International Journal of Molecular Sciences

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Open AccessEditorial

New Pharmacological Approaches for Rare Diseases

by Silvia Ortega-Gutiérrez

Int. J. Mol. Sci. 2023, 24(8), 7275; https://doi.org/10.3390/ijms24087275 - 14 Apr 2023

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Abstract

The expression “rare disease” describes a group of diseases whose individual prevalence 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 [...] Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

Research

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24 pages, 5602 KiB

Open AccessArticle

Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model

by Nafisa Neault, Aymeric Ravel-Chapuis, Stephen D. Baird, John A. Lunde, Mathieu Poirier, Emiliyan Staykov, Julio Plaza-Diaz, Gerardo Medina, Francisco Abadía-Molina, Bernard J. Jasmin and Alex E. MacKenzie

Int. J. Mol. Sci. 2023, 24(4), 3794; https://doi.org/10.3390/ijms24043794 - 14 Feb 2023

Cited by 3 | Viewed by 2299

Abstract

Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form [...] Read more.

Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin–long repeat; HSA^LR) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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17 pages, 3179 KiB

Open AccessArticle

Exploring the Therapeutic Potential of Ectoine in Duchenne Muscular Dystrophy: Comparison with Taurine, a Supplement with Known Beneficial Effects in the mdx Mouse

by Caroline Merckx, Jana Zschüntzsch, Stefanie Meyer, Robrecht Raedt, Hanne Verschuere, Jens Schmidt, Boel De Paepe and Jan L. De Bleecker

Int. J. Mol. Sci. 2022, 23(17), 9567; https://doi.org/10.3390/ijms23179567 - 24 Aug 2022

Cited by 5 | Viewed by 1759

Abstract

Duchenne Muscular Dystrophy (DMD) is a debilitating muscle disorder that condemns patients to year-long dependency on glucocorticoids. Chronic glucocorticoid use elicits many unfavourable side-effects without offering satisfying clinical improvement, thus, the search for alternative treatments to alleviate muscle inflammation persists. Taurine, an osmolyte [...] Read more.

Duchenne Muscular Dystrophy (DMD) is a debilitating muscle disorder that condemns patients to year-long dependency on glucocorticoids. Chronic glucocorticoid use elicits many unfavourable side-effects without offering satisfying clinical improvement, thus, the search for alternative treatments to alleviate muscle inflammation persists. Taurine, an osmolyte with anti-inflammatory effects, mitigated pathological features in the mdx mouse model for DMD but interfered with murine development. In this study, ectoine is evaluated as an alternative for taurine in vitro in CCL-136 cells and in vivo in the mdx mouse. Pre-treating CCL-136 cells with 0.1 mM taurine and 0.1 mM ectoine prior to exposure with 300 U/mL IFN-γ and 20 ng/mL IL-1β partially attenuated cell death, whilst 100 mM taurine reduced MHC-I protein levels. In vivo, histopathological features of the tibialis anterior in mdx mice were mitigated by ectoine, but not by taurine. Osmolyte treatment significantly reduced mRNA levels of inflammatory disease biomarkers, respectively, CCL2 and SPP1 in ectoine-treated mdx mice, and CCL2, HSPA1A, TNF-α and IL-1β in taurine-treated mdx mice. Functional performance was not improved by osmolyte treatment. Furthermore, ectoine-treated mdx mice exhibited reduced body weight. Our results confirmed beneficial effects of taurine in mdx mice and, for the first time, demonstrated similar and differential effects of ectoine. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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15 pages, 1676 KiB

Open AccessArticle

A New Method of Myostatin Inhibition in Mice via Oral Administration of Lactobacillus casei Expressing Modified Myostatin Protein, BLS-M22

by Dong Kyung Sung, Hyeongseop Kim, Sang Eon Park, Jiwon Lee, Ju-A Kim, Young-Chul Park, Hong Bae Jeon, Jong Wook Chang and Jeehun Lee

Int. J. Mol. Sci. 2022, 23(16), 9059; https://doi.org/10.3390/ijms23169059 - 13 Aug 2022

Cited by 4 | Viewed by 2973

Abstract

Myostatin is a member of the transforming growth factor-beta superfamily and is an endogenous negative regulator of muscle growth. This study aimed to determine whether an oral administration of Lactobacillus casei expressing modified human myostatin (BLS-M22) could elicit sufficient levels of myostatin-specific antibody [...] Read more.

