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Pharmaceutics
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Novel Therapeutic Approaches in Rare Genetic Diseases
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Novel Therapeutic Approaches in Rare Genetic Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 16116

Special Issue Editors

Dr. Alessandra Rossi

E-Mail Website
Guest Editor
Food and Drug Department, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
Interests: drug delivery; pharmaceutical legislation; galenic preparations
Special Issues, Collections and Topics in MDPI journals
Dr. Raj Nayan Sewduth

E-Mail Website
Guest Editor
VIB, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Interests: novel anti-cancer agents; protein modification; drug discovery; disease modeling
Special Issues, Collections and Topics in MDPI journals
Dr. Elisabetta Grillo

E-Mail Website
Guest Editor
Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Interests: mechanisms of tumorigenesis; cancer metabolism; tumor angiogenesis; receptor tyrosine kinases; novel anti-cancer agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Remarkable progress has been made in identifying the genetic basis of rare diseases, thanks to the development of novel technologies. Recent technical advances have delivered new knowledge on disease mechanisms, and are unraveling novel therapeutic approaches. We are interested in novel articles and reviews on the topic of novel disease mechanisms, unraveling novel therapeutic strategies using novel technologies such as drug repurposing screens, single-cell and multi-omics technologies. We believe that this Special Issue will be of interest for a large number of researchers involved in the crosstalk between genetic alterations and drug therapy design.

We are pleased to invite you to submit an article concerning the identification of novel drug delivery approaches or formulations in genetic diseases. This research area has developed tremendously in the recent years due to novel technological advances. This growing number of studies indicates the strong interest of researchers in this field of research, demonstrating the need for Special Issues combining articles and reviews focusing on the advancements in the design of drug delivery approaches in rare pathological conditions.

This Special Issue aims to combine articles describing novel drug delivery approaches in response to a better understanding of the pathogenesis of rare genetic diseases such as rare cancers or less-frequent syndromes; as well as reviews covering recent drug design concerning specific diseases. This Special Issue aims to encourage publishing studies/reviews of novel therapies in rare genetic diseases which remain massively under-studied.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Validation of novel drugs to treat rare genetic diseases using in vitro/in vivo models;
  • Identification of novel drug delivery approaches using novel technologies;
  • Better understanding of drug delivery mechanisms in rare diseases using modeling.

We look forward to receiving your contributions. 

Prof. Dr. Alessandra Rossi
Dr. Raj Nayan Sewduth
Dr. Elisabetta Grillo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design
  • targeted delivery of drugs
  • drug response modeling in diseases
  • drug mechanisms in pathogenesis
  • drug repurposing

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Published Papers (6 papers)

