboration with the NCATS. The goal of this collaborative initiative is to generate a platform where all the real-world clinical outcome data are open-sourced at one place and from which knowledge can be gained to enhance drug repurposing through the identification of lead candidates. Also, the platform will provide information about unmet medical needs for diseases, assistance in regulatory roadmaps, and during clinical trials to identify safe and effective drugs for new indications.

The importance of patient associations and advocacy groups in the development of therapeutic approaches has been recognized in the last years in all disease areas, including rare diseases. These organizations are now considered an integral part in the research process, since they foster collaborations between academia, pharmaceutical companies, and clinicians and act as a link between the patients and the researchers providing useful information about patient’s expectations and needs. They are also actively involved in shaping Consortia’s research agendas and help ensure the feasibility and success of research protocols by assisting with study design and patient recruitment. In addition, besides organizing educational programs, facilitating networking amongst patient groups, and providing patient services, they also raise funds to finance academic research preclinical projects and clinical trials (Merkel et al., 2016). One example is the International Rare Diseases Research Consortium (IRDiRC) which ‘unites national and international governmental and non-profit funding bodies, companies (including pharmaceutical and biotech enterprises), umbrella patient advocacy organizations, and scientific researchers to promote international collaboration and advance rare diseases research worldwide’ (https://irdirc.org/about-us/).

Most individual patient associations or foundations are, in general, part of bigger non-profit patient organizations such as the National Organization for Rare Disorders (Nord) (https://rarediseases.org/), EURORDIS (European Organization for Rare diseases, https://www.eurordis.org) or Findacure https://www.findacure.org.uk/. The Orphanet database (https://www.orpha.net/consor/cgi-bin/index.php) provides compiled information about rare diseases and patients’ organizations registered in Europe.

Concerning rare neurodegenerative diseases, the European Reference Network for Rare Neurological Disorders (ERN-RND) http://www.ern-rnd.eu/, established by the EU supports patients and families affected by rare neurological diseases and facilitates the participation of patients in clinical trials with repurposed medicinal products. The neurodegenerative rare diseases covered by this network include several ataxias and Huntington’s disease.

Cures Within Reach (https://www.cureswithinreach.org) is another philanthropic organization dedicated to fund research projects related with drug, device, and nutraceutical repurposing to provide fast and safe treatments for unmet clinical needs in different common and rare diseases. Healx, the only commercial company with this type of model (https://healx.io/), combines artificial intelligence and collaborates with academic institutions, biotech, pharma, and patient groups to identify and progress novel therapies. Currently, Healx has 18 therapies listed in the pipeline.

Understanding the drivers of pharmaceutical research and development (R&D) is important to foster innovation in the pharmaceutical market. The pharmaceutical industry is responsive to the potential market size: when it increases, the entry of new non-generic drugs and new molecular entities (i.e., those more profitable) also increases (Acemoglu and Linn, 2004). This constitutes an issue in the case of rare diseases. In fact, the interest of pharmaceutical companies in orphan drug development is traditionally low due to the relatively high cost of investment compared to the low market return of the product, precisely because of the small market size (https://www.eurordis.org/IMG/pdf/princeps document-EN.pdf). Given the lack of competition, therapy products for rare diseases have a commercial potential, namely, when their market price is extremely high. For instance, gene therapy onasemnogene abeparvovec (Zolgensma^®) has a market price of more than €2m. The justification for setting a high market price is the high costs of R&D, manufacturing and distribution, and the small market size. But by setting such a high price, potentially lifesaving therapies are prohibitive for most patients and, in practice, patients cannot have access to these medicinal products (Fischer et al., 2019).

Nevertheless, the price of drugs to treat rare diseases varies considerably. If we consider the case of repurposed drugs for Huntington’s disease currently available in Belgium, the average price is €1,280, with the cheapest drug listing a public price of €11,09 and the most expensive one listing a price equal to €4,982.

Verifying the veracity of high development costs is generally difficult. As a matter of fact, it is challenging to estimate the costs of drug development, namely, because pharmaceutical companies do not generally make the costs of drug development publicly available. Nevertheless, Dimasi et al., 2016 found that it can be more than $2b, while Wouters et al., (2020) estimated a mean of approximately $1.3b, with the latter including a large sample of orphan drugs. Jayasundara et al., (2019) found a higher clinical cost of drug development for non-orphan drugs with respect to orphan drugs. Despite the evidence of lower costs for developing orphan drugs, there is a lack of drugs to treat rare diseases.

Additionally, pharmaceutical companies might take into consideration potential competition from drugs previously adopted in the market with the same active ingredient but approved for other authorized indication or patient groups. In this situation, the drug might have a lower price or can even face competition from a generic drug. Therefore, companies could be discouraged from trying to repurpose the drug as they would pay for the research and development, while the company which has the older product in the market would take the profits. In order to quantify the extent to which this situation impacts the decision of pharmaceutical companies to try to repurpose drugs, one would need to know how many of the repurposed drugs actually have a generic competitor, for how long, and how many patients would be treated by the older drug in order to estimate potential foregone profits. In the examples considered in this article, this is almost never the case. Due to the recognition of a need to foster the development of medicinal products to treat rare diseases, different economic and regulatory incentives have been provided to the sponsors of orphan products worldwide. The first specific regulation, the Orphan Drug Act (ODA), was approved by the US in 1983, and its incentives include 1) 7 years of market exclusivity to sponsors of approved orphan products; 2) tax credits; and 3) research grants. In Europe, the regulation on orphan medicinal products (Regulation (EC) No 141/2000) provides different incentives to sponsors, such as a) scientific advice on study protocols provided by the EMA (protocol assistance); b) 10 years of market exclusivity, which can be extended by 2 years for pediatric investigation; and c) reduced fees for regulatory activities. These incentives have attracted small and medium enterprises (SMEs), academia, pharmaceutical companies, public–private partnerships, and patient advocacy groups to work in rare diseases.

