Danon Disease

The study is a single arm Phase 2 clinical trial to characterize the safety and efficacy of RP-A501, a recombinant adeno-associated serotype 9 (rAAV9 capsid containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene) in male patients with Danon Disease. Male subjects ≥8 years of age will receive a single intravenous infusion of RP-A501.

Polycystic Ovarian Syndrome is a point of concern these days in female population around the world.The patients feel psychological and mentally unhealthy. PCO effects around 6- 14% of women worldwide. PCOS is characterized by hormonal dis-regulation and hyperinsulinemia. Improvements in sex hormones and insulin sensitivity in PCOS women, either through lifestyle changes or through pharmaceutical intervention, have consistently resulted in a marked improvement in the reproductive and metabolic abnormalities in PCOS Commonly prescribed treatment for PCOS include oral contraceptives (OCPs), metformin, pioglitazone, estrogen, GnRH agonist, myo-inositol, letrozole and clomiphene citrate. Despite their effectiveness in symptom relief and ovulation induction, these treatments are associated with adverse effects including weight gain, cardiac issues, lactic acidosis, dysmenorrhea, and abdominal discomfort (Hussain et al., 2022). Given the limitations of conventional drugs, Herbal therapies are gaining attention for their multi-targeted ability to restore natural hormonal balance, improve ovulation and offer symptom relief with minimal side effects (Hussain et al., 2022). In this context, the present study is designed to explore the therapeutic benefits of a novel polyherbal formulation that includes Momordica charantia L., Linum usitatissimum, Symplocos racemose bark, Allium cepa L., Tribulus terrestris, and eggshell. These ingredients were selected based on their various pharmacological properties that are relevant to the pathophysiology of PCOS. This study will evaluate the safety and effectiveness of Melats P in achieving a successful menstruation regulation in PCOS women.We will recruit 3 groups , First group with conventional treatment (Metformin ) , Second with Alternative medicine having a herbal Formulation ( Melats P) and Third group patients will receive both Conventional (Metformin) and Herbal Formulationn (Melats P).

This is an international observational study with both retrospective and prospective data collection. The study is designed to describe the natural history of Danon disease, a rare X-linked genetic disorder, and one of the most severe and penetrant forms of inherited cardiomyopathy. This study will collect data about the clinical course of Danon disease, including signs and symptoms, key clinical events, and the impact of the disease on quality of life as managed with the current standard of care. A hybrid (retrospective and prospective data collection) approach is being used to generate robust and longitudinal data. A subset of patients will be used as an External Control Arm for comparison to RP-A501 Trial participants.

This is a multi-centre, observational study of children with rare inherited cardiac conditions. The focus of the study will be on children with clinically diagnosed cardiomyopathy and their unaffected parents, with collection of baseline demographic data, imaging data, and genotyping data. Children and their parents will been rolled over a 5-year period. Sub-sets of patients with confirmed diagnoses of other heritable cardiovascular diseases with onset \<16 years will also be recruited.These will include children who following evaluation by their clinical multidisciplinary team (which will include a geneticist or genetic counsellor) are likely to have a rare monogenic condition. Other affected family members of eligible patients may be also invited to participate in the study. Information for this study will be collected primarily from investigations performed as part of the participants' routine clinical care including whole genome sequencing commissioned by NHS England. The study will seek consent to access and export this data. Procedures performed as part of this study may include venepuncture and/or saliva collection and carry minimal risk to the patient. Parents of participants that are recruited into the study will donate a blood sample (or saliva sample if unable to provide blood) and consent will be requested for collection of health information and results of relevant investigations carried out as part of their routine clinical care (e.g. an echocardiogram). Other family members that are recruited into the study will donate a blood sample (or saliva sample if unable to provide blood) and consent will be requested for collection of health information. Family members of deceased patients with cardiomyopathy or other inherited cardiac conditions may be asked if they wish to donate stored samples that may have been taken prior to death or as part of a post-mortem examination to establish cause of death. Any discussion with regard to the use of stored samples for this project will be initiated by the clinical care team for the deceased patient and their family to minimise any potential distress to the family. Sub-sets of patients may be asked to donate tissue samples taken as part of their clinical care.

