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Rare Disease and Orphan Drugs Journal

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The Rare Disease and Orphan Drugs Journal (RDODJ) is an international, peer-reviewed, open access journal for the publication of innovative research works on various aspects of this rapidly growing multidisciplinary and interdisciplinary field.
RDODJ will report on scientific advances in the genetics of rare diseases, the molecular basis of the pathologies, and translational research on diagnosis, prevention and treatment.
In addition, RDODJ aims to provide a forum for scientific studies and discussion covering the important regulatory, socio-economic and human science issues related to rare diseases and orphan drugs.
The ultimate objective of RDODJ is to promote the dissemination of research results and scientific discussion among the research community, practitioners, and patient-advocacy organizations.

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Aashish Adhikari

Briar Cliff University

ARINDAM BHATTACHARJEE

Julianne O'Daniel

Françoise Houdayer

Vanderbilt University

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Papers by Rare Disease and Orphan Drugs Journal

A systematic review of real-world applications of genome sequencing for newborn screening

Rare Disease and Orphan Drugs Journal, 2023

Aim: With the costs of genomic sequencing falling quickly and an ever-increasing number of clinic... more Aim: With the costs of genomic sequencing falling quickly and an ever-increasing number of clinical laboratories equipped with new-generation sequencing machines, healthcare systems around the world are getting ready to enter the era of genomic newborn screening (NBS). However, the adoption of Genomic Sequencing (GS), encompassing whole-exome sequencing (WES) and whole-genome sequencing (WGS), in NBS programs raises a number of clinical, ethical, and legal questions as well as organizational and economic challenges. This systematic review is part of a feasibility study to assess the introduction of WGS for NBS in Lombardy region with the specific aim of gathering evidence from existing pilots in the field whose results have been published. in the USA) have been published recently; however, this evidence is not yet sufficient to put an end to the broad and animated debate on the use of GS for NBS. Ethical, legal, and social issues still constitute great challenges and major barriers to wide and uniform adoption of GS in NBS. On the clinical side, a number of issues remain unaddressed, such as the benefits and limitations of the different approaches (targeted sequencing, GS only versus GS+standard NBS), the genes/diseases to include and the frequency of incidental findings, identification of carrier status, and variants of uncertain significance (VUS). Further pilots and consultations with involved stakeholders will be necessary before GS-based NBS can be accepted and systematically implemented in national healthcare programs.

Correction: A report and review of the recurrent c.811C > T variant and mutation spectrum of Kindler syndrome in East Asians: a diagnostic odyssey of 2 weeks versus 49 years

Rare Disease and Orphan Drugs Journal, 2023

Cathepsin C: structure, function, and pharmacological targeting

Rare Disease and Orphan Drugs Journal, 2023

Cathepsin C is a papain-like cysteine peptidase known primarily for its involvement in the activa... more Cathepsin C is a papain-like cysteine peptidase known primarily for its involvement in the activation of serine peptidases in neutrophils and other immune cells. Its critical role in this process qualifies cathepsin C as a target for the treatment of inflammatory diseases, and its most advanced inhibitor, brensocatib (Insmed), is currently in phase 3 clinical trials for the treatment of non-cystic fibrosis bronchiectasis. Beyond neutrophils, its importance is highlighted by loss-of-function mutations that cause the recessively inherited Papillon-Lefèvre syndrome. At the molecular level, cathepsin C has several structural and functional features that set it apart from other members of the family and enable its selective targeting. It possesses dipeptidyl-peptidase activity (its other common name is dipeptidyl-peptidase I) due to the presence of an additional exclusion domain that also controls its stepwise tetramerization during maturation. In this review article, we summarize the current state of the art regarding the biochemical properties of cathepsin C, its physiological and pathological roles in neutrophils and beyond, and recent advances in the development and evaluation of cathepsin C inhibitors.

Coenzyme Q10, Vitamin E and Polyvitamin B: an exploratory double-blind randomized cross-over study in Phelan-McDermid Syndrome

Rare Disease and Orphan Drugs Journal, 2023

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Auti... more Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a "metabolic support therapy" (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability. Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods. Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

Coenzyme Q10, Vitamin E and Polyvitamin B: an exploratory double-blind randomized cross-over study in Phelan-McDermid Syndrome

Rare Disease and Orphan Drugs Journal, 2023

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Auti... more Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a "metabolic support therapy" (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability. Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods. Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

RNA antisense and silencing strategies using synthetic drugs for rare muscular and neuromuscular diseases