Myostatin is a member of the transforming growth factor-beta superfamily and is an endogenous negative regulator of muscle growth. This study aimed to determine whether an oral administration of Lactobacillus casei expressing modified human myostatin (BLS-M22) could elicit sufficient levels of myostatin-specific antibody and improve the dystrophic features of an animal model of Duchenne muscular dystrophy (DMD; mdx mouse). BLS-M22 is a recombinant L. casei engineered to harbor the pKV vector and poly-gamma-glutamic acid gene linked to a modified human myostatin gene. Serological analysis showed that anti-myostatin IgG titers were significantly increased, and serum creatine kinase was significantly reduced in the BLS-M22-treated mdx mice compared to the control mice. In addition, treatment of BLS-M22 resulted in a significant increase in body weight and motor function (Rotarod behavior test). Histological analysis showed an improvement in the dystrophic features (fibrosis and muscle hypertrophy) of the mdx mice with the administration of BLS-M22. The circulating antibodies generated after BLS-M22 oral administration successfully lowered serum myostatin concentration. Myostatin blockade resulted in serological, histological, and functional improvements in mdx mice. Overall, the findings suggest the potential of BLS-M22 to treat DMD; however, further clinical trials are essential to ascertain its efficacy and safety in humans. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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15 pages, 3661 KiB

Open AccessArticle

Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

by Francesco Bellomo, Ester De Leo, Anna Taranta, Laura Giaquinto, Gianna Di Giovamberardino, Sandro Montefusco, Laura Rita Rega, Anna Pastore, Diego Luis Medina, Diego Di Bernardo, Maria Antonietta De Matteis and Francesco Emma

Int. J. Mol. Sci. 2021, 22(23), 12829; https://doi.org/10.3390/ijms222312829 - 27 Nov 2021

Cited by 10 | Viewed by 2308

Abstract

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy [...] Read more.

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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15 pages, 33028 KiB

Open AccessArticle

BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis

by Marta Gómez-Almería, Sonia Burgaz, Carlos Costas-Insua, Carmen Rodríguez-Cueto, Irene Santos-García, Ignacio Rodríguez-Crespo, Concepción García, Manuel Guzmán, Eva de Lago and Javier Fernández-Ruiz

Int. J. Mol. Sci. 2021, 22(22), 12533; https://doi.org/10.3390/ijms222212533 - 20 Nov 2021

Cited by 5 | Viewed by 2703

Abstract

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, [...] Read more.

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP^+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP^+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP^+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP^+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB₁) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB₁ receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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18 pages, 23383 KiB

Open AccessArticle

Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related

by Anabel Rico, Garazi Guembelzu, Valle Palomo, Ana Martínez, Ana Aiastui, Leire Casas-Fraile, Andrea Valls, Adolfo López de Munain and Amets Sáenz

Int. J. Mol. Sci. 2021, 22(14), 7367; https://doi.org/10.3390/ijms22147367 - 8 Jul 2021

Cited by 5 | Viewed by 2891

Abstract

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence [...] Read more.

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients’ muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3β (GSK-3β), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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17 pages, 2678 KiB

Open AccessArticle

Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

by Isabel Lastres-Becker, Gracia Porras, Marina Arribas-Blázquez, Inés Maestro, Daniel Borrego-Hernández, Patricia Boya, Sebastián Cerdán, Alberto García-Redondo, Ana Martínez and Ángeles Martin-Requero

Int. J. Mol. Sci. 2021, 22(6), 3007; https://doi.org/10.3390/ijms22063007 - 16 Mar 2021

Cited by 16 | Viewed by 2966

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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Review