The investigators will conduct a pilot feasibility and efficacy trial of a newly developed family health communication tool (called Let's Get REAL) in increasing youth involvement in real-time stem cell transplant and cellular therapy decisions (SCTCT). The investigators will pilot the intervention among 24 youth and their parents, stratified by youth age (stratum 1, 8-12 years of age and stratum 2, 13-17 years of age).

Study Objective: This study aims to validate and apply novel Cardiac Magnetic Resonance (CMR) imaging biomarkers to improve the diagnostic precision and risk stratification of rare cardiomyopathies (e.g., cardiac amyloidosis, Fabry disease, Danon disease, Noonan disease). Clinical Problem: Rare cardiomyopathies are often challenging to diagnose due to overlapping phenotypic features with more common disorders and their heterogeneous presentation. Current risk stratification tools are imperfect, leading to delays in diagnosis and suboptimal timing of interventions. Methodology \& Innovation: The study will employ advanced CMR techniques that move beyond standard volumetric and functional assessment. This includes, but is not limited to: T1/T2 Mapping: For quantitative tissue characterization to detect diffuse fibrosis or edema without contrast. Extracellular Volume (ECV) Fraction: To quantify the expansion of the extracellular space, a key marker in amyloidosis and other infiltrative diseases. Feature Tracking Strain Analysis: To assess subtle myocardial deformation abnormalities that precede a decline in ejection fraction. Late Gadolinium Enhancement (LGE) Pattern Refinement: For more precise characterization of scar and infiltration patterns. Potential Impact for Clinical Practice: Referral \& Diagnosis: This research could provide more definitive, non-invasive diagnostic data, streamlining the referral pathway to specialist centers and reducing diagnostic odysseys for patients. Risk Stratification: The novel biomarkers investigated have the potential to offer superior prognostic value compared to current clinical models. This can aid in identifying high-risk patients earlier, guiding decisions regarding device therapy (ICD) initiation or referral for advanced therapies. Management: By providing a more detailed "tissue phenotype," the findings could help monitor disease progression and response to emerging targeted therapies more sensitively.

The immediate goal of this research is to create a natural history database to collect information from individuals who have a rare GSD. A repository of clinical, laboratory, and biochemical information on individuals with a rare GSD will allow a more definitive description of the different subtypes to be developed, which will permit development of treatment strategies in the future. Duke will be the only site where this study takes place. However, since these are rare disorders, participants who receive care at other institutions will be included. The investigators will collect retrospective data from patient charts on diagnosed individuals, as far back as necessary to capture the clinical course of their disorder. Prospective data collected from patient charts after enrollment will be captured as well. Participant's medical records will be continually reviewed for the duration of the study. Data will be collected from medical records and will only pertain to clinically relevant information, including, but not limited to: demographic and diagnostic information, tissue biopsy results, medical and family history, review of systems, imaging studies, results of liver, muscle, and nerve function testing, and urine and blood laboratory results.