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Research

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15 pages, 2052 KiB  
Article
RETRACTED: An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis
by Anna-Maria Wiesinger, Brian Bigger, Roberto Giugliani, Christina Lampe, Maurizio Scarpa, Tobias Moser, Christoph Kampmann, Georg Zimmermann and Florian B. Lagler
Pharmaceutics 2023, 15(5), 1565; https://doi.org/10.3390/pharmaceutics15051565 - 22 May 2023
Cited by 1 | Viewed by 2774 | Retraction
Abstract
Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to [...] Read more.
Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to provide evidence justifying fast access to innovative individual treatment trials (ITTs) with immunomodulators and a high-quality evaluation of drug effects by implementing a risk–benefit model for MPS. The iterative methodology of our developed decision analysis framework (DAF) consists of the following steps: (i) a comprehensive literature analysis on promising treatment targets and immunomodulators for MPS; (ii) a quantitative risk–benefit assessment (RBA) of selected molecules; and (iii) allocation phenotypic profiles and a quantitative assessment. These steps allow for the personalized use of the model and are in accordance with expert and patient representatives. The following four promising immunomodulators were identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra might be the treatment of choice for patients with neurocognitive involvement. Nevertheless, a RBA should always be completed on an individual basis. Our evidence-based DAF model for ITTs directly addresses the substantial unmet medical need in MPS and characterizes a first approach toward precision medicine with immunomodulatory drugs. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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18 pages, 3878 KiB  
Article
Decreased Levels of Chaperones in Mucopolysaccharidoses and Their Elevation as a Putative Auxiliary Therapeutic Approach
by Magdalena Żabińska, Lidia Gaffke, Patrycja Bielańska, Magdalena Podlacha, Estera Rintz, Zuzanna Cyske, Grzegorz Węgrzyn and Karolina Pierzynowska
Pharmaceutics 2023, 15(2), 704; https://doi.org/10.3390/pharmaceutics15020704 - 20 Feb 2023
Cited by 4 | Viewed by 2291
Abstract
Mucopolysaccharidoses (MPS) are rare genetic disorders belonging to the lysosomal storage diseases. They are caused by mutations in genes encoding lysosomal enzymes responsible for degrading glycosaminoglycans (GAGs). As a result, GAGs accumulate in lysosomes, leading to impairment of cells, organs and, consequently, the [...] Read more.
Mucopolysaccharidoses (MPS) are rare genetic disorders belonging to the lysosomal storage diseases. They are caused by mutations in genes encoding lysosomal enzymes responsible for degrading glycosaminoglycans (GAGs). As a result, GAGs accumulate in lysosomes, leading to impairment of cells, organs and, consequently, the entire body. Many of the therapies proposed thus far require the participation of chaperone proteins, regardless of whether they are therapies in common use (enzyme replacement therapy) or remain in the experimental phase (gene therapy, STOP-codon-readthrough therapy). Chaperones, which include heat shock proteins, are responsible for the correct folding of other proteins to the most energetically favorable conformation. Without their appropriate levels and activities, the correct folding of the lysosomal enzyme, whether supplied from outside or synthesized in the cell, would be impossible. However, the baseline level of nonspecific chaperone proteins in MPS has never been studied. Therefore, the purpose of this work was to determine the basal levels of nonspecific chaperone proteins of the Hsp family in MPS cells and to study the effect of normalizing GAG concentrations on these levels. Results of experiments with fibroblasts taken from patients with MPS types I, II, IIIA, IIIB, IIIC, IID, IVA, IVB, VI, VII, and IX, as well as from the brains of MPS I mice (Idua−/−), indicated significantly reduced levels of the two chaperones, Hsp70 and Hsp40. Interestingly, the reduction in GAG levels in the aforementioned cells did not lead to normalization of the levels of these chaperones but caused only a slight increase in the levels of Hsp40. An additional transcriptomic analysis of MPS cells indicated that the expression of other genes involved in protein folding processes and the cell response to endoplasmic reticulum stress, resulting from the appearance of abnormally folded proteins, was also modulated. To summarize, reduced levels of chaperones may be an additional cause of the low activity or inactivity of lysosomal enzymes in MPS. Moreover, this may point to causes of treatment failure where the correct structure of the enzyme supplied or synthesized in the cell is crucial to lower GAG levels. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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16 pages, 2886 KiB  
Article
Identification of Novel CSF-Derived miRNAs in Treated Paediatric Onset Spinal Muscular Atrophy: An Exploratory Study
by Arlene M. D’Silva, Didu Kariyawasam, Pooja Venkat, Chelsea Mayoh and Michelle A. Farrar
Pharmaceutics 2023, 15(1), 170; https://doi.org/10.3390/pharmaceutics15010170 - 3 Jan 2023
Cited by 10 | Viewed by 2306
Abstract
The availability of disease modifying therapies for spinal muscular atrophy (SMA) have created an urgent need to identify clinically meaningful biomarkers that provide insight into disease progression and therapeutic response. microRNAs (miRNA) have been shown to be involved in the pathogenesis of SMA [...] Read more.
The availability of disease modifying therapies for spinal muscular atrophy (SMA) have created an urgent need to identify clinically meaningful biomarkers that provide insight into disease progression and therapeutic response. microRNAs (miRNA) have been shown to be involved in the pathogenesis of SMA and have the potential to provide insight within the field of SMA. miRNA-sequencing was utilized to identify differential miRNA expression in the cerebrospinal fluid (CSF) in six children with SMA treated with nusinersen in this exploratory study. Fourteen differentially expressed miRNAs were significantly altered in CSF from baseline to follow-up during treatment with nusinersen. The greatest magnitude of change was noted in miR-7-5p, miR-15a-5p, miR-15b-3p/5p, miR-126-5p, miR-128-2-5p and miR-130a-3p which encompassed a spectrum of functions predominantly in neurogenesis, neuronal differentiation and growth. The dominant signaling pathways identified in this study were the mammalian target of rapamycin and the mitogen-activated protein kinase signaling pathways. This study identified multiple miRNAs that were involved in the complex interplay between neurodevelopment and neurodegeneration. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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10 pages, 254 KiB  
Article
Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes
by Jarosław Dulski, Michael G. Heckman, Launia J. White, Kamila Żur-Wyrozumska, Troy C. Lund and Zbigniew K. Wszolek
Pharmaceutics 2022, 14(12), 2778; https://doi.org/10.3390/pharmaceutics14122778 - 12 Dec 2022
Cited by 19 | Viewed by 1924
Abstract
Mutations in the CSF1R gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disease with rapid progression and ominous prognosis. Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP. [...] Read more.
Mutations in the CSF1R gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disease with rapid progression and ominous prognosis. Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP. However, different therapy results were observed, and it was not elucidated which patient should be referred for HSCT. This study aimed to determine predictors of good and bad HSCT outcomes in CSF1R-ALSP. We retrospectively analyzed 15 patients, 14 symptomatic and 1 asymptomatic, with CSF1R-ALSP that underwent HSCT. Median age of onset was 39 years, and the median age of HSCT was 43 years. Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%). Median post-HSCT follow-up was 26 months. Good outcomes were associated with gait problems as initial (p = 0.041) and predominant (p = 0.017) manifestation and younger age at HSCT (p = 0.044). Cognitive impairment as first manifestation was a predictor of a bad outcome (p = 0.016) and worsening of cognition post-HSCT (p = 0.025). In conclusion, gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)