Rare Disease and Orphan Drugs Journal, 2023

Rare diseases occur in their large majority from a genetic cause, which makes them good candidate... more Rare diseases occur in their large majority from a genetic cause, which makes them good candidates for genetic RNA drugs. The basic concepts, principles, mechanisms of action and chemical optimizations of synthetic antisense oligonucleotides (ASO) and small interfering RNA (siRNA) are illustrated. These drugs act either by leading to RNA degradation, or as steric blockers of RNA translation, microRNA antagonists, splicing modulators or inducers of exon skipping. Chemical modifications and delivery techniques differ and are adapted to their distinct functions. The successes, potential, and challenges of synthetic RNA drugs are illustrated for several muscular and neuromuscular diseases: Duchenne muscular dystrophy, spinal muscular atrophy, transthyretin amyloidosis, Type 1 myotonic dystrophy, centronuclear myopathy, oculopharyngeal muscular dystrophy.

Biallelic cubilin pathogenic variants as a cause of « benign » proteinuria: implications for clinical management

by Rare Disease and Orphan Drugs Journal and Valentine Gillion

The recent description of a cohort with both adults and children harboring biallelic pathogenic v... more The recent description of a cohort with both adults and children harboring biallelic pathogenic variants of CUBN changed the paradigm of the management of isolated proteinuria. Indeed, the detection of proteinuria in a patient, regardless of age, often leads to an exhaustive checkup including kidney biopsy but also the prescription of reninangiotensin system (RAS) blockers to slow the progression of kidney disease. Patients with CUBN variants have nondetrimental proteinuria and are non-responsive to RAS blockers. We herein describe 2 siblings treated for isolated proteinuria for several years, eventually diagnosed with CUBN biallelic pathogenic variants (c.703 C > T and c.10363-3A > G). We review the physio-pathological mechanisms of this newly discovered disease and discuss implications for clinical management.

Pathogenesis of autoimmune and hereditary pancreatitis with a focus on neutrophil granulocytes and neutrophil serine proteases

by Rare Disease and Orphan Drugs Journal and Ali Aghdassi

Rare Disease and Orphan Drugs Journal, 2023

Hereditary and autoimmune pancreatitis are two rare forms of inflammatory pancreatic disorders. B... more Hereditary and autoimmune pancreatitis are two rare forms of inflammatory pancreatic disorders. Both share similarities with acute, acute recurrent, and chronic pancreatitis. Regarding their pathogenesis, the premature activation of the digestive protease trypsinogen and the infiltration of inflammatory cells such as polymorphonuclear leukocytes and macrophages into the pancreas are highly relevant and can reciprocally amplify inflammation. Neutrophil serine proteases are the main components of neutrophil granulocytes and have different pro-inflammatory effects in many diseases. However, their role in pancreatitis is still limited. This section focuses on known findings regarding the role of this group of enzymes in hereditary and autoimmune pancreatitis.

Sustainable approaches for drug repurposing in rare diseases: recommendations from the IRDiRC Task Force

Rare Disease and Orphan Drugs Journal, 2023

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of ra... more Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases. Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects.

Histological and biochemical methods to assess aminoacyl-tRNA synthetase expression in human post-mortem brain tissue

Rare Disease and Orphan Drugs Journal, 2023

Aminoacyl-tRNA synthetases are essential, non-redundant enzymes that catalyze the charging of tRN... more Aminoacyl-tRNA synthetases are essential, non-redundant enzymes that catalyze the charging of tRNAs with their cognate amino acids. This reaction is a prerequisite for protein translation in all cells. Mutations in human aminoacyl-tRNA synthetases are often associated with defects of the peripheral and central nervous system and are the underlying cause of many rare diseases including neuropathies and leukodystrophies. A comprehensive understanding of aminoacyl-tRNA synthetase expression domains is key to understanding these disorders and developing novel targeted treatment strategies. Here, we describe histological and biochemical methods to analyze the expression pattern of the aspartyl-tRNA synthetase AspRS in human post-mortem brain tissue. The same methods can readily be applied to other members of the aminoacyl-tRNA synthetase superfamily or, more generally, to other cytosolic proteins in the human brain.

Connecting academia and industry for innovative drug repurposing in rare diseases: it is worth a try

Rare Disease and Orphan Drugs Journal, 2023

There are different approaches to drug repurposing (DR) depending on the status of the repurposab... more There are different approaches to drug repurposing (DR) depending on the status of the repurposable drug/molecule (approved, investigational, withdrawn, shelved), the context, and the stakeholders involved. The purpose of this perspective paper is to highlight the complexity of academia-industry collaborations in DR for rare diseases and go beyond stereotypes to consider realistic and mutually reinforcing cooperation among various stakeholders, including not only academia and industry but also regulators, legal experts, and payers, leading to benefits for patients with unmet medical needs. Key questions are addressed through the presentation of select DR case studies. Some ongoing and promising European and international initiatives are introduced and some recommendations are proposed.