In spite of these incentives, according to the EU in 2020, there were over 2,380 medicines with orphan designation but, as of August 2021, only a few more than 200 drugs had marketing authorization (https://www.ema.europa.eu/en/documents/report/annual-report-use-special-contribution-orphan-medicinal-products-2020_en.pdf). Therefore, rare diseases are still underserved in terms of drug development in comparison with non-rare diseases. Considering the need of addressing unmet needs of rare diseases’ patients, the European Commission launched an initiative which aims at revising the legislation to incentivize the development of medicines for rare diseases and children (Commission, 2021). The objective is to provide solutions to possible shortcomings of the current legislation and take into account the exclusive role of member states in crucial areas such as pricing and reimbursement of medicines. This will also be addressed within the Pharmaceutical Strategy for Europe, which has a broader set of objectives, including fostering healthcare and pharmaceutical innovation (Commission, 2020). The low number of orphan drugs authorized with respect to the large number of orphan designations is explained by the high investment needed for new drug development, and the long duration of the process that is accompanied by the regulatory hurdles and organizational issues faced while performing clinical trials in rare diseases (Ashburn and Thor, 2004; Wastfelt et al., 2006). Indeed, despite the availability of original safety data on the previous approved indication, to receive marketing authorization, the repurposed drugs need to be tested for their efficacy, safety, and tolerability in clinical trials. These clinical studies conducted to provide the benefit/risk data are expensive and complex due to the frequent complexity of the diseases, the low number of patients affected, and their wide geographical distribution (Ashburn and Thor, 2004; Wastfelt et al., 2006). Additionally, within rare diseases, pharmaceutical companies tend to target more profitable areas. In fact, R&D is higher for diseases with an older average age at death (i.e., in adulthood instead of infancy or childhood), which provides additional evidence that R&D is concentrated in more profitable areas; and in rare diseases in high-prevalence categories, which corroborates evidence that market share is a driver of R&D (Raïs Ali and Tubeuf, 2019).

Traditionally, the business model of leading pharmaceutical companies consisted in in-house drug development, from R&D until commercialization, and a general focus on blockbuster drugs. However, this is changing for several reasons, such as rising development costs, competition from generics, and end of patents of some blockbuster drugs (Phillips, 2013). The industry is facing an increasing productivity gap because the cost per new drug is growing while the number of new drug introductions is not accompanying this increase (Grabowski, 2004).

Drug repurposing, namely, for rare diseases can be an interesting business for pharmaceutical companies and has been considered a possible response to the productivity gap (Boguski et al., 2009). In the last 20–25 years, a number of companies and non-profit organizations devoted to drug repurposing have emerged, with a reduced number of failures (Naylor et al., 2015). Meanwhile, some of these companies were acquired by larger ones, and some leading pharmaceutical companies have created departments devoted to repurposing (Sleigh S. H. and Barton C. L., 2010). More recently, several drugs repositioned for COVID-19 are being considered, which has increased the interest in drug repurposing.

As mentioned before, from a business perspective, drug repurposing in rare diseases can be attractive, namely, because of its reduced costs compared to de novo drug development, potentially diminished risk of failure, reduced time required for approval, and higher pricing. However, a significant proportion of rare diseases affect children, which represents a challenge since in most cases the clinical trials conducted for the drugs to be repurposed only included adults. Despite drug repurposing being a viable strategy to find treatments for some rare diseases, new business models are needed to foster this approach. This includes collaborative strategies combining the strength of different agents, such as pharmaceutical and biotechnology companies, venture capitalists, and academia (Pushpakom et al., 2019). Cha et al. (2018) identified three key players in the market, each one with a different business model: academia/research institutes, repurposing technology companies, and pharmaceutical companies. The former, that usually sponsors a significant proportion of phase I and phase II trials for repurposed drugs, faces lower economic or commercial constraints while being more dependent on public funding. The repurposing technology companies are bound by their business model, which includes consulting services, offering drugs databases, and drug pipelines (Sleigh SH. and Barton CL., 2010; Sleigh S. H. and Barton C. L., 2010; Naylor et al., 2015). Some of these companies collaborate with leading pharmaceutical companies. Pharmaceutical companies have a more prominent role in drug discovery and development and tend to be profit seekers. A few might have some ethical concerns or embrace, for example, corporate social responsibility. Overall, there is no unique or widely adopted business model used by pharmaceutical companies for drug repurposing, but three business models frequently used have been identified (Naylor et al., 2015): the in-house model, in which the pharmaceutical companies have their own department or resources devoted to drug repurposing (this model has already been abandoned by some companies); the out-licensing model, in which pharmaceutical companies provide access to their compounds on an out-licensing basis (this limits exposure to risk and additional costs for the corresponding compound); and the extended profiling model, in which a drug candidate starts being evaluated for new indications immediately after a successful first-in-human study.

