Busulfan conditioning allows high engraftment of human genome edited hematopoietic stem cells and improved central nervous system correction in a mucopolysaccharidosis type I mouse model

SummaryLysosomal enzyme deficiencies comprise a large group of genetic disorders that generally lack effective treatments. A potential treatment approach is to engineer the patient’s own hematopoietic system to express high levels of the deficient enzyme, thereby correcting the biochemical defect and halting disease progression. Here, we present an efficient ex vivo genome editing approach using CRISPR/Cas9 that targets the lysosomal enzyme iduronidase to the CCR5 safe harbor locus in human CD34+ hematopoietic stem and progenitor cells. The modified cells secrete supra-endogenous enzyme levels, maintain long-term repopulation and multi-lineage differentiation potential, and can correct biochemical and phenotypic abnormalities in an immunocompromised mouse model of Mucopolysaccharidosis type I. Our studies provide support for the development of human, genome-edited CD34+ hematopoietic stem and progenitor cells for the treatment of a multi-systemic lysosomal storage disorder. Our safe harbor approach constitutes a flexible platform for the expression of lysosomal enzymes, exemplifying a potential new paradigm for the treatment of these diseases.

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Long-term evolution of mucopolysaccharidosis type I in twins treated with enzyme replacement therapy plus hematopoietic stem cells transplantation

Heliyon ◽

10.1016/j.heliyon.2021.e07740 ◽

2021 ◽

pp. e07740

Author(s):

Luis M. Carbajal-Rodríguez ◽

Martín Pérez-García ◽

Raymundo Rodríguez-Herrera ◽

Haydeé Salazar Rosales ◽

Alberto Olaya-Vargas

Keyword(s):

Stem Cells ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I ◽

Hematopoietic Stem ◽

Enzyme Replacement ◽

Term Evolution ◽

Stem Cells Transplantation ◽

Hematopoietic Stem Cells Transplantation

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Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I

Human Gene Therapy ◽

10.1089/hum.2017.187 ◽

2017 ◽

Vol 28 (7) ◽

pp. 576-587 ◽

Cited By ~ 19

Author(s):

Lalitha R. Belur ◽

Alexa Temme ◽

Kelly M. Podetz-Pedersen ◽

Maureen Riedl ◽

Lucy Vulchanova ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Gene Delivery ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Neurologic Disease ◽

Mucopolysaccharidosis Type I ◽

Adeno Associated Virus ◽

System A ◽

The Central Nervous System

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Cognitive impairment in patients with hematological malignancies at a long-term period after the transplantation of allogeneic hematopoietic stem cells

V M BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY ◽

10.31363/2313-7053-2020-1-20-29 ◽

2020 ◽

pp. 20-29

Author(s):

D. E. Vybornykh ◽

S. Yu. Fedorova ◽

S. O. Khrushchev ◽

M. Yu. Drokov ◽

E. G. Gemdzhian ◽

...

Keyword(s):

Stem Cells ◽

Central Nervous System ◽

Nervous System ◽

Hematopoietic Stem Cells ◽

Hematological Malignancies ◽

Cognitive Impairments ◽

Toxic Encephalopathy ◽

Hematopoietic Stem ◽

The Central Nervous System

A comprehensive assessment of clinical, clinico-psychopathological, neurological, neuropsychological and instrumental examinations in a single study allows for a more detailed study of cognitive impairments in patients with CSC at a long-term period (12-15 months) after the transplantation of allogeneic hematopoietic stem cells.Purpose. Assessment of cognitive impairments in patients with hematological malignancies at a long-term period after the transplantation of allogeneic hematopoietic stem cells.Materials and methods. Clinical, psychopathological, clinical, psychological, neuropsychological, neurophysiological and neurovisual methods were used to examine 36 patients with various hematological malignancies in the period of 12-15 months after allo-HSCT. Statistical data analysis was performed using the methods of descriptive statistics, analysis of contingency tables and dispersive (with repeated measurements) analysis.Results and discussion. At a long-term period of the study (12-15 months), it was found that cognitive impairments are largely eliminated under the influence of a temporary factor, as well as the treatment of associated conditions (mental disorders, infectious complications, etc.). However, their level does not reach the normal (or close to them) values characteristics of the pre-transplant stage. Among the causes of this phenomenon, mention may be made of the organic lesions of the central nervous system, which are recorded during EEG, CEP, MRI / CT studies, and toxic encephalopathy due to exposure to chemotherapeutic and immunosuppressive drugs.Conclusion. The dynamics of cognitive impairments in general reflects the dynamics of the multifactor effects of various hazards accompanying the transplantation of allogeneic hematopoietic stem cells on the central nervous system. In this case, it can be stated with confidence that the allo-HSCT procedure in the overwhelming majority of cases does not lead to critical cognitive impairments.

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