Neutrophil serine proteases

Rare Disease and Orphan Drugs Journal, 2023

The identification and characterization of the four active neutrophil serine proteases (NSPs) hav... more The identification and characterization of the four active neutrophil serine proteases (NSPs) have provided a better understanding of their roles in various physiological and pathological processes. The availability of appropriate tools such as substrates, inhibitors, and activity-based probes (ABPs) for studying their activity and functions in cells has become increasingly important. In this paper, the authors provide a comprehensive overview of the current knowledge on the tools available for studying NSPs. The substrates, inhibitors, and ABPs developed to date are described, including their strengths and limitations. The authors also discuss the potential implications of these tools for future research on NSPs, including their potential use in the development of new therapeutics for various diseases. Overall, this paper highlights the importance of understanding the activity and functions of NSPs and provides valuable information on the tools available for studying these proteases.

Immune cell-derived serine protease as pathogenic drivers of vascular remodeling in pulmonary arterial hypertension

by Rare Disease and Orphan Drugs Journal and Grazyna Kwapiszewska

Rare Disease and Orphan Drugs Journal, 2023

In recent years, accumulating evidence has shown that pulmonary arterial hypertension (PAH) has a... more In recent years, accumulating evidence has shown that pulmonary arterial hypertension (PAH) has a strong underlying inflammatory component. Vascular remodeling, a common pathology observed in all forms of pulmonary hypertension (PH), is accompanied by a pronounced accumulation of leukocytes around and within the vessels. Proteolytic products of immune cells, particularly neutrophil and mast cell serine proteases, have been shown to play a central pathogenic role in vascular remodeling and PAH development. Serine proteases are involved in many aspects of the inflammatory response, such as extracellular matrix degradation, regulation of bioavailability of cytokines, chemokines, and growth factors, and dysregulation of their activity can have devastating consequences. In this review, we will focus on immune dysregulation in PAH and shed light on the pro-inflammatory role of serine proteases in vascular pathology observed in the context of this disease.

Health disparities in Turner Syndrome: UTHealth Turner Syndrome Research Registry

Rare Disease and Orphan Drugs Journal, 2023

Aim: Turner Syndrome (TS) is caused by partial or complete absence of the second sex chromosome i... more Aim: Turner Syndrome (TS) is caused by partial or complete absence of the second sex chromosome in a phenotypic female. TS is associated with recognizable congenital anomalies and chronic health conditions. The principal objective of this study was to evaluate the health-related knowledge and insight of participants.

Methods: In 2015, we founded the UTHealth Turner Syndrome Research Registry for longitudinal follow-up of individuals with TS. Study participants were recruited from UTHealth Houston clinics and the Turner Syndrome Society of the United States. Participants completed a questionnaire about demographics, karyotype, congenital anomalies, health history, frequency of contact with care providers, and knowledge of care providers about TS.

Results: Forty percent of registry participants indicated that they did not know their karyotypes. Knowledge of karyotype, which can predict clinical outcomes in TS, markedly varied by self-reported race and ethnicity but not by age. Participants also reported significant gaps in routine medical and gynecologic care.

Conclusion: We identified knowledge gaps and health disparities that could benefit from improved provider and patient education.

Cathepsin K: both a likely biomarker and a new therapeutic target in lymphangioleiomyomatosis

Rare Disease and Orphan Drugs Journal, 2023

Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by cystic lung destruction... more Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by cystic lung destruction and lymphangiomas and is associated with a high risk of osteoporosis-related bone fractures. Its diagnosis is based on pulmonary anatomopathological criteria combined with chest computed tomography. VEGF-D is the only serum diagnostic biomarker used in the clinic, while inhibition of the mTOR pathway by rapamycin is currently the only reference therapy for LAM. Human cathepsin K (CatK), a potent collagenase predominantly found in osteoclasts, is considered as a valuable target for anti-osteoporosis and bone cancer therapy. Recently, CatK, which is overexpressed in lung cysts, was proposed as a putative LAM biomarker. Moreover, CatK may take part in the LAM pathophysiology by participating in pulmonary cystic destruction and bone degradation. Accordingly, targeting collagenolytic activity of CatK by exosite-binding inhibitors in combination with mTOR inhibition could represent an innovative therapeutic option for reducing lung destruction in LAM.