The HTT gene encodes for a large 350-kDa protein, also called HTT, which is ubiquitously expressed but enriched in the brain (Aronin et al., 1995; Trottier et al., 1995). The normal function of HTT is currently unknown. HTT is folded in a super helical structure containing a hydrophobic core. In the mutated HTT (mHTT), the CAG expansion results in a polyglutamine (polyQ) tract starting in residue 18 of the polypeptide. This expanded polyQ region may be proteolytically cleaved, and it has been proposed that the mHTT fragments generated may induce neurodegeneration (Halliday et al., 1998; Barbaro et al., 2015; Ghosh and Tabrizi, 2018). In addition, it was shown that the mHTT protein is highly aggregation-prone, resulting in intranuclear and intracytoplasmic inclusions throughout the brain (Difiglia et al., 1997). Many studies report that mHTT aggregates can be either toxic or protective depending on the disease stage, their subcellular localization, and their association with other partners or organelles (Saudou et al., 1998; Slow et al., 2003; Slow et al., 2005; Leitman et al., 2013). When present in the nucleus, these aggregates sequester transcription factors resulting in gene expression alterations (Labbadia and Morimoto, 2013), while when present in the cytosol, they may bind to diverse proteins resulting in an altered autophagy-lysosome pathway, reduced protein translation, synaptic dysfunction, reduced axonal transport, mitochondrial toxicity, and energy imbalance among others (Labbadia and Morimoto, 2013; McColgan and Tabrizi, 2018) (Figure 1). There is currently no treatment to prevent or delay the progression of HD; however, some pharmaceutical and non-pharmaceutical interventions (physiotherapists, psychologists, and social workers) aiming to relieve the multiple symptomatic manifestations of the disease are beneficial for some patients and contribute to improve their quality of life (Frank, 2014). Within the pharmaceutical approaches, some neuroleptics with anti-dopaminergic activity or acting as selective serotonin reuptake inhibitors (SSRIs) may be used in the management of psychosis-associated symptoms in HD-like anxiety, depression, and irritability (Mittal and Eddy, 2013; Unti et al., 2017).

Tetrabenazine (Xenazine^®), originally indicated as an anti-psychotic drug, is a repurposed molecule approved in 2008 by the U.S. Food and Drug Administration (FDA) for the treatment of chorea in HD (Jankovic and Clarence-Smith, 2011). This authorization was based on the positive results of four controlled clinical trials performed in the United States with HD patients (Huntington Study, 2006; Frank et al., 2008; Frank, 2009). Tetrabenazine is a reversible vesicular monoamine transporter 2 (VMAT2) inhibitor which blocks the uptake of cytosolic monoamines and prevents dopamine release from synaptic vesicles (Login et al., 1982). An extensive review on the mechanism of action, pharmacodynamics, pharmacokinetics, and metabolism of this drug can be found in the study by Jankovic and Clarence-Smith, (2011). Following the positive results from a randomized double-blind, placebo-controlled trial, in April 2017, the FDA also approved AUSTEDO (deutetrabenazine), another molecule with VMAT2 inhibitor activity, to treat chorea in HD (Huntington Study et al., 2016).

Some repurposed medicinal products have received the orphan designation by the EMA for the treatment of Huntington’s disease but have not been authorized yet: for example, cysteamine bitartrate (https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3141306) and lithium citrate tetrahydrate (https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu309706). In the EU, cysteamine bitartrate is used under the name of Cystagon^® and Procysbi^® for the treatment of nephropathic cystinosis. In HD, this drug was shown to be neuroprotective in several mouse models by improving weight loss and motor abnormalities and prolonging animal survival. It has been proposed that the drug may reduce nerve damage and improve motor function by blocking the activity of the enzyme transglutaminase, shown to be increased in HD patients and involved in nerve injury, by increasing the secretion of the brain-derived neurotrophic factor (BDNF) that improves neuron survival and function, and by other still unidentified mechanisms (Dedeoglu et al., 2002; Karpuj et al., 2002; Van Raamsdonk et al., 2005; Bailey and Johnson, 2006; Borrell-Pages et al., 2006; Arbez et al., 2019). A randomized, double-blind, placebo-controlled trial with cysteamine bitartrate showed that the drug is safe and well tolerated by HD patients, but failed to demonstrate efficacy in the full-patient cohort (Verny et al., 2017). A post hoc analysis in which patients were stratified by disease severity based on their initial motor scores suggested that the drug reduced the progression of the disease in patients with the most severe motor impairment. Further clinical studies are needed to prove the efficacy of the drug. Lithium is an inhibitor of glycogen synthase kinase-3 and inositol monophosphatase that have been used as mood stabilizers for several decades (Yatham et al., 2018). Recent studies performed in several preclinical HD models suggest that this molecule is able to increase the clearance of intracellular protein aggregates, to confer neuroprotection, and to improve motor dysfunction and coordination (Scheuing et al., 2014). Several blind and unblind clinical studies using lithium for short periods of time in HD patients showed improvement in choreatic movements, motor function, and mood stabilization in some but not all patients (Anden et al., 1973; Dalen, 1973; Mattsson, 1973; Aminoff and Marshall, 1974; Danivas et al., 2013; Raja et al., 2013). Further blinded trials with larger patient cohorts are needed to determine the effectiveness of this drug. Table 1 provides further information about the aforementioned drugs, including pharmaceutical companies or academic institutions involved in designing and running the clinical trials, whether the drugs received orphan designation from the EMA and/or the FDA, and the sponsors that made the orphan designation request.

Additional new and repurposed drugs that received orphan designation for HD but are not yet approved for its treatment can be found in the Orphanet portal (https://www.orpha.net/consor/cgi-bin/index.php).

Without being an exhaustive list, here we will provide some examples of current drug repurposing–based approaches for HD at different stages of development (Table 1). A detailed review about all ongoing “de novo” or repurposing-based strategies for HD treatment can be found in the study by Caron et al., (2018).

As mentioned above, mHTT aggregates may compromise autophagic clearance by perturbing cargo recognition and autophagosome motility which results in cell death (Martinez-Vicente et al., 2010; Zatyka et al., 2020). In fly and mouse models of HD, rapamycin-mediated mTOR inhibition enhanced the autophagic flux and clearance of unfolded mHTT resulting in reduced toxicity (Ravikumar et al., 2002; Ravikumar et al., 2004; Sarkar et al., 2005; Sarkar et al., 2007a; Sarkar et al., 2007b). Since rapamycin has numerous side effects, Williams et al. (2008) screened a library of FDA-approved drugs looking for autophagic enhancers with mTOR-independent activity. This screening identified clonidine, verapamil, loperamide, nimodipine, and minoxidil among others as drugs with autophagic enhancing activity. In vitro assays showed that all of them were able to reduce mHTT aggregation and toxicity in neuroblastoma cells (Williams et al., 2008). The authors also showed that calpain inhibition reduced mHTT aggregation and toxicity. Similarly, the antihypertensive drug (L-type calcium channel blocker) felodipine was shown to induce autophagy and clear mHTT in a mouse model of HD (Siddiqi et al., 2019).