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24 pages, 1259 KiB

Open AccessReview

Mechanisms of Myofibre Death in Muscular Dystrophies: The Emergence of the Regulated Forms of Necrosis in Myology

by Maximilien Bencze

Int. J. Mol. Sci. 2023, 24(1), 362; https://doi.org/10.3390/ijms24010362 - 26 Dec 2022

Cited by 6 | Viewed by 4044

Abstract

Myofibre necrosis is a central pathogenic process in muscular dystrophies (MD). As post-lesional regeneration cannot fully compensate for chronic myofibre loss, interstitial tissue accumulates and impairs muscle function. Muscle regeneration has been extensively studied over the last decades, however, the pathway(s) controlling muscle [...] Read more.

Myofibre necrosis is a central pathogenic process in muscular dystrophies (MD). As post-lesional regeneration cannot fully compensate for chronic myofibre loss, interstitial tissue accumulates and impairs muscle function. Muscle regeneration has been extensively studied over the last decades, however, the pathway(s) controlling muscle necrosis remains largely unknown. The recent discovery of several regulated cell death (RCD) pathways with necrotic morphology challenged the dogma of necrosis as an uncontrolled process, opening interesting perspectives for many degenerative disorders. In this review, we focus on how cell death affects myofibres in MDs, integrating the latest research in the cell death field, with specific emphasis on Duchenne muscular dystrophy, the best-known and most common hereditary MD. The role of regulated forms of necrosis in myology is still in its infancy but there is increasing evidence that necroptosis, a genetically programmed form of necrosis, is involved in muscle degenerating disorders. The existence of apoptosis in myofibre demise will be questioned, while other forms of non-apoptotic RCDs may also have a role in myonecrosis, illustrating the complexity and possibly the heterogeneity of the cell death pathways in muscle degenerating conditions. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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18 pages, 1081 KiB

Open AccessReview

New Aspects on the Treatment of Retinopathy of Prematurity: Currently Available Therapies and Emerging Novel Therapeutics

by Juhee Ryu

Int. J. Mol. Sci. 2022, 23(15), 8529; https://doi.org/10.3390/ijms23158529 - 1 Aug 2022

Cited by 19 | Viewed by 5329

Abstract

Retinopathy of prematurity (ROP) is a rare proliferative ocular disorder in preterm infants. Because of the advancements in neonatal care, the incidence of ROP has increased gradually. Now, ROP is one of the leading causes of blindness in children. Preterm infants with immature [...] Read more.

Retinopathy of prematurity (ROP) is a rare proliferative ocular disorder in preterm infants. Because of the advancements in neonatal care, the incidence of ROP has increased gradually. Now, ROP is one of the leading causes of blindness in children. Preterm infants with immature retinal development are exposed to supplemental oxygen inside an incubator until their cardiopulmonary system is adequately developed. Once they are returned to room air, the relatively low oxygen level stimulates various angiogenesis factors initiating retinal neovascularization. If patients with ROP are not offered adequate and timely treatment, they can experience vision loss that may ultimately lead to permanent blindness. Although laser therapy and anti-vascular endothelial growth factor agents are widely used to treat ROP, they have limitations. Thus, it is important to identify novel therapeutics with minimal adverse effects for the treatment of ROP. To date, various pharmacologic and non-pharmacologic therapies have been assessed as treatments for ROP. In this review, the major molecular factors involved in the pathogenesis of ROP, currently offered therapies, therapies under investigation, and emerging novel therapeutics of ROP are discussed. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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15 pages, 309 KiB

Open AccessReview

Adverse Events in NMOSD Therapy

by Katrin Giglhuber and Achim Berthele

Int. J. Mol. Sci. 2022, 23(8), 4154; https://doi.org/10.3390/ijms23084154 - 9 Apr 2022

Cited by 10 | Viewed by 3815

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral immunosuppressants and repurposed monoclonal antibodies that target the interleukin-6 pathway or B cells were the mainstays of drug treatment. Recently, [...] Read more.

Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral immunosuppressants and repurposed monoclonal antibodies that target the interleukin-6 pathway or B cells were the mainstays of drug treatment. Recently, these drug treatments have been complemented by new biologics developed and approved specifically for NMOSD. In principle, all of these drugs are effective, but treatment recommendations that take this into account are still pending. Instead, the choice of a drug may depend on other criteria such as drug safety or tolerability. In this review, we summarise current knowledge on the adverse effects of azathioprine, mycophenolate mofetil, rituximab, tocilizumab, eculizumab, satralizumab, and inebilizumab in NMOSD. Infections, cytopenias, and infusion-related reactions are most common, but the data are as heterogeneous as the manifestations are diverse. Nevertheless, knowledge of safety issues may facilitate treatment choices for individual patients. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

16 pages, 2186 KiB

Open AccessReview

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

by Jon Macicior, Beatriz Marcos-Ramiro and Silvia Ortega-Gutiérrez

Int. J. Mol. Sci. 2021, 22(13), 7190; https://doi.org/10.3390/ijms22137190 - 3 Jul 2021

Cited by 16 | Viewed by 5246

Abstract

Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by [...] Read more.

Hutchinson–Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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21 pages, 1904 KiB

Open AccessReview

New Therapies to Correct the Cystic Fibrosis Basic Defect

by Christelle Bergeron and André M. Cantin

Int. J. Mol. Sci. 2021, 22(12), 6193; https://doi.org/10.3390/ijms22126193 - 8 Jun 2021

Cited by 9 | Viewed by 7598

Abstract

Rare diseases affect 400 million individuals worldwide and cause significant morbidity and mortality. Finding solutions for rare diseases can be very challenging for physicians and researchers. Cystic fibrosis (CF), a genetic, autosomal recessive, multisystemic, life-limiting disease does not escape this sad reality. Despite [...] Read more.

Rare diseases affect 400 million individuals worldwide and cause significant morbidity and mortality. Finding solutions for rare diseases can be very challenging for physicians and researchers. Cystic fibrosis (CF), a genetic, autosomal recessive, multisystemic, life-limiting disease does not escape this sad reality. Despite phenomenal progress in our understanding of this disease, treatment remains difficult. Until recently, therapies for CF individuals were focused on symptom management. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its product, a protein present at the apical surface of epithelial cells regulating ion transport, allowed the scientific community to learn about the basic defect in CF and to study potential therapies targeting the dysfunctional protein. In the past few years, promising therapies with the goal to restore CFTR function became available and changed the lives of several CF patients. These medications, called CFTR modulators, aim to correct, potentialize, stabilize or amplify CFTR function. Furthermore, research is ongoing to develop other targeted therapies that could be more efficient and benefit a larger proportion of the CF community. The purpose of this review is to summarize our current knowledge of CF genetics and therapies restoring CFTR function, particularly CFTR modulators and gene therapy. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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29 pages, 1190 KiB

Open AccessReview

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

by Marina Stavrou, Irene Sargiannidou, Elena Georgiou, Alexia Kagiava and Kleopas A. Kleopa

Int. J. Mol. Sci. 2021, 22(11), 6048; https://doi.org/10.3390/ijms22116048 - 3 Jun 2021

Cited by 31 | Viewed by 8364

Abstract

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing [...] Read more.

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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14 pages, 5422 KiB

Open AccessReview

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia

by Marta Weronika Lato, Anna Przysucha, Sylwia Grosman, Joanna Zawitkowska and Monika Lejman

Int. J. Mol. Sci. 2021, 22(9), 4502; https://doi.org/10.3390/ijms22094502 - 26 Apr 2021

Cited by 35 | Viewed by 8851

Abstract

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10–15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization [...] Read more.

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10–15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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21 pages, 1921 KiB

Open AccessReview

Mitophagy Modulation, a New Player in the Race against ALS

by Enrique Madruga, Inés Maestro and Ana Martínez

Int. J. Mol. Sci. 2021, 22(2), 740; https://doi.org/10.3390/ijms22020740 - 13 Jan 2021

Cited by 24 | Viewed by 4666

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS. Full article

(This article belongs to the Special Issue New Pharmacological Approaches for Rare Diseases)

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