A report and review of the recurrent c.811C>T variant and mutation spectrum of Kindler syndrome in East Asians: a diagnostic odyssey of 2 weeks versus 49 years

Rare Disease and Orphan Drugs Journal, 2023

Kindler Syndrome (KS) is one of the rarest subtypes of epidermolysis bullosa (EB). It is characte... more Kindler Syndrome (KS) is one of the rarest subtypes of epidermolysis bullosa (EB). It is characterised by congenital blistering, skin fragility, photosensitivity, and poikilodermatous skin changes. It is an autosomal recessive condition with an established disease-causing mechanism of having biallelic pathogenic variants in the FERMT1 gene. Multiple variants have been reported worldwide since the discovery in 1954. This case report describes two patients of Chinese descent with molecularly confirmed KS, one diagnosed in infancy while the other in midadulthood. It highlights the importance and clinical utility of diagnosing KS in children versus adults. The identification of recurrent c.811C>T variant in both patients also expedited the review of local databases and the existing mutation spectrum KS in East Asians.

Elastase-dependent congenital neutropenia

Rare Disease and Orphan Drugs Journal, 2023

Congenital neutropenia, which refers to an inherited deficiency in neutrophils, is a rare patholo... more Congenital neutropenia, which refers to an inherited deficiency in neutrophils, is a rare pathologic condition that affects approximately 0.0001-0.0009% of the general population. While congenital neutropenia can result from mutations in approximately 30 genes, its leading cause is gain-of-function mutations in the ELANE gene, which encodes the neutrophil granule serine protease, neutrophil elastase. This review focuses on established and novel concepts in the genetic, molecular and cellular mechanisms underlying neutrophil elastase-dependent neutropenia, and discusses possible new avenues for neutropenia research as well as potential novel treatment options that target pathogenic elastase variants.

Burden of cerebral adrenoleukodystrophy on affected children and their families through the eyes of family caregivers

Rare Disease and Orphan Drugs Journal, 2022

Aim: This research assessed the needs of family caregivers of children with cerebral adrenoleukod... more Aim: This research assessed the needs of family caregivers of children with cerebral adrenoleukodystrophy (cALD), focusing on the diagnostic process; the burden of the disease on the child and their caregiver's quality of life; and the physical, social, psychological, professional, and financial impacts on the whole family. Methods: Family caregivers of children with cALD were recruited via the European Leukodystrophies Association International's online platform, Leuconnect, to respond to a quantitative survey and a quality-of-life questionnaire and participate in a qualitative semi-structured interview. The questions focused on disease experience from onset to diagnosis and consequences on current life. Twelve family caregivers of 14 children were interviewed. Results: cALD diagnosis took an average of 16.5 months, and 8 of 12 children were misdiagnosed, with parents often describing a lack of listening from doctors. Caregivers described bedridden children whose poor quality of life correlated with a high Neurologic Function Score. On average, they needed to care for their children 7.7 h/day, with serious consequences for their employment, social life, and psychological state. the skills of general practitioners and public knowledge of pathology. By gathering information on precise daily routines centered around a dependent child, we can better understand how to effectively support families by adapting not only the global care of the child but also to the following needs expressed for the entire family: better information, coordination of both care and administrative procedures, and real respite.

The discovery of the Papillon-Lefèvre syndrome, a rare cathepsin C related lysosomal disease

Rare Disease and Orphan Drugs Journal, 2022

From the perspective of unmet medical needs, drug repurposing for rare diseases offers a great op... more From the perspective of unmet medical needs, drug repurposing for rare diseases offers a great opportunity. There are more than 7000 rare diseases, and over 95% of them lack an approved therapeutic agent, but new drug development for specific rare diseases is not a priority for the pharmaceutical industry. Drug repositioning would be a particularly attractive approach for rare diseases for both scientific and commercial reasons. Two special issues on the topic: “Cathepsin C and Neutrophil serine proteases in rare diseases” for Rare Disease and Orphan Drugs Journal resulted from the 3rd International Symposium on Cathepsin C, IsyCatC III (Tours/France, April 2022) organized in memory of Dr. Paul Henri Papillon & Dr. Paul Philippe Henri Lefèvre.

Targeting neutrophil serine proteinases in alpha-1 antitrypsin deficiency

Rare Disease and Orphan Drugs Journal, 2022

Alpha-1 antitrypsin (AAT) is the most abundant irreversible serine proteinase inhibitor in the ci... more Alpha-1 antitrypsin (AAT) is the most abundant irreversible serine proteinase inhibitor in the circulation and plays a major role in protecting lung tissue against destruction from neutrophil serine proteinases. Genetic mutation of AAT leads to reduced circulating levels and AAT deficiency (AATD) which is associated with an increased risk of developing emphysema. This observation suggests that the balance between AAT and neutrophil serine proteinase is crucial in maintaining tissue homoeostasis. In AATD, the overexuberant proteinase activity resulting from inadequate AAT control creates a self-perpetuating inflammatory cycle, driving progressive tissue injury. Reestablishing this physiological balance is therefore critical for preserving lung architecture, function, and abrogating disease progression. Several avenues within this pathophysiological pathway are being explored. This chapter addresses the pathophysiological process, current treatments targeting the pathway, and alternative approaches within the pathway that can potentially mitigate proteinase imbalance.