Abnormal immune activation and inflammatory processes resulting from the central nervous system (CNS) and peripheral immune cell dysfunction have also been highlighted as important contributors to the pathophysiology of HD (Bjorkqvist et al., 2008). Laquinimod is an immunomodulatory drug developed for the treatment of multiple sclerosis. In the context of HD, it was shown that in vitro, this molecule reduces apoptosis in primary neurons derived from YAC128 mice, a HD model (Garcia-Miralles et al., 2016). Moreover, chronic laquinimod administration in these animals improved white matter integrity, motor and psychiatric phenotypes, and reduced IL-6 serum levels (Garcia-Miralles et al., 2016). A 12-month phase II clinical trial for HD with this molecule showed no effect on the motor score but revealed a significant reduction in caudate atrophy that was more evident in patients with early HD (Caron et al., 2018), pointing to a promising role of immunomodulators for the treatment of HD. Further clinical studies are required to support the neuroprotective effect of all these drugs in HD patients.

Cures Within Reach is currently funding two clinical trials in HD with repurposed drugs. One of them, led by Dr. Anderson from the Georgetown University, will study the safety and tolerability of nilotinib, a FDA-approved cancer drug for the treatment of chronic myeloid leukemia, in 10 HD patients with early-to-moderate HD. Based on previous findings from clinical trials with nilotinib in Parkinson’s disease (Pagan et al., 2016; Pagan et al., 2020; Pagan et al., 2021) they hypothesize that this drug may contribute to reduce the accumulation of toxic mHTT and have protective brain effects in HD. The second trial is led by Dr. Furr-Stimming from the University of Texas and aims to study the safety and tolerability of Neudexta, a drug currently used for the treatment of the pseudobulbar effect. This drug was shown to importantly ameliorate agitation in patients with Alzheimer’s disease (Cummings et al., 2015). Based on that, it was hypothesized that it may be useful to treat irritability in HD.

The International Huntington’s Disease Association http://huntington-disease.org/is a multinational federation created in 1979 that resembles 32 different Huntington’s disease societies from all over the world. The member societies promote medical professional education; provide individual and family support; and fund psychosocial, clinical, and biomedical research related with Huntington’s disease in their respective countries.

In addition, the Huntington’s disease coalition for the patient engagement (HD-COPE) is a global Huntington’s disease patient advocacy organization working in collaboration with the European Huntington’s Association (EHA), Huntington’s Disease Society of America (HDSA), and Huntington’s Society of Canada (HSC) formed in September 2017 to give patients’ voice in the clinical trials (https://hdsa.org/news/global-huntingtons-disease-patient-advocacy-organizations-unite-to-form-huntingtons-disease-coalition-for-patient-engagement-hd-cope/).

FXN encodes for a 210-amino acid mitochondrial protein called frataxin that regulates iron homeostasis by modulating iron storage, iron–sulfur cluster (Fe–S), and heme biosynthesis and iron carriage (Adamec et al., 2000; Emond et al., 2000; Schulz et al., 2000; Adinolfi et al., 2002; Becker et al., 2002; Gerber et al., 2003; Yoon and Cowan, 2003; 2004; Adinolfi et al., 2009; Paupe et al., 2009; Condo et al., 2010; Tsai and Barondeau, 2010). Accordingly, it was shown that reduced frataxin expression results in impaired function and/or expression of FeS-containing enzymes, such as catalase, and several respiratory chain proteins resulting in iron accumulation in the mitochondrial matrix, mitochondrial dysfunction, and oxidative stress (Babcock et al., 1997; Rotig et al., 1997; Puccio et al., 2001). In several FRDA models, frataxin deficiency has been associated with reduced NRF2 (nuclear factor (erythroid-derived 2) 2–like transcription factor) levels (Paupe et al., 2009; D’oria et al., 2013; Shan et al., 2013). NRF2 exhibits antioxidant properties by regulating the expression of antioxidant and cytoprotective genes (Kim et al., 2001). It also reduces inflammation, improves mitochondrial function, and maintains protein homeostasis (Dinkova-Kostova et al., 2018). Therefore, reduced NRF2 expression or activity importantly contributes to frataxin deficiency–induced cytotoxicity in FRDA (Figure 2). There is currently no approved therapy to prevent, delay, or revert the manifestations of the disease; however, the beneficial effect of many molecules targeting different aspects of the FRDA pathophysiology has been tested or is currently under study. In the beginning, the therapeutic approaches for FRDA were mostly focused on treating the downstream effects of frataxin deficiency, namely, improving iron homeostasis and mitochondrial function or reducing oxidative stress. In recent years, many of the approaches under study are centered on the upregulation of frataxin protein expression to restore frataxin levels. Indeed, increasing frataxin protein expression in FRDA patients to the levels found in carrier individuals that are asymptomatic is expected to provide a cure for the disease and stabilize disease progression. Compiling expert information on previous and current research studies for the treatment of FRDA can be found in the study by Clay et al., (2019).

The Friedreich’s Ataxia Research Alliance (FARA, https://www.curefa.org) is a non-profit, voluntary organization that partners with government agencies, corporations, and advocacy groups to support scientific research focused on the development of therapeutic strategies to stop the advancement of or cure FRDA.

