Citation: Ortega-Gutiérrez, S. New Pharmacological Approaches for Rare Diseases. Int. J. Mol. Sci. 2023, 24, 7275. https://doi.org/10.3390/ ijms24087275 Received: 2 April 2023 Accepted: 12 April 2023 Published: 14 April 2023 Copyright: © 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). International Journal of Molecular Sciences Editorial New Pharmacological Approaches for Rare Diseases Silvia Ortega-Gutiérrez Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain; siortega@ucm.es The expression “rare disease” describes a group of diseases whose individual preva- lence is low (between 3.9 and 6.6 in 10,000 subjects depending on the country) but which in total affect up to the 3–6% of the worldwide population. The low prevalence of each disease represents an obstacle for the development of individually focused research programs, which are often limited by the scarcity of biological samples and the difficulty to access complete patient databases to perform statistically sounded preclinical and clinical studies. This fact translates into insufficient medical expertise and, consequently, into inadequate care offerings for these patients. Hence, the rare diseases field represents a currently unmet clinical need and provides, at the same time, an exciting area for basic and applied research. The intention of this Special Issue on “New Pharmacological Approaches for Rare Diseases” is to promote awareness of the field and to provide an up-to-date perspective of those emerging therapeutic strategies that are nowadays under active development and have the potential to generate, in the upcoming years, new pharmacological treatments to face these kind of largely ignored and usually fatal diseases. Around 80% of rare diseases are of genetic origin and, of those, 70% already start in childhood. Among them, muscular dystrophies (MDs) constitute an important class. The term encompasses more than 30 ge- netic diseases characterized by the progressive weakness and degeneration of the skeletal muscles that control movement [1]. In this field, Bencze provides an overview of the most important mechanisms of myofiber death in MDs [2]. New ongoing therapeutic approaches for treating specific MDs are also discussed for application in myotonic dystrophy type 1 (DM1), the most common form of adult MD, in Duchenne MD [3], or in limb-girdle MD R1 calpain 3-related (LGMDR1). These strategies explore different drug discovery approaches, including drug repurposing of the antitumor drug vorinostat for DM1 [4], the potential of natural products such as ectoine or of biologicals such as BLS-M22 for Duchenne MD [5,6], or the validation of glycogen synthase kinase 3β (GSK-3β) as a new therapeutic target for LGMDR1 [7]. Emerging therapies for other genetic rare diseases such as inherited peripheral neuropathies, collectively called Charcot–Marie–Tooth disease (CMT), are also covered [8]. Although CMT is considered rare, it is the most common hereditary neuropathy within neuromuscular diseases affecting approximately 1 in 2500 people. Rare diseases affect all organs, including the immune system, and significant examples include autoimmune diseases such as neuromyelitis optica spectrum disorders (NMOSD), characterized by acute inflammation of the optic nerve and the spinal cord, and T-cell- associated tumors, such as acute lymphoblastic leukemia (ALL), which is the most common pediatric malignancy and of which T-cell ALL (T-ALL) comprises 10–15% of cases. In this Special Issue, Giglhuber and Berthele