A systematic review of real-world applications of genome sequencing for newborn screening

Rare Disease and Orphan Drugs Journal, 2023

Aim: With the costs of genomic sequencing falling quickly and an ever-increasing number of clinic... more Aim: With the costs of genomic sequencing falling quickly and an ever-increasing number of clinical laboratories equipped with new-generation sequencing machines, healthcare systems around the world are getting ready to enter the era of genomic newborn screening (NBS). However, the adoption of Genomic Sequencing (GS), encompassing whole-exome sequencing (WES) and whole-genome sequencing (WGS), in NBS programs raises a number of clinical, ethical, and legal questions as well as organizational and economic challenges. This systematic review is part of a feasibility study to assess the introduction of WGS for NBS in Lombardy region with the specific aim of gathering evidence from existing pilots in the field whose results have been published. in the USA) have been published recently; however, this evidence is not yet sufficient to put an end to the broad and animated debate on the use of GS for NBS. Ethical, legal, and social issues still constitute great challenges and major barriers to wide and uniform adoption of GS in NBS. On the clinical side, a number of issues remain unaddressed, such as the benefits and limitations of the different approaches (targeted sequencing, GS only versus GS+standard NBS), the genes/diseases to include and the frequency of incidental findings, identification of carrier status, and variants of uncertain significance (VUS). Further pilots and consultations with involved stakeholders will be necessary before GS-based NBS can be accepted and systematically implemented in national healthcare programs.

Correction: A report and review of the recurrent c.811C > T variant and mutation spectrum of Kindler syndrome in East Asians: a diagnostic odyssey of 2 weeks versus 49 years

Rare Disease and Orphan Drugs Journal, 2023

Cathepsin C: structure, function, and pharmacological targeting

Rare Disease and Orphan Drugs Journal, 2023

Cathepsin C is a papain-like cysteine peptidase known primarily for its involvement in the activa... more Cathepsin C is a papain-like cysteine peptidase known primarily for its involvement in the activation of serine peptidases in neutrophils and other immune cells. Its critical role in this process qualifies cathepsin C as a target for the treatment of inflammatory diseases, and its most advanced inhibitor, brensocatib (Insmed), is currently in phase 3 clinical trials for the treatment of non-cystic fibrosis bronchiectasis. Beyond neutrophils, its importance is highlighted by loss-of-function mutations that cause the recessively inherited Papillon-Lefèvre syndrome. At the molecular level, cathepsin C has several structural and functional features that set it apart from other members of the family and enable its selective targeting. It possesses dipeptidyl-peptidase activity (its other common name is dipeptidyl-peptidase I) due to the presence of an additional exclusion domain that also controls its stepwise tetramerization during maturation. In this review article, we summarize the current state of the art regarding the biochemical properties of cathepsin C, its physiological and pathological roles in neutrophils and beyond, and recent advances in the development and evaluation of cathepsin C inhibitors.

Coenzyme Q10, Vitamin E and Polyvitamin B: an exploratory double-blind randomized cross-over study in Phelan-McDermid Syndrome

Rare Disease and Orphan Drugs Journal, 2023

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Auti... more Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a "metabolic support therapy" (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability. Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods. Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

Coenzyme Q10, Vitamin E and Polyvitamin B: an exploratory double-blind randomized cross-over study in Phelan-McDermid Syndrome

Rare Disease and Orphan Drugs Journal, 2023

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Auti... more Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a "metabolic support therapy" (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability. Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods. Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

RNA antisense and silencing strategies using synthetic drugs for rare muscular and neuromuscular diseases

Rare Disease and Orphan Drugs Journal, 2023

Rare diseases occur in their large majority from a genetic cause, which makes them good candidate... more Rare diseases occur in their large majority from a genetic cause, which makes them good candidates for genetic RNA drugs. The basic concepts, principles, mechanisms of action and chemical optimizations of synthetic antisense oligonucleotides (ASO) and small interfering RNA (siRNA) are illustrated. These drugs act either by leading to RNA degradation, or as steric blockers of RNA translation, microRNA antagonists, splicing modulators or inducers of exon skipping. Chemical modifications and delivery techniques differ and are adapted to their distinct functions. The successes, potential, and challenges of synthetic RNA drugs are illustrated for several muscular and neuromuscular diseases: Duchenne muscular dystrophy, spinal muscular atrophy, transthyretin amyloidosis, Type 1 myotonic dystrophy, centronuclear myopathy, oculopharyngeal muscular dystrophy.

