aHUS-iPSC-EC: Functional Implications of Rare Gene Mutations in aHUS Open the Door to Personalized Therapy

Sponsor

Mario Negri Institute for Pharmacological Research (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05805202

Collaborator

(none)

112

Enrollment

Location

Arms

22.5

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Hemolytic Uremic Syndrome (HUS) is a rare disease characterized by rupture of red blood cells (hemolytic anemia), low platelet count (thrombocytopenia), and thrombotic occlusion of small vessels (thrombotic microangiopathy), with prevalent involvement of the kidneys.

SEU, in its typical form is caused by gastrointestinal infection with Escherichia coli.

The atypical form of SEU (aSEU), which is not caused by an Escherichia coli infection, is a very rare disease that may have a genetic origin; it affects both children and adults and may occur in a sporadic or familial form. Many studies have shown that about 60% of cases of atypical HUS are associated with genetic abnormalities of the complement system (particularly the so-called "alternative pathway"), which is a key part of the immune system for responding to infection. Complement consists of a series of proteins that, when activated, create a so-called "cascade," which leads to the elimination of the infectious agent, either directly or through other cells. Complement is finely regulated in such a way as to prevent damage to healthy cells in one's own body. Genetic defects in some of these complement regulatory proteins cause reduced protection of the endothelial surface (thus the vessel wall) against complement activation.

Recently, new mutations have been described in a gene unrelated to the complement pathway, the DKGE gene, which codes for the intracellular isoform of diacylglycerol kinase . In these patients, small renal vessel occlusion appears to occur as a result of altered endothelial cell proliferation and angiogenesis through mechanisms apparently unrelated to complement activation. However, to date these mechanisms are poorly studied. Throughout the entire project statistical methods will be applied to optimize the characterization of the abnormalities in phenotype and function of iPSC-EC derived from aHUS patients with either DGKE or MCP genetic abnormalities as compared with control iPSC-EC, including identifying potential drugs that could correct the abnormalities

Condition or Disease	Intervention/Treatment	Phase
Atypical Hemolytic Uremic Syndrome	Other: Blood sampling and urine analysis	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

112 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Screening

Official Title:

Functional Implications of Rare Gene Mutations in aHUS Open the Door to Personalized Therapy

Anticipated Study Start Date :

Apr 15, 2023

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: aHUS Patient The study will include 110 patients consenting adult and pediatric patients with a diagnosis of atypical hemolytic uremic syndrome and carrying mutations in the MCP or DGKE genes. New patients will be selected through clinical and genetic screening of the inhabitants of a small island of South Italy (Linosa) with high incidence of patients affected by DGKE mutations and characterized by a high rate of endogamy	Other: Blood sampling and urine analysis A blood sample of 10- 20 ml from pediatric patients, 30-50 ml from adult patients will be collected for each patient and healthy voluntarees
Other: Healthy volunteer 2 healthy subjects will undergo urine analysis (multistick) and only subjects with normal parameters will be enrolled as controls.	Other: Blood sampling and urine analysis A blood sample of 10- 20 ml from pediatric patients, 30-50 ml from adult patients will be collected for each patient and healthy voluntarees

Arm

Intervention/Treatment

Experimental: aHUS Patient

The study will include 110 patients consenting adult and pediatric patients with a diagnosis of atypical hemolytic uremic syndrome and carrying mutations in the MCP or DGKE genes. New patients will be selected through clinical and genetic screening of the inhabitants of a small island of South Italy (Linosa) with high incidence of patients affected by DGKE mutations and characterized by a high rate of endogamy

Other: Blood sampling and urine analysis

A blood sample of 10- 20 ml from pediatric patients, 30-50 ml from adult patients will be collected for each patient and healthy voluntarees

Other: Healthy volunteer

2 healthy subjects will undergo urine analysis (multistick) and only subjects with normal parameters will be enrolled as controls.

Other: Blood sampling and urine analysis

A blood sample of 10- 20 ml from pediatric patients, 30-50 ml from adult patients will be collected for each patient and healthy voluntarees

Outcome Measures

Primary Outcome Measures

Generation and characterization of patient-specific and healthy donor iPSC [once during the study]
Differentiation of iPSC into endothelial cells [once during the study]
Characterizationof iPSC into endothelial cells [once during the study]
Cell culture viability [once during the study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Adults and children with aHUS defined by history of microangiopathic hemolytic anemia and thrombocytopenia (hematocrit (Ht) <30%, hemoglobin (Hb) <10 g/dL, LDH >500 IU/L, undetectable haptoglobin, fragmented erythrocytes in the peripheral blood smear with negative Coomb's test, and platelet count <150,000/microL), associated with acute renal failure.
Written informed consent

Exclusion Criteria:

TTP (ADAMTS13 activity <10%)
STEC-HUS (presence of stx and eae genes or Shiga-toxin in the stools and/or serum antibodies against Shiga-toxin and/or STEC LPS).
Disseminated intravascular coagulation (prolonged thromboplastin time and lower than normal fibrinogen levels).