describe the main adverse events associated with the current treatments of NMOSD aiming at rationalizing treatment choices on an individualized basis by taking into account the safety concerns associated with the different drugs [9], and Lato et al. review the recent development of targeted therapeutic approaches for T-ALL, illustrating the growing potential of personalized medicine based on thorough molecular profiling [10]. Additionally, drug repurposing could represent another strategy with potential for identifying treatments for underexplored diseases such as nephropathic cystinosis, a lysosomal storage disease that eventually can lead to renal failure [11]. Some Int. J. Mol. Sci. 2023, 24, 7275. https://doi.org/10.3390/ijms24087275 https://www.mdpi.com/journal/ijms https://doi.org/10.3390/ijms24087275 https://doi.org/10.3390/ijms24087275 https://creativecommons.org/ https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://www.mdpi.com/journal/ijms https://www.mdpi.com https://orcid.org/0000-0002-0257-6754 https://doi.org/10.3390/ijms24087275 https://www.mdpi.com/journal/ijms https://www.mdpi.com/article/10.3390/ijms24087275?type=check_update&version=1 Int. J. Mol. Sci. 2023, 24, 7275 2 of 3 rare diseases, such as retinopathy of prematurity (ROP), an ocular disorder in preterm infants, have increased gradually [12], whereas others, as is the case for cystic fibrosis, have reduced their incidence [13] due to advances in the field [14]. Finally, among very rare diseases, the Hutchinson–Gilford progeria syndrome (HGPS) or progeria, a pathology that affects all organs except the central nervous system characterized by a global accelerated aging phenotype, stands out [15]. Progeria exemplifies how scientific research can signifi- cantly improve the outcome of a disease, from the characterization of the molecular cause and the precise description of associated cellular defects to the first marketed drug for its treatment in two decades [16–19], with important biomedical advances related with gene therapy awaiting on the near horizon [20]. Among the sporadic rare diseases, that is, with random occurrence and with no clear associated risk factors nor family history of the disease, amyotrophic lateral sclerosis (ALS) deserves special attention. ALS affects motor neurons that control voluntary muscle movement and is considered a fatal disease since it lacks a cure or even an effective treatment to reverse or effectively delay its progression [21]. In this context, the relevance of mitophagy modulation [22] and other molecular alterations [23] together with the specific role of chaperone protein BiP [24] in ALS have been explored. These findings could open uncharted directions that may aid in the identification of novel therapeutic strategies for facing this devastating disorder. Rare diseases represent a very complex field that, for its very own features, entails enormous economic and societal implications. Nonetheless, as has been demonstrated through recent history, research provides continuous advances. We are confident that the work covered in this Special Issue contributes to stimulate research on this fascinating area that can translate, in the near future, into new therapies, meaning we will be able to provide hope to the millions of patients currently suffering from a rare disease. Conflicts of Interest: The author declares no conflict of interest. References 1. Guiraud, S.; Aartsma-Rus, A.; Vieira, N.M.; Davies, K.E.; van Ommen, G.J.; Kunkel, L.M. The pathogenesis and therapy of muscular dystrophies. Annu. Rev. Genomics Hum. Genet. 