Review

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41 pages, 918 KiB  
Review
Novel Therapeutic Approaches in Inherited Neuropathies: A Systematic Review
by Manon Hustinx, Ann-Marie Shorrocks and Laurent Servais
Pharmaceutics 2023, 15(6), 1626; https://doi.org/10.3390/pharmaceutics15061626 - 30 May 2023
Cited by 2 | Viewed by 2473
Abstract
The management of inherited neuropathies relies mostly on the treatment of symptoms. In recent years, a better understanding of the pathogenic mechanisms that underlie neuropathies has allowed for the development of disease-modifying therapies. Here, we systematically review the therapies that have emerged in [...] Read more.
The management of inherited neuropathies relies mostly on the treatment of symptoms. In recent years, a better understanding of the pathogenic mechanisms that underlie neuropathies has allowed for the development of disease-modifying therapies. Here, we systematically review the therapies that have emerged in this field over the last five years. An updated list of diseases with peripheral neuropathy as a clinical feature was created based on panels of genes used clinically to diagnose inherited neuropathy. This list was extended by an analysis of published data by the authors and verified by two experts. A comprehensive search for studies of human patients suffering from one of the diseases in our list yielded 28 studies that assessed neuropathy as a primary or secondary outcome. Although the use of various scales and scoring systems made comparisons difficult, this analysis identified diseases associated with neuropathy for which approved therapies exist. An important finding is that the symptoms and/or biomarkers of neuropathies were assessed only in a minority of cases. Therefore, further investigation of treatment efficacy on neuropathies in future trials must employ objective, consistent methods such as wearable technologies, motor unit indexes, MRI or sonography imaging, or the use of blood biomarkers associated with consistent nerve conduction studies. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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21 pages, 391 KiB  
Review
Pharmacologic Management of Monogenic and Very Early Onset Inflammatory Bowel Diseases
by Anne E. Levine, Dominique Mark, Laila Smith, Hengqi B. Zheng and David L. Suskind
Pharmaceutics 2023, 15(3), 969; https://doi.org/10.3390/pharmaceutics15030969 - 17 Mar 2023
Cited by 4 | Viewed by 3401
Abstract
Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort [...] Read more.
Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort where precision therapeutics can be applied. With the advent of rapid genetic sequencing platforms, these monogenic immunodeficiencies that cause inflammatory bowel disease are increasingly being identified. This subpopulation of IBD called very early onset inflammatory bowel disease (VEO-IBD) is defined by an age of onset of less than six years of age. Twenty percent of VEO-IBDs have an identifiable monogenic defect. The culprit genes are often involved in pro-inflammatory immune pathways, which represent potential avenues for targeted pharmacologic treatments. This review will provide an overview of the current state of disease-specific targeted therapies, as well as empiric treatment for undifferentiated causes of VEO-IBD. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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