Biallelic cubilin pathogenic variants as a cause of « benign » proteinuria: implications for clinical management

by Rare Disease and Orphan Drugs Journal and Valentine Gillion

The recent description of a cohort with both adults and children harboring biallelic pathogenic v... more The recent description of a cohort with both adults and children harboring biallelic pathogenic variants of CUBN changed the paradigm of the management of isolated proteinuria. Indeed, the detection of proteinuria in a patient, regardless of age, often leads to an exhaustive checkup including kidney biopsy but also the prescription of reninangiotensin system (RAS) blockers to slow the progression of kidney disease. Patients with CUBN variants have nondetrimental proteinuria and are non-responsive to RAS blockers. We herein describe 2 siblings treated for isolated proteinuria for several years, eventually diagnosed with CUBN biallelic pathogenic variants (c.703 C > T and c.10363-3A > G). We review the physio-pathological mechanisms of this newly discovered disease and discuss implications for clinical management.

Pathogenesis of autoimmune and hereditary pancreatitis with a focus on neutrophil granulocytes and neutrophil serine proteases

by Rare Disease and Orphan Drugs Journal and Ali Aghdassi

Rare Disease and Orphan Drugs Journal, 2023

Hereditary and autoimmune pancreatitis are two rare forms of inflammatory pancreatic disorders. B... more Hereditary and autoimmune pancreatitis are two rare forms of inflammatory pancreatic disorders. Both share similarities with acute, acute recurrent, and chronic pancreatitis. Regarding their pathogenesis, the premature activation of the digestive protease trypsinogen and the infiltration of inflammatory cells such as polymorphonuclear leukocytes and macrophages into the pancreas are highly relevant and can reciprocally amplify inflammation. Neutrophil serine proteases are the main components of neutrophil granulocytes and have different pro-inflammatory effects in many diseases. However, their role in pancreatitis is still limited. This section focuses on known findings regarding the role of this group of enzymes in hereditary and autoimmune pancreatitis.

Sustainable approaches for drug repurposing in rare diseases: recommendations from the IRDiRC Task Force

Rare Disease and Orphan Drugs Journal, 2023

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of ra... more Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases. Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects.

Histological and biochemical methods to assess aminoacyl-tRNA synthetase expression in human post-mortem brain tissue

Rare Disease and Orphan Drugs Journal, 2023

Aminoacyl-tRNA synthetases are essential, non-redundant enzymes that catalyze the charging of tRN... more Aminoacyl-tRNA synthetases are essential, non-redundant enzymes that catalyze the charging of tRNAs with their cognate amino acids. This reaction is a prerequisite for protein translation in all cells. Mutations in human aminoacyl-tRNA synthetases are often associated with defects of the peripheral and central nervous system and are the underlying cause of many rare diseases including neuropathies and leukodystrophies. A comprehensive understanding of aminoacyl-tRNA synthetase expression domains is key to understanding these disorders and developing novel targeted treatment strategies. Here, we describe histological and biochemical methods to analyze the expression pattern of the aspartyl-tRNA synthetase AspRS in human post-mortem brain tissue. The same methods can readily be applied to other members of the aminoacyl-tRNA synthetase superfamily or, more generally, to other cytosolic proteins in the human brain.

Connecting academia and industry for innovative drug repurposing in rare diseases: it is worth a try

Rare Disease and Orphan Drugs Journal, 2023

There are different approaches to drug repurposing (DR) depending on the status of the repurposab... more There are different approaches to drug repurposing (DR) depending on the status of the repurposable drug/molecule (approved, investigational, withdrawn, shelved), the context, and the stakeholders involved. The purpose of this perspective paper is to highlight the complexity of academia-industry collaborations in DR for rare diseases and go beyond stereotypes to consider realistic and mutually reinforcing cooperation among various stakeholders, including not only academia and industry but also regulators, legal experts, and payers, leading to benefits for patients with unmet medical needs. Key questions are addressed through the presentation of select DR case studies. Some ongoing and promising European and international initiatives are introduced and some recommendations are proposed.