The WFS1 gene encodes an endoplasmic reticulum (ER) transmembrane protein called wolframin or WFS1 that is highly expressed in the brain, pancreas, heart, lungs, liver, and kidneys (Yamada et al., 2006). The ER is an essential organelle for secretory cells, such as pancreatic β-cells and neurons, since most secretory proteins are synthesized, folded, and modified within the ER before being transported into the Golgi for secretion (Schwarz and Blower, 2016). It has been demonstrated that WFS1 deficiency causes ER stress in pancreatic β-cells, neurons, retinal ganglion cells, and oligodendrocytes, resulting in dysfunction and degeneration of the affected tissues (Ishihara et al., 2004; Fonseca et al., 2005; Riggs et al., 2005; Fonseca et al., 2010; Fonseca et al., 2011; Fischer and Ehrlich, 2020). WFS1 regulates ER calcium homeostasis and ER stress by interacting with the sarcoplasmic ER calcium (SERCA) pump and the ER stress transducer ATF6, respectively (Fonseca et al., 2005; Zatyka et al., 2008; Fonseca et al., 2009; Fonseca et al., 2010; Fonseca et al., 2011; Hatanaka et al., 2011; Lu et al., 2014; Zatyka et al., 2015). Accordingly, WFS1-deficiency results in ER calcium depletion, enhanced cytosolic Ca²⁺, calpain activation, and cell death (Lu et al., 2014). Moreover, it was also demonstrated that WFS1 regulates secretory granule acidification in β-cells and neurons (Gharanei et al., 2013; Sutt et al., 2015) and that the ER dysfunction caused by WFS1 deficiency is accompanied by altered mitochondrial function in β-cells and neurons contributing to diabetes and neurodegeneration (Cagalinec et al., 2016; Maxwell et al., 2020). Using a rat model of the disease, it was recently demonstrated that the lack of functional WFS1 alters calcium homeostasis in cardiac myocytes as a result of reduced expression of the plasmalemmal sodium–calcium exchanger type 1 (NCX1) (Kurekova et al., 2020).

Regarding Wolfram syndrome 2, the CISD2 gene encodes a highly conserved zinc finger Fe–S cluster containing a protein called CISD2 or Miner1. This protein is localized in the ER and in the mitochondrial-associated membranes (MAMs) (Amr et al., 2007). Its function is still unknown, but it has been proposed that it plays an important role in iron donation to the mitochondria, regulation of oxidative stress, and preservation of mitochondrial and ER Ca²⁺ homeostasis (Wiley et al., 2013; Wang et al., 2014). CISD2 deficiency alters the Ca²⁺ flux between the ER and the mitochondria resulting in mitochondrial dysfunction and reduced mitochondrial integrity, that is accompanied by an upregulation of autophagy and pro-apoptotic factors (Chen et al., 2009; Sohn et al., 2013; Danielpur et al., 2016; Holt et al., 2016). Despite the exact mechanism not being known, preclinical experiments in several Wolfram syndrome 2 cases showed that CISD2 deficiency leads to neuronal and β-cell death, a process probably mediated by calpain activation (Lu et al., 2014) (Figure 3).

There are currently no approved therapeutic options to prevent, delay, or cure Wolfram syndrome, but numerous drug repurposing–based approaches are currently under investigation to manage the clinical manifestations of the disease. Since ER stress is deleterious for pancreatic β-cells and neurons, and is a hallmark of Wolfram syndrome, it has been proposed that reducing ER stress may have beneficial outcomes in this life-threatening disease. Accordingly, different ER stress–targeting approaches are being tested, for example, ER calcium stabilizers, chemical chaperones, GLP-1 analogs, and modulators of ER stress (Urano, 2016; Abreu et al., 2021; Pallotta et al., 2019).

As mentioned above, there are currently no approved drugs for the treatment of Wolfram syndrome; however, two repurposed medical compounds, namely, dantrolene sodium and sodium valproate received orphan designation for this disease (https://www.orpha.net).

Dantrolene sodium was initially approved by the FDA for malignant hyperthermia and muscle spasms derived from spinal cord injury, stroke, cerebral palsy, or multiple sclerosis. This drug acts as an ER calcium stabilizer by inhibiting ryanodine receptors on the ER (Fruen et al., 1997). In the context of Wolfram syndrome, preclinical studies using different models of the disease showed that dantrolene is able to suppress β-cell and neuronal death by preventing calcium leakage from the ER (Lu et al., 2014). This drug received orphan designation for Wolfram syndrome from EMA and the FDA. An open-label, phase Ib/IIa trial in pediatric and adult Wolfram syndrome patients with dantrolene sodium was recently performed (Abreu et al., 2021). The primary objective of the study was to assess the safety and tolerability of the molecule, and the secondary objectives were to evaluate the efficacy of the treatment in improving residual pancreatic β-cell function, visual acuity, quality of life, and measures related to vision and neurological functions. The study showed that dantrolene sodium is well tolerated by Wolfram syndrome patients, but β-cell function, visual acuity, and neurological functions were not significantly improved after 6 months of treatment (Abreu et al., 2021). However, a patient subgroup analysis revealed a significant improvement in β-cell function in subjects who possessed the greatest degree of β-cell function at the baseline. Moreover, the inflammation markers IL-1β and IL-21, that are increased in Wolfram syndrome patients as a result of ER stress (Oslowski et al., 2012), were significantly decreased in dantrolene-treated subjects (Abreu et al., 2021). These results suggest that this molecule may be beneficial in treating certain manifestations of the disease and justifies further investigation in using dantrolene sodium and other small molecules targeting the ER for the treatment of Wolfram syndrome.