2015, 16, 281–308. [CrossRef] [PubMed] 2. Bencze, M. Mechanisms of myofibre death in muscular dystrophies: The emergence of the regulated forms of necrosis in myology. Int. J. Mol. Sci. 2022, 24, 362. [CrossRef] 3. Markati, T.; Oskoui, M.; Farrar, M.A.; Duong, T.; Goemans, N.; Servais, L. Emerging therapies for Duchenne muscular dystrophy. Lancet Neurol. 2022, 21, 814–829. [CrossRef] [PubMed] 4. Neault, N.; Ravel-Chapuis, A.; Baird, S.D.; Lunde, J.A.; Poirier, M.; Staykov, E.; Plaza-Diaz, J.; Medina, G.; Abadía-Molina, F.; Jasmin, B.J.; et al. Vorinostat improves myotonic dystrophy type 1 splicing abnormalities in DM1 muscle cell lines and skeletal muscle from a DM1 mouse model. Int. J. Mol. Sci. 2023, 24, 3794. [CrossRef] 5. Merckx, C.; Zschüntzsch, J.; Meyer, S.; Raedt, R.; Verschuere, H.; Schmidt, J.; De Paepe, B.; De Bleecker, J.L. Exploring the therapeutic potential of ectoine in Duchenne muscular dystrophy: Comparison with taurine, a supplement with known beneficial effects in the mdx mouse. Int. J. Mol. Sci. 2022, 23, 9567. [CrossRef] 6. Sung, D.K.; Kim, H.; Park, S.E.; Lee, J.; Kim, J.A.; Park, Y.C.; Jeon, H.B.; Chang, J.W.; Lee, J. A new method of myostatin inhibition in mice via oral administration of Lactobacillus casei expressing modified myostatin protein, BLS-M22. Int. J. Mol. Sci. 2022, 23, 9059. [CrossRef] [PubMed] 7. Rico, A.; Guembelzu, G.; Palomo, V.; Martínez, A.; Aiastui, A.; Casas-Fraile, L.; Valls, A.; López de Munain, A.; Sáenz, A. Allosteric modulation of GSK-3β as a new therapeutic approach in limb girdle muscular dystrophy R1 calpain 3-related. Int. J. Mol. Sci. 2021, 22, 7367. [CrossRef] 8. Stavrou, M.; Sargiannidou, I.; Georgiou, E.; Kagiava, A.; Kleopa, K.A. Emerging therapies for Charcot-Marie-Tooth inherited neuropathies. Int. J. Mol. Sci. 2021, 22, 6048. [CrossRef] 9. Giglhuber, K.; Berthele, A. Adverse events in NMOSD therapy. Int. J. Mol. Sci. 2022, 23, 4154. [CrossRef] 10. Lato, M.W.; Przysucha, A.; Grosman, S.; Zawitkowska, J.; Lejman, M. The new therapeutic strategies in pediatric T-Cell acute lymphoblastic leukemia. Int. J. Mol. Sci. 2021, 22, 4502. [CrossRef] 11. Bellomo, F.; De Leo, E.; Taranta, A.; Giaquinto, L.; Di Giovamberardino, G.; Montefusco, S.; Rega, L.R.; Pastore, A.; Medina, D.L.; Di Bernardo, D.; et al. Drug repurposing in rare diseases: An integrative study of drug screening and transcriptomic analysis in nephropathic cystinosis. Int. J. Mol. Sci. 2021, 22, 12829. [CrossRef] [PubMed] 12. Ryu, J. New aspects on the treatment of retinopathy of prematurity: Currently available therapies and emerging novel therapeutics. Int. J. Mol. Sci. 2022, 23, 8529. [CrossRef] https://doi.org/10.1146/annurev-genom-090314-025003 https://www.ncbi.nlm.nih.gov/pubmed/26048046 https://doi.org/10.3390/ijms24010362 https://doi.org/10.1016/S1474-4422(22)00125-9 https://www.ncbi.nlm.nih.gov/pubmed/35850122 https://doi.org/10.3390/ijms24043794 https://doi.org/10.3390/ijms23179567 https://doi.org/10.3390/ijms23169059 https://www.ncbi.nlm.nih.gov/pubmed/36012334 https://doi.org/10.3390/ijms22147367 https://doi.org/10.3390/ijms22116048 https://doi.org/10.3390/ijms23084154 https://doi.org/10.3390/ijms22094502 https://doi.org/10.3390/ijms222312829 https://www.ncbi.nlm.nih.gov/pubmed/34884638 https://doi.org/10.3390/ijms23158529 Int. J. Mol. Sci. 2023, 24, 7275 3 of 3 13. Scotet, V.; L’Hostis, C.; Férec, C. The changing epidemiology of cystic fibrosis: Incidence, survival and impact of