A Novel Genome-Edited Hematopoietic Blood Cell System for Amyotrophic Lateral Sclerosis (ALS) Therapy
用於肌萎縮側索硬化症 (ALS) 治療的新型基因組編輯造血細胞系統
- A novel genome-edited hematopoietic blood cell system expressing the hematopoietic transcription factor EKLF(K54R) with change of the SUMOylating site brings new
opportunities of disease therapy and extension of health span / life span;
- In preclinical study, mice expressing the orthologous mutant EKLF (K74R) lived long and healthy with better motor activity, and their bone marrow mononuclear cells,
BMMNC(K74R), mitigated the motor dysfunction of an ALS mouse model, TDP-43(N390D/+).
- 表達造血轉錄因子 EKLF(K54R) 並改變 SUMOylating 位點的新型基因組編輯造血血細胞系統帶來了新的疾病治療和延長健康/壽命的機會；
- 在臨床前研究中，表達直系同源突變體 EKLF (K74R) 的小鼠壽命長且健康，具有更好的運動活動，以及它們的骨髓單核細胞，BMMNC(K74R)，減輕了 ALS 小鼠模型 TDP-43(N390D/+) 的運動功能障礙。
Targeted indication
ALS therapy:
by EKLF(K54) genome-edited human mononuclear cells (MNC)
Status
Pre-clinical studies and MOA identification
Key features
- - A blood system expressing the mutant EKLF (K74) allows mice, and human by implication, to live long and healthy;
- - High anti-ALS capability of the mouse bone marrow MNC (K74R).
Market
- The global ALS Treatment market size is projected to reach USD$ 470.1 M by 2028, from USD$ 285.9 M in 2021, at a compound annual growth rate (CAGR) of 6.9% during 2022-2028. Currently, there are 4 chemical compounds and 1 antibody available for prescription by medical doctors. However, none of them is effective in ALS therapy, therefore, development of new drugs for ALS is in urgent need;
- - Our pre-clinical studies have shown that mouse Eklf(K74R) as well as human EKLF(K54) genome-edited hematopoietic blood cells have better therapeutic effects than WT, suggesting that it will be clinically superior to unmodified MNC cell therapy in the future.
MODE OF ACTION
Mouse BMMNC (K74R) can mitigate ALS motor dysfunction due to increase of the number of spinal motor neurons. Also, inflammatory cytokines, e.g., IL-6, and immune check point protein, e.g., PD-1 and PD-L1, in the Eklf (K74R) mouse blood were low indicating the mitigation of ALS symptom via modulation of the inflammatory and immune pathways in spinal cord.
EXPERIMENTAL RESULTS
Eklf (K74R) mice lived with extended lifespan and healthspan;
No obvious side effects on ALS rodent model after BMMNC (K74R) transplantation;
Human MNCs from umbilical cord blood have been used in several clinical trials from phase I-III.
The above suggest that MNC transplantation is preclinically safe and without toxicity
Effects of ALS therapy by mouse BMMNC(K74R). (A) ALS mice receiving the bone marrow mononuclear cells (BMMNC) from the Eklf (K74R) (purple bar) exhibited significantly better exercise ability than the control group (red bar). Motor dysfunction and survival curve were also improved in the ALS mice carrying Eklf (K74R) (data not shown) (B) Increase number of spinal motor neuron in ALS mice receiving the BMMNC (K74R) compared to ALS mice and ALS mice receiving BMMNC(WT).
INTELLECTUAL PROPERTY
SELECTED PUBLICATIONS
Shyu et al. (2022). Advanced Science,9, e2201409.
Hung et al.(2020). International Journal of Molecular Sciences, 21(22): 8448.
BUSINESS OPPORTUNITY
Licensing and/or Collaboration, Sponsored Research
CONTACT
service@biip-dcc.org