Sodium valproate is a drug indicated to treat different neuropsychiatric disorders, such as epilepsy, bipolar disorder, and migraine. This molecule exerts its beneficial effects through multiple mechanisms of action (Johannessen and Johannessen, 2003; Rosenberg, 2007). In the context of Wolfram syndrome, sodium valproate was shown to increase WFS1 mRNA expression in neuronal cells by activating its promoter. Moreover, this drug was shown to enhance the dissociation of WFS1 from GRP94, suggesting that it may have ER stress–modulating effects (Kakiuchi et al., 2009). A recent study showed that sodium valproate also reduces ER stress and cell apoptosis in Wolfram syndrome 1 models caused by dominant WFS1 mutations (Batjargal et al., 2020). This drug received orphan designation for Wolfram syndrome from the EMA and the FDA. A phase II, placebo-controlled clinical trial with 70 pediatric and adult Wolfram syndrome patients has been launched (Trial Number: NCT03717909, https://clinicaltrials.gov/ct2/show/study/NCT03717909). The aim of this study is to assess the efficacy, safety, and tolerability of sodium valproate in the treatment of Wolfram syndrome patients. The primary outcome of this trial is visual acuity, and the secondary outcomes are safety, tolerability, and neurological outcomes.

Table 3 provides additional information about the aforementioned drugs, including pharmaceutical companies or academic institutions involved in designing and running the clinical trials, and whether the drugs received orphan designation from the EMA and/or the FDA, and the sponsors that made the orphan designation request.

GLP-1 analogs also appear as a promising therapeutic opportunity for Wolfram syndrome (Table 3). As mentioned before, these molecules are used for the treatment of type 2 diabetes and were shown to alleviate ER stress (Cunha et al., 2009; Drucker, 2018) and enhance the expression of anti-apoptotic proteins (Yusta et al., 2006; Cunha et al., 2009). Moreover, some of them cross the blood–brain barrier and confer neuroprotection (Holst et al., 2011; Hunter and Holscher, 2012; Porter et al., 2013; Zhang et al., 2018). In addition, it was shown that topical administration of GLP-1 analogs prevents retinal neurodegeneration, suggesting that these molecules may be useful to treat diabetes, neurodegeneration, and blindness in Wolfram syndrome (Hernandez et al., 2016; Hernandez et al., 2017). Accordingly, it was shown that acute exenatide injection in a mouse model of the disease enhances insulin secretion (Sedman et al., 2016) and that prolonged exenatide and liraglutide administration in WFS1-deficient mice and rats prevent glucose intolerance and improve glucose-stimulated insulin secretion by reducing cellular stress (Kondo et al., 2018; Toots et al., 2018). Additionally, a follow-up study performed with WFS1-deficient rats showed that the 6-month liraglutide treatment in these animals reduced neuroinflammation and improved ER stress in the inferior olive (Seppa et al., 2019). Moreover, this drug protected retinal ganglion cells from cell death and optic nerve axons from degeneration, suggesting that GLP-1 analogs may, indeed, be beneficial in preventing neurodegeneration and vision loss (Seppa et al., 2019). GLP-1 agonist treatment significantly improved the glycemic control in a patient with a dominant form of Wolfram syndrome, suggesting that treatment with these drugs should also be considered in patients with dominant forms of Wolfram syndrome (Scully and Wolfsdorf, 2020).

Exenatide was shown to also be beneficial in Wolfram syndrome 2. Indeed, in a β-cell model of the disease, these drugs improved glucose-stimulated insulin secretion, reduced the accumulation of labile iron in the mitochondria, and alleviated oxidative stress. Moreover, exenatide administration in one Wolfram syndrome 2 patient resulted in a 70% reduction in daily insulin requirements, improved glycemic control, and 7-fold increase in maximal insulin secretion (Danielpur et al., 2016). Altogether, these results provide evidence of the important therapeutic potential of these drugs in Wolfram syndrome. Accordingly, a clinical trial with exenatide in Wolfram syndrome 2 (Trial Number: NCT010302327) was launched, and a second one with liraglutide (Victoza^®) in Wolfram syndrome 1 patients has recently been announced by Washington University with the help of the Snow Foundation (https://thesnowfoundation.org/trial-of-liraglutide-in-wolfram-syndrome/). If these drugs are shown to slowdown or revert some of the clinical manifestations of the pathology, it will constitute a great advancement in the management of this life-threatening orphan disease.

Many Wolfram syndrome patient associations exist that importantly contribute to fund preclinical and clinical research projects focused on the development of therapeutic opportunities for the disease. The Wolfram Syndrome Research Alliance (WSRA) (https://www.wsresearchalliance.org/foundations-supporting-ws-research.html) serves as a centralized portal to connect and coordinate the efforts of researchers, clinicians, and governmental and non-profit agencies to accelerate the development of effective treatments. This portal also provides the full list of existing Wolfram syndrome patient associations, the research groups currently working on the disease, and a pipeline of the potential therapies under study. Accordingly, different studies based on Wolfram Syndrome are funded by various patient advocacy groups. As mentioned in some examples, the clinical trial of sodium valproate (NCT03717909) initiated in October 2018, is supported by Wolfram Syndrome United Kingdom https://www.findacure.org.uk/drug-repurposing and United Kingdom Research and Innovation (UKRI) https://gtr.ukri.org/projects?ref=MR%2FP007732%2F1, the trial with dantrolene sodium, has been funded by the Snow Foundation and the Ellie White Foundation, and the Liraglutide trial (Victoza) in the United States is currently supported by the Snow Foundation https://thesnowfoundation.org/clinical-trials. The Eye Hope foundation http://www.eyehopefoundation.org/en and the Alianza de Familias Afectadas por el syndrome de wolfram https://afasw.com/have been funding research projects related with the repurposing of GLP-1 analogs for the treatment of Wolfram syndrome among others. The Association Syndrome de Wolfram (https://www.association-du-syndrome-de-wolfram.org/) organizes a family day so that families can get together and share their experiences in coping with the disease. This also provides a way for obtaining mutual support. Additionally, researchers, doctors, and psychologists are invited to provide useful information, namely, about new research and clinical trials.