the CFTR gene discovery. Genes 2020, 11, 589. [CrossRef] [PubMed] 14. Bergeron, C.; Cantin, A.M. New therapies to correct the cystic fibrosis basic defect. Int. J. Mol. Sci. 2021, 22, 6193. [CrossRef] [PubMed] 15. Macicior, J.; Marcos-Ramiro, B.; Ortega-Gutiérrez, S. Small-molecule therapeutic perspectives for the treatment of progeria. Int. J. Mol. Sci. 2021, 22, 7190. [CrossRef] [PubMed] 16. Eriksson, M.; Brown, W.T.; Gordon, L.B.; Glynn, M.W.; Singer, J.; Scott, L.; Erdos, M.R.; Robbins, C.M.; Moses, T.Y.; Berglund, P.; et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003, 423, 293–298. [CrossRef] 17. Marcos-Ramiro, B.; Gil-Ordóñez, A.; Marín-Ramos, N.I.; Ortega-Nogales, F.J.; Balabasquer, M.; Gonzalo, P.; Khiar-Fernández, N.; Rolas, L.; Barkaway, A.; Nourshargh, S.; et al. Isoprenylcysteine carboxylmethyltransferase-based therapy for Hutchinson-Gilford progeria syndrome. ACS Cent. Sci. 2021, 7, 1300–1310. [CrossRef] 18. Osorio, F.G.; Navarro, C.L.; Cadiñanos, J.; López-Mejía, I.C.; Quirós, P.M.; Bartoli, C.; Rivera, J.; Tazi, J.; Guzmán, G.; Varela, I.; et al. Splicing-directed therapy in a new mouse model of human accelerated aging. Sci. Transl. Med. 2011, 3, 106ra107. [CrossRef] 19. Suzuki, M.; Jeng, L.J.B.; Chefo, S.; Wang, Y.; Price, D.; Li, X.; Wang, J.; Li, R.J.; Ma, L.; Yang, Y.; et al. FDA approval sum- mary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies. Genet. Med. 2023, 25, 100335. [CrossRef] 20. Koblan, L.W.; Erdos, M.R.; Wilson, C.; Cabral, W.A.; Levy, J.M.; Xiong, Z.M.; Tavarez, U.L.; Davison, L.M.; Gete, Y.G.; Mao, X.; et al. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice. Nature 2021, 589, 608–614. [CrossRef] 21. Kiernan, M.C.; Vucic, S.; Talbot, K.; McDermott, C.J.; Hardiman, O.; Shefner, J.M.; Al-Chalabi, A.; Huynh, W.; Cudkowicz, M.; Talman, P.; et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat. Rev. Neurol. 2021, 17, 104–118. [CrossRef] [PubMed] 22. Madruga, E.; Maestro, I.; Martínez, A. Mitophagy modulation, a new player in the race against ALS. Int. J. Mol. Sci. 2021, 22, 740. [CrossRef] [PubMed] 23. Lastres-Becker, I.; Porras, G.; Arribas-Blázquez, M.; Maestro, I.; Borrego-Hernández, D.; Boya, P.; Cerdán, S.; García-Redondo, A.; Martínez, A.; Martin-Requero, Á. Molecular alterations in sporadic and SOD1-ALS immortalized lymphocytes: Towards a personalized therapy. Int. J. Mol. Sci. 2021, 22, 3007. [CrossRef] [PubMed] 24. Gómez-Almería, M.; Burgaz, S.; Costas-Insua, C.; Rodríguez-Cueto, C.; Santos-García, I.; Rodríguez-Crespo, I.; García, C.; Guzmán, M.; de Lago, E.; Fernández-Ruiz, J. BiP heterozigosity aggravates pathological deterioration in experimental amyotrophic lateral sclerosis. Int. J. Mol. Sci. 2021, 22, 12533. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. https://doi.org/10.3390/genes11060589 https://www.ncbi.nlm.nih.gov/pubmed/32466381 https://doi.org/10.3390/ijms22126193 https://www.ncbi.nlm.nih.gov/pubmed/34201249 https://doi.org/10.3390/ijms22137190 https://www.ncbi.nlm.nih.gov/pubmed/34281245 https://doi.org/10.1038/nature01629 https://doi.org/10.1021/acscentsci.0c01698 https://doi.org/10.1126/scitranslmed.3002847 https://doi.org/10.1016/j.gim.2022.11.003 https://doi.org/10.1038/s41586-020-03086-7 https://doi.org/10.1038/s41582-020-00434-z https://www.ncbi.nlm.nih.gov/pubmed/33340024 https://doi.org/10.3390/ijms22020740 https://www.ncbi.nlm.nih.gov/pubmed/33450997 https://doi.org/10.3390/ijms22063007 https://www.ncbi.nlm.nih.gov/pubmed/33809456 https://doi.org/10.3390/ijms222212533 References