The research goal of this study is to obtain CD34+ hematopoietic stem cells (HSC) from peripheral blood and/or bone marrow, and Mononuclear Cells (lymphocytes and monocytes), and granulocytes (grans) from peripheral blood that will be used in the laboratory and/or in the clinic to develop new cell therapies for patients with inherited or acquired disorders of immunity or blood cells. Development of novel cellular therapies requires access to HSC, Mononuclear Cells and/or granulocytes as the essential starting materials for the pre-clinical laboratory development of gene therapies and other engineered cell products. HSC or blood cells from healthy adult volunteers serve both as necessary experimental controls and also as surrogates for patient cells for clinical scale-up development. HSC or blood cells from patients serve both as the necessary experimental substrate for novel gene therapy and cellular engineering development for specific disorders and as pre-clinical scale up of cellular therapies. Collection of cells from adult patients collected in the NIH Department of Transfusion Medicine (DTM) under conditions conforming to accepted blood banking clinical practice may also be used directly in or cryopreserved for future use in other NIH protocols that have all required regulatory approvals allowing such use. In summary, the research goal of this protocol is -the collection of HSC or blood cells that may be used for both laboratory research and/or for clinical treatment in other approved protocols. Participants include: 1. Adult patients with any primary immune deficiency (PID) or other blood disorder where collection is both for clinical use in another approved treatment protocol to benefit the patient and for laboratory research; 2. Adult patients with any primary immune deficiency (PID) or blood disorder where collection is for laboratory research use only. 3. Healthy adult volunteers where the collection is for laboratory research use only. The majority of subjects will have HSC collected from peripheral blood by apheresis. Daily subcutaneous injections of G-CSF (granulocyte colony stimulating factor/filgrastim) for 5 to 6 days is a standard of care method used to mobilize HSC to the peripheral blood prior to apheresis, and will be used for most subjects. Plerixafor (Mozobil) is approved as standard of care for use in combination with G-CSF to mobilize HSC. Some adult patients will have a clinical scale aspiration collection of bone marrow to obtain HSC for clinical use in another approved treatment protocol. Some adult participants may have a small sample needle aspiration collection of bone marrow obtained for laboratory research purposes only. Mononuclear cells and/or Granulocytes (gran) will be collected from peripheral blood by apheresis following no stimulation, using G-CSF alone, or a using a combined single dose of G-CSF (480mcg) and Dexamethasone (8mg) prior to collection as is the standard of care pre-treatment used in the NIH DTM for collection of granulocyte transfusions from healthy donors. As noted, HSC, mononuclear cells, and gran collection from patients with PID or other blood disorders may be used for laboratory research or may be designated for future clinical treatment of the patient under separate treatment protocol. HSC, mononuclear cells, and gran collection from healthy volunteers will be designated entirely for laboratory research. HSC will be used for the following clinical purposes, where clinical treatments would occur under separate IRB approved protocols: 1. Autologous HSC from patients may be genetically modified and infused into the patient for treatment of an infection or the underlying disease (Gene therapy); 2. Autologous HSC from patients may serve as back up (rescue product) for patients undergoing matched unrelated donor transplantation or haploidential related or unrelated donor transplantation. Mononuclear Cells (lymphocytes and monocytes) and granulocytes will be used for the following clinical purposes, 1. Autologous lymphocytes may be genetically modified and infused into the patient for treatment of an infection or the underlying disease (Gene therapy); 2. Autologous lymphocytes, monocytes and granulocytes (neutrophils) may be transfected with mRNAs to transiently express a therapeutic protein for treatment of an infection or the underlying disease (Gene therapy). HSC, lymphocytes, monocytes and granulocytes will be used for laboratory research studies that include: Delineating the pathophysiology of inherited immune deficiencies; Delineating the physiology of and improving engraftment of hematopoietic stem cells; Determining how hematopoietic stem cells may be maintained in ex vivo culture without losing pluripotent potential; Delineating the molecular mechanisms responsible for lineage specific differentiation; Developing efficient methods for gene transfer into hematopoietic stem cells for corrective gene therapy; Developing methods for restoration of function in defective peripheral blood monocytes and/or granulocytes; Further characterization of peripheral blood monocytes and/or granulocytes from patients with PID.

Calciphylaxis, also known as uremic calcifying arteriolopathy (UCA), is a rare disease that causes painful ischemic skin lesions due to microvascular calcification and thrombosis of the dermis and subcutaneous adipose tissue. Patients with end-stage renal disease (ESRD) are the main target for calciphylaxis. Rheopheresis is a therapeutic apheresis to treat microcirculatory disorders. This double filtration plasmapheresis eliminates a defined spectrum of high molecular weight proteins from human plasma including relevant factors for vascular inflammation and thrombose. The investigators propose a prospective randomized controlled trial to compared the efficacy of rheopheresis as adjuvant treatment to the standard of care compared to standard care with Sham-apheresis.