The pathophysiological mechanisms of the disease are not well understood; however, it is known that aggregation and accumulation of ubiquitylated protein inclusions in the cytosol of motor neurons are a neuropathological hallmark of ALS (Hardiman et al., 2017). Interestingly, in around 97% of ALS patients, these aggregates are constituted of TDP43 protein (even in the absence of TARDBP mutations). In some more rare cases, these protein aggregates are constituted of other mutated proteins, such as SOD1. Despite the protein aggregates being the hallmark of ALS, it has been proposed that the high–molecular weight protein complexes (that are present before the aggregate formation) might, in fact, be the real mediators of cell toxicity (Ross and Poirier, 2005).

Multiple factors may contribute to neuronal damage in ALS. Indeed, a large number of cellular alterations have been detected which, in most cases, are the consequence of the identified mutations. Briefly, impaired protein homeostasis and altered autophagy, aberrant RNA metabolism, increased oxidative stress, mitochondrial dysfunction, impaired DNA repair, dysregulated endosomal and vesicle transport, neuroinflammation, glial dysfunction, axonopathy, hyperexcitability, and oligodendrocyte degeneration are the main cellular disturbances detected in ALS (Rowland and Shneider, 2001; Hardiman et al., 2017; Mejzini et al., 2019) (Figure 4). For a detailed description of these mechanisms and their associated genes, refer to the articles by Hardiman et al. (2017) and Mejzini et al. (2019).

Currently two orphan-designated drugs received marketing authorization for the treatment of ALS. The first one, riluzole, received this authorization in the United States and Europe, while the second, edaravone, was only authorized by the FDA since the marketing authorization request to the EMA was withdrawn by the developing company in May 2019 (https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-withdrawal-marketing-authorisation-application-radicava-edaravone_fr.pdf). Riluzole is not a repurposed drug but an anti-glutamatergic compound, specifically developed for the treatment of ALS. It is shown to slow muscle strength deterioration in ALS patients and prolong their survival (Bensimon et al., 1994; Lacomblez et al., 1996a; Lacomblez et al., 1996b; Bensimon et al., 2002).

On the other hand, edaravone is a free radical scavenger that lowers neuronal damage and was initially approved in Japan for the treatment of acute cerebral infarction (Edaravone Acute Infarction Study, 2003). Administration of this molecule soon after the onset of the symptoms improved motor function and decreased SOD1 deposition in rodent ALS models (Ito et al., 2008; Aoki et al., 2011). In a phase II clinical trial with ALS patients, edaravone was relatively safe and well tolerated, and slowed the progression in motor dysfunction (Yoshino and Kimura, 2006). An initial phase III trial, however, failed to demonstrate the efficacy of edaravone to delay the disease progression (Abe et al., 2014). Nevertheless, a post hoc analysis of this trial showed that patients with early symptoms were more prone to respond to the treatment (Takei et al., 2017). Based on these results, an additional phase III clinical trial was performed in which the recruitment criteria were modified in order to work with a more clinically homogeneous patient population who were more likely to respond to the treatment (Writing and Edaravone, 2017). In this study, edaravone was shown to be effective in slowing down the decline in motor function in ALS individuals, fulfilling the criteria identified in the post hoc analysis of the previous phase III study, but not in a wider ALS population, who did not meet this criterion (Writing and Edaravone, 2017). Since all these clinical studies were performed in Japan, and the ALS genetics may vary between populations (Hardiman et al., 2017; Mejzini et al., 2019), further studies are needed to confirm the extrapolability of these findings to other ethnicities. Interestingly, a recent analysis of post-marketing clinical outcomes of edaravone in different countries showed that the drug induced a moderate reduction in disease progression in Kuwait and Korea, while no beneficial effects were reported in Italy and Israel (Ortiz et al., 2020). Further post-marketing reports on the clinical outcomes of edaravone administration are still needed to get a better view of the effectiveness of this drug. Despite riluzole and edaravone being available for the treatment of some ALS patients, there is currently no therapy that can benefit all of them. Therefore, further disease-modifying treatments are needed to handle this life-threatening disease.

Accordingly, because of preclinical and clinical research efforts, more than 30 additional repurposed and non-repurposed substances have received orphan designation for ALS without being yet authorized (https://www.orpha.net/consor/cgi-bin/index.php). Arimoclomol and ambroxol are only two examples of orphan-designated repurposed drugs.

Arimoclomol is a drug originally developed for the treatment of diabetic neuropathy and insulin resistance (Kurthy et al., 2002). This compound is a hydroxylamine derivative that works as a heat shock protein (Hsp) co-inducer in conditions of cellular stress (Hargitai et al., 2003). Treatment with this molecule results in the upregulation of several Hsps, including Hsp60, HsP70, Hsp90, and Grp94 (Vigh et al., 1997). Modulation of the Hsp response was shown to be beneficial for diseases associated with protein aggregation since it reduces the protein aggregation itself and diminishes cellular stress and apoptosis (Kalmar et al., 2005; Kalmar et al., 2014). Related with ALS, arimoclomol was shown to improve limb strength, neuron survival, and life span of SOD1^G93A mice, a fALS model, while reducing the abundance of ubiquitin-positive aggregates in the motor neurons (Kieran et al., 2004; Kalmar et al., 2008). In addition, arimoclomol was shown to be safe and well tolerated in a double-blind, placebo-controlled trial performed with rapidly progressive SOD1-mutant ALS patients (Benatar et al., 2018). This initial study also suggested that the molecule could have therapeutic benefit for these patients (Benatar et al., 2018). Unfortunately, a randomized, placebo-controlled, phase III clinical trial with arimoclomol (ORARIALS-01 phase III trial, NCT03491462), that was started in 2018 and whose results were much awaited, failed to improve motor function and patient survival upon chronic treatment, as well as the ability to perform daily tasks, time to permanent assisted ventilation, and changes in lung function (defined as secondary endpoints of the study) https://alsnewstoday.com/news-posts/2021/05/11/arimoclomol-fails-phase-3-als-trial-does-not-show-efficacy-per-topline-data/).