Neutrophil serine proteases

Rare Disease and Orphan Drugs Journal, 2023

The identification and characterization of the four active neutrophil serine proteases (NSPs) hav... more The identification and characterization of the four active neutrophil serine proteases (NSPs) have provided a better understanding of their roles in various physiological and pathological processes. The availability of appropriate tools such as substrates, inhibitors, and activity-based probes (ABPs) for studying their activity and functions in cells has become increasingly important. In this paper, the authors provide a comprehensive overview of the current knowledge on the tools available for studying NSPs. The substrates, inhibitors, and ABPs developed to date are described, including their strengths and limitations. The authors also discuss the potential implications of these tools for future research on NSPs, including their potential use in the development of new therapeutics for various diseases. Overall, this paper highlights the importance of understanding the activity and functions of NSPs and provides valuable information on the tools available for studying these proteases.

Immune cell-derived serine protease as pathogenic drivers of vascular remodeling in pulmonary arterial hypertension

by Rare Disease and Orphan Drugs Journal and Grazyna Kwapiszewska

Rare Disease and Orphan Drugs Journal, 2023

In recent years, accumulating evidence has shown that pulmonary arterial hypertension (PAH) has a... more In recent years, accumulating evidence has shown that pulmonary arterial hypertension (PAH) has a strong underlying inflammatory component. Vascular remodeling, a common pathology observed in all forms of pulmonary hypertension (PH), is accompanied by a pronounced accumulation of leukocytes around and within the vessels. Proteolytic products of immune cells, particularly neutrophil and mast cell serine proteases, have been shown to play a central pathogenic role in vascular remodeling and PAH development. Serine proteases are involved in many aspects of the inflammatory response, such as extracellular matrix degradation, regulation of bioavailability of cytokines, chemokines, and growth factors, and dysregulation of their activity can have devastating consequences. In this review, we will focus on immune dysregulation in PAH and shed light on the pro-inflammatory role of serine proteases in vascular pathology observed in the context of this disease.

Health disparities in Turner Syndrome: UTHealth Turner Syndrome Research Registry

Rare Disease and Orphan Drugs Journal, 2023

Aim: Turner Syndrome (TS) is caused by partial or complete absence of the second sex chromosome i... more Aim: Turner Syndrome (TS) is caused by partial or complete absence of the second sex chromosome in a phenotypic female. TS is associated with recognizable congenital anomalies and chronic health conditions. The principal objective of this study was to evaluate the health-related knowledge and insight of participants.

Methods: In 2015, we founded the UTHealth Turner Syndrome Research Registry for longitudinal follow-up of individuals with TS. Study participants were recruited from UTHealth Houston clinics and the Turner Syndrome Society of the United States. Participants completed a questionnaire about demographics, karyotype, congenital anomalies, health history, frequency of contact with care providers, and knowledge of care providers about TS.

Results: Forty percent of registry participants indicated that they did not know their karyotypes. Knowledge of karyotype, which can predict clinical outcomes in TS, markedly varied by self-reported race and ethnicity but not by age. Participants also reported significant gaps in routine medical and gynecologic care.

Conclusion: We identified knowledge gaps and health disparities that could benefit from improved provider and patient education.

Cathepsin K: both a likely biomarker and a new therapeutic target in lymphangioleiomyomatosis

Rare Disease and Orphan Drugs Journal, 2023

Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by cystic lung destruction... more Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by cystic lung destruction and lymphangiomas and is associated with a high risk of osteoporosis-related bone fractures. Its diagnosis is based on pulmonary anatomopathological criteria combined with chest computed tomography. VEGF-D is the only serum diagnostic biomarker used in the clinic, while inhibition of the mTOR pathway by rapamycin is currently the only reference therapy for LAM. Human cathepsin K (CatK), a potent collagenase predominantly found in osteoclasts, is considered as a valuable target for anti-osteoporosis and bone cancer therapy. Recently, CatK, which is overexpressed in lung cysts, was proposed as a putative LAM biomarker. Moreover, CatK may take part in the LAM pathophysiology by participating in pulmonary cystic destruction and bone degradation. Accordingly, targeting collagenolytic activity of CatK by exosite-binding inhibitors in combination with mTOR inhibition could represent an innovative therapeutic option for reducing lung destruction in LAM.

A report and review of the recurrent c.811C>T variant and mutation spectrum of Kindler syndrome in East Asians: a diagnostic odyssey of 2 weeks versus 49 years

Rare Disease and Orphan Drugs Journal, 2023

Kindler Syndrome (KS) is one of the rarest subtypes of epidermolysis bullosa (EB). It is characte... more Kindler Syndrome (KS) is one of the rarest subtypes of epidermolysis bullosa (EB). It is characterised by congenital blistering, skin fragility, photosensitivity, and poikilodermatous skin changes. It is an autosomal recessive condition with an established disease-causing mechanism of having biallelic pathogenic variants in the FERMT1 gene. Multiple variants have been reported worldwide since the discovery in 1954. This case report describes two patients of Chinese descent with molecularly confirmed KS, one diagnosed in infancy while the other in midadulthood. It highlights the importance and clinical utility of diagnosing KS in children versus adults. The identification of recurrent c.811C>T variant in both patients also expedited the review of local databases and the existing mutation spectrum KS in East Asians.

