臨床研究等提出・公開システム

Clinical research for auto-transplantation of lcat-gene transduced preadipocytes in patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency (Clinical research for auto-transplantation of lcat-gene transduced preadipocytes in patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency)

Gene/cell therapy for familial LCAT deficiency by auto-transplantation of lcat-gene transduced preadipocytes (Gene/cell therapy for familial LCAT deficiency)

Yokote Koutaro

Oct. 06, 2021

1

A 34-year-old male patient, based on published papers, a mutation in the LCAT gene resulted in p.Pro69Leu amino acid residue substitution in the LCAT protein. No particular medical history or complications were observed at the time of the screening examination.

Written informed consent was obtained on January 25, 2017 for the first case. Lippsuction was performed on February 2, 2017, and administration of the LCAT gene-transduced preadipocytes to the subject was performed on February 23, 2017. After that, according to the implementation plan, the observation period and the follow-up survey period were completed. The final visit of the follow-up period was October 6, 2021. This period ended without any major deviations.

Pain at the site of cell administration (resolved within a few days with administration of analgesics)

The primary endpoint was the occurrence (frequency and type) of adverse events. Adverse events observed in one case were 1) pain at the site of liposuction, 2) pain at the site of cell administration, and 3) hypertension. 1) was due to liposuction, and was quickly recovered by administration of analgesics. 2) reported as above. 3) was judged to be due to exacerbation of the primary disease (LCAT deficiency). Administration of antihypertensives improved the symptoms. No RCR in subject's blood sample or tumorigenicity of the transplanted cells in immunodeficient-mice was observed. In addition, no abnormalities were observed in other clinical findings.

This study was discontinued after only one case, due to a change in the development policy to move to clinical trials for the practical use. Post-administration pain was recognized but no abnormalities were observed. Blood LCAT activity was sustained. Abnormal lipoproteins and hemoglobin-haptoglobin complex associated with anemia were decreased, suggesting sustained LCAT supplementation. There were no serious safety concerns in at least one patient, and the results suggested the efficacy of the treatment.

Dec. 28, 2023

Nov. 01, 2022

https://www.sciencedirect.com/science/article/pii/S2405844022025592?via%3Dihub

https://jrct.mhlw.go.jp/latest-detail/jRCTa030190230

Yokote Koutaro

Chiba university

1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba

kyokote@faculty.chiba-u.jp

Mori Shigemasa

Chiba University

1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba

+81-43-222-7171

byoin-kshien@chiba-u.jp

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Patients who are determined to be suffering from familial LCAT deficiency based on the following diagnosis criteria.
(1) Patient with LCAT genetic abnormality, as determined by a genetic diagnosis (test) (Excluding, however, patients in which LCAT Full length proteins are not expressed due to occurrence of termination codon or frame shift mutation).
(2) Patients present low HDL-cholesterol levels with one or some of following manifestation, Corneal opacity, Renal dysfunction (proteinuria), Hemolytic anemia.
(3) Plasma (or serum) LCAT activity is lower than the standard minimum limit.
2) Patients whose poor quality of life and prognosis are predicted due to clinical symptoms (especially corneal opacity and renal dysfunction) .
3) Patients older than 16.
4) Patient who provides written informed consent. If the patient is a minor, written consent must be obtained from the patient as well as a parent or guardian.

1) Patients that show no LCAT full length protein variation and/or patients in which LCAT proteins are not detected in the blood.
2) Patients with concomitant acute liver disease as a result of lipid metabolism (Acute hepatitis, cirrhosis of the liver) or kidney disease.
3) Mal- or undernourished, or suffering from a nutritional disorder such as Cachexia.
4) Will undergo a blood and/or plasma transfusion within one month prior receiving LCAT replacement therapy.
5) Patients testing positive for severe viral infection (Hepatitis B, Hepatitis C, HIV, Adult T-cell leukemia, Parvovirus B19, or Syphilis)
6) Liposuction surgery deemed too challenging to undergo.
7) Women who are pregnant, nursing, or could become pregnant
8) Patients suffering from an illness that leads to low blood cholesterol other than LCAT deficiency (ApoA-1 hypercholesterolemia, Tangier disease)
9) Patients determined ineligible by the principal-investigator and co-investigator in charge for any reason.

Both

Familial LCAT deficiency

D014182

auto-transplantation

Adipose tissue is extirpated from patient with familial LCAT deficiency syndrome and subjected to primary culture by ceiling culture. Normal LCAT gene is transduced into the obtained preadipocytes by retroviral vector-mediated gene transduction. Propagated LCAT-secreting preadipocytes are then subcutaneously transplanted into the patient.

D007863

cholesterol, High-density lipoprotein, Corneal opacity, Renal failure, Hemolytic anemia

Purpose of this study is to evaluate adverse event(s) of LCAT replacement by auto-transplantation of lcat-gene transduced preadipocytes.

Effects of LCAT replacement on main symptoms of the LCAT deficiency (Plasma (or serum) LCAT activity, HDL-cholesterol, cholesteryl ester/total cholesterol ratio, renal manifestation, visual impairment, corneal opacity, and anemia) are exploratively evaluated.

Complete

+81-6-6210-8293

June. 02, 2016