Ambroxol, a beta-glucocerebrosidase 2 (GBA2) inhibitor originally indicated as a generic expectorant and mucolytic drug to treat respiratory tract infectious disorders (Nobata et al., 2006), has been recently found to be a potential drug candidate for ALS treatment. In a fALS transgenic mouse model, the SOD1^G86R mouse, this drug delayed the disease onset, improved motor function, and rescued neuronal death by regulating the glycosphingolipid metabolism, a pathway that is importantly altered in the CNS of these mice and ALS patients (Dodge et al., 2015; Henriques et al., 2015; Henriques et al., 2017; Bouscary et al., 2019; Bouscary et al., 2020). Despite these promising results in mice, clinical trials are still needed to evaluate the safety and effectiveness of this drug in ALS patients. Table 4 provides additional information about the aforementioned drugs, including pharmaceutical companies or academic institutions involved in designing and running the clinical trials, and whether the drugs received orphan designation from the EMA and/or the FDA, and the sponsors that made the orphan designation request.

Besides the molecules described above, a large number of additional repurposed drugs are currently being tested as potential therapeutic agents for ALS. Between them, neuroleptics have been identified as lead compounds for the management of the disease. Recently Patten et al (2017) performed a phenotypic drug screening of an approved drug compound library containing 3,850 molecules on C. elegans transgenics-expressing mutant TDP-43 (a protein mutated in ALS patients). Since the worms expressing the mutated protein exhibit paralysis phenotypes, this model allows the identification of compounds with beneficial effects in motor function. From the 24 compounds identified as potentially beneficial, 13 were neuroleptics. The positive hits were retested in worms and in zebrafish, expressing mutated TDP-43, FUS, and SOD1. These studies identified pimozide, an FDA-approved neuroleptic used to treat chronic psychosis, Tourette syndrome, and tics (Shapiro et al., 1987), as the drug with the strongest beneficial effect in motor function in these two models and a rodent model of fALS—the SOD1^G37R mouse (Patten et al., 2017). Despite these promising results, a recent study with two other ALS mouse models showed that the chronic administration of pimozide does not attenuate motor and pathological deficits and, in some cases, had deleterious effects (Pozzi et al., 2018). Regarding the effect of the drug in humans, an initial clinical study analyzing the effect of pimozide in ALS patients compared to other potentially neuroprotective compounds suggested that this drug may reduce the patient’s disease progression (Szczudlik et al., 1998). Since this trial was unblinded, a factor that may importantly influence the results, two additional trials were performed: a pilot randomized, double-blinded, placebo-controlled trial with ALS patients to assess the safety and tolerability of pimozide, and phase II randomized, placebo-controlled, double-blinded, multi-centre clinical trial of pimozide in 100 ALS patients to evaluate the effectiveness of the drug in slowing ALS progression. The former showed that the drug is safe and well tolerated in doses up to 4 mg/day (Patten et al., 2017), while the latter, initiated in October 2017, has not been finished yet.

An inducible drug repurposing screening using pluripotent stem cell (iPSC)–derived motor neurons from an ALS patient with an SOD1 mutation identified bosutinib, a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia, as a drug with potential therapeutic benefits for ALS (Imamura et al., 2017). This molecule was not only beneficial for the cells mentioned before but also increased the survival of iPSC-derived motor neurons from patients with sALS or other forms of fALS (Imamura et al., 2017), and the contractability of iPSC-derived skeletal muscle cells from ALS patients (Osaki et al., 2018). In addition, bosutinib modestly extended the survival of an ALS mouse model with SOD1 mutation (Imamura et al., 2017). Based on these promising findings, an open-label, multicenter, phase I, dose-escalating clinical trial with bosutinib in ALS patients (iDReAM study) has recently been designed to assess the safety, tolerability, and efficacy of the molecule (Imamura et al., 2019). No results are yet available for this trial.

Besides these efforts, in silico approaches are currently being actively used for the identification of repurposed drug candidates with potential beneficial effects in ALS. These strategies that exploit current knowledge on disease-associated genes and disease mechanisms, protein–protein interactions, signaling networks, and drug-target interactions allow to save time and resources on the identification of candidate compounds. Accordingly, Fiscon et al. (2021) exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets to identify drug candidates for ALS. This approach allowed to identify 403 repurposable drugs that were strongly associated with the disease. Most of these compounds belonged to drug families already identified as having disease-modifying potential, but some were non-customary ALS drugs (Fiscon et al., 2021). Among the latter, modafinil, a compound that elevates histamine levels in the neocortex and the hypothalamus and which is currently indicated for the treatment of hypersomnolence and narcolepsy (Ishizuka et al., 2010), was identified as the drug with the highest predictive score for ALS alone or combined with other drugs that are currently being tested in clinical trials (Fiscon et al., 2021). In the past, modafinil was proposed as a drug used to treat fatigue in ALS patients. An open-label, control study and a placebo-controlled trial with modafinil showed that this drug is safe and well tolerated and may, indeed, decrease fatigue in ALS patients (Carter et al., 2005; Rabkin et al., 2009). These results and the ones from the in silico prediction study (Fiscon et al., 2021) point to modafinil as a promising drug for ALS treatment whose beneficial effect needs to be proved in further clinical trials.

The main characteristics of the drugs mentioned above are summarized in Table 4.

There are a large number of ALS patient associations and foundations that are compiled in the North database (https://rarediseases.org/rare-diseases/amyotrophic-lateral-sclerosis/). The ALS association (https://www.als.org/), ALS Canada (https://www.als.ca/), the International Alliance of ALS/MND associations (https://www.als-mnd.org/), and ALS Liga België Vzw–Ligue SLA Belgique Asbl (https://als.be/fr/qui-sommes-nous) are just a few examples of non-profit organizations that provide assistance to people with ALS, coordinate multidisciplinary care, and fund research programs all over the word to discover treatments and a cure for ALS.