Elastase-dependent congenital neutropenia

Rare Disease and Orphan Drugs Journal, 2023

Congenital neutropenia, which refers to an inherited deficiency in neutrophils, is a rare patholo... more Congenital neutropenia, which refers to an inherited deficiency in neutrophils, is a rare pathologic condition that affects approximately 0.0001-0.0009% of the general population. While congenital neutropenia can result from mutations in approximately 30 genes, its leading cause is gain-of-function mutations in the ELANE gene, which encodes the neutrophil granule serine protease, neutrophil elastase. This review focuses on established and novel concepts in the genetic, molecular and cellular mechanisms underlying neutrophil elastase-dependent neutropenia, and discusses possible new avenues for neutropenia research as well as potential novel treatment options that target pathogenic elastase variants.

Burden of cerebral adrenoleukodystrophy on affected children and their families through the eyes of family caregivers

Rare Disease and Orphan Drugs Journal, 2022

Aim: This research assessed the needs of family caregivers of children with cerebral adrenoleukod... more Aim: This research assessed the needs of family caregivers of children with cerebral adrenoleukodystrophy (cALD), focusing on the diagnostic process; the burden of the disease on the child and their caregiver's quality of life; and the physical, social, psychological, professional, and financial impacts on the whole family. Methods: Family caregivers of children with cALD were recruited via the European Leukodystrophies Association International's online platform, Leuconnect, to respond to a quantitative survey and a quality-of-life questionnaire and participate in a qualitative semi-structured interview. The questions focused on disease experience from onset to diagnosis and consequences on current life. Twelve family caregivers of 14 children were interviewed. Results: cALD diagnosis took an average of 16.5 months, and 8 of 12 children were misdiagnosed, with parents often describing a lack of listening from doctors. Caregivers described bedridden children whose poor quality of life correlated with a high Neurologic Function Score. On average, they needed to care for their children 7.7 h/day, with serious consequences for their employment, social life, and psychological state. the skills of general practitioners and public knowledge of pathology. By gathering information on precise daily routines centered around a dependent child, we can better understand how to effectively support families by adapting not only the global care of the child but also to the following needs expressed for the entire family: better information, coordination of both care and administrative procedures, and real respite.

The discovery of the Papillon-Lefèvre syndrome, a rare cathepsin C related lysosomal disease

Rare Disease and Orphan Drugs Journal, 2022

From the perspective of unmet medical needs, drug repurposing for rare diseases offers a great op... more From the perspective of unmet medical needs, drug repurposing for rare diseases offers a great opportunity. There are more than 7000 rare diseases, and over 95% of them lack an approved therapeutic agent, but new drug development for specific rare diseases is not a priority for the pharmaceutical industry. Drug repositioning would be a particularly attractive approach for rare diseases for both scientific and commercial reasons. Two special issues on the topic: “Cathepsin C and Neutrophil serine proteases in rare diseases” for Rare Disease and Orphan Drugs Journal resulted from the 3rd International Symposium on Cathepsin C, IsyCatC III (Tours/France, April 2022) organized in memory of Dr. Paul Henri Papillon & Dr. Paul Philippe Henri Lefèvre.

Targeting neutrophil serine proteinases in alpha-1 antitrypsin deficiency

Rare Disease and Orphan Drugs Journal, 2022

Alpha-1 antitrypsin (AAT) is the most abundant irreversible serine proteinase inhibitor in the ci... more Alpha-1 antitrypsin (AAT) is the most abundant irreversible serine proteinase inhibitor in the circulation and plays a major role in protecting lung tissue against destruction from neutrophil serine proteinases. Genetic mutation of AAT leads to reduced circulating levels and AAT deficiency (AATD) which is associated with an increased risk of developing emphysema. This observation suggests that the balance between AAT and neutrophil serine proteinase is crucial in maintaining tissue homoeostasis. In AATD, the overexuberant proteinase activity resulting from inadequate AAT control creates a self-perpetuating inflammatory cycle, driving progressive tissue injury. Reestablishing this physiological balance is therefore critical for preserving lung architecture, function, and abrogating disease progression. Several avenues within this pathophysiological pathway are being explored. This chapter addresses the pathophysiological process, current treatments targeting the pathway, and alternative approaches within the pathway that can potentially mitigate proteinase imbalance.