iPS Cell-Derived Neural Glial cells (iGRP) Therapy

REPROCELL is advancing research and development aiming for clinical applications by creating iPS cell-derived neural glial progenitor cells (iGRP: glial-restricted progenitor cells) as a new therapeutic strategy for central nervous system disorders.

To date, Q Therapeutics Inc. in the United States has developed fetal tissue-derived neural glial progenitor cells (GRP: Q-Cell®), which have demonstrated efficacy in various central nervous system disorders in preclinical studies. The FDA has completed the review of the Investigational New Drug (IND) application for clinical trials targeting Amyotrophic Lateral Sclerosis (ALS) and Transverse Myelitis (TM) in the U.S. However, the use of fetal tissue as the raw material for these neural glial progenitor cells raised challenges related to stable supply and ethical concerns.

Therefore, REPROCELL has addressed the issues of raw material supply and ethics by replacing fetal tissue with iPS cells as the source of the cells, enabling the stable and large-scale production of neural glial progenitor cells (iGRP).

Mechanism of Action

In the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and Transverse Myelitis (TM), abnormalities in neural glial cells, which support motor neurons, have been increasingly recognized as a cause of motor neuron cell death. iPS-derived neural glial progenitor cells (iGRP), induced from induced pluripotent stem (iPS) cells, are believed to play a role in suppressing motor neuron cell death and protecting their function in ALS and TM through mechanisms such as the supply of growth factors, toxin removal, and regulation of immune responses."

Therapeutic Indications

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Due to progressive muscle atrophy and weakness, the survival period without respiratory support is estimated to be approximately 2 to 4 years^[1].

In Japan, there are approximately 10,000 ALS patients, with 1,000 to 2,000 new cases diagnosed each year. The majority of patients are between the ages of 50 and 74, and the male-to-female ratio is estimated to be 1.3:1, indicating a higher prevalence in men.

"The full pathophysiology of ALS has not yet been fully elucidated; however, it is known that the degeneration of motor neurons is closely linked to glial cells, such as astrocytes and oligodendrocytes^[2].

The therapeutic effects of currently approved drugs in clinical practice are extremely limited, highlighting the need for the development of new treatment options.

[1] Mejzini R, et al. ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now? Front Neurosci. 2019 Dec 6; 13:1310. PMID: 31866818

[2] Haidet-Phillips AM, et al. Human glial progenitor engraftment and gene expression is independent of the ALS environment. Exp Neurol. 2015 Feb; 264:188-99. Epub 2014 Dec 16. PMID: 25523812

Due to abnormalities in neural glial cells, motor neuron cell death occurs, leading to impaired neural transmission to muscles.

Transverse Myelitis (TM)

Transverse Myelitis (TM) is an acquired focal inflammatory disease that often leads to sudden muscle weakness, sensory disturbances, and bowel/bladder dysfunction. While it typically occurs independently, it can also arise as a complication of infections or as part of a continuum of other neuroinflammatory diseases. The condition affects the spinal cord transversely, causing bilateral impairments; however, in some cases, the impact may be partial or asymmetrical.

The duration of the illness ranges from 3 to 6 months in some cases, but can also result in permanent disability. When the impairment reaches its peak, 50% of patients become completely paralyzed in the lower body, and almost all patients experience some degree of bladder and bowel dysfunction^[3].

As autoimmune mechanisms are believed to play a role in the onset of Transverse Myelitis (TM), immunosuppressive drugs and steroids are currently common treatment methods. In cases where symptoms worsen despite these treatments, plasmapheresis, where a patient's blood is withdrawn and replaced with plasma from a healthy donor, may also be performed. However, the effectiveness of these treatments remains unclear, and further development of more effective therapies is needed.

[3] Simone CG, et al. Transverse Myelitis. 2022 Nov 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. PMID: 32644728.

The transverse inflammation in the spinal cord causes damage to the nervous system, disrupting neural transmission within the spinal cord.

Based on the results of non-clinical trials of Q-Cell®, GRP is expected to be effective in various central nervous system disorders as follows:

• Demyelinating diseases: Amyotrophic Lateral Sclerosis (ALS), Transverse Myelitis (TM), Cerebral Palsy, Stroke, Multiple Sclerosis
• Neurodegenerative diseases: Huntington's disease, Spinal Cord Injury, Traumatic Brain Injury, Parkinson's disease, Alzheimer's disease

Status of Development Progress

In October 2018, a clinical trial plan for Q-Cell® derived from fetal tissue, targeting Transverse Myelitis (TM), was announced at the University of Texas. In this trial, Q-Cell® will be administered to 9 patients with severe TM to evaluate its safety and efficacy.

In disease model animal studies, the survival duration of disease model mice receiving GRP administration was prolonged, and myelin formation was observed.

(A) Compared to disease model mice (Shiverer: black line), the survival duration of disease model mice administered with human glial progenitor cells GRP (Q-Cell®: orange line) was extended^[4]. (B)This is an observation of sheath-deficient model mice. Compared to non-transplanted mice, the Q-Cell® transplanted mice retained motor function.

[4] Lyczek A, et al. Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin. Exp Neurol. 2017 May;291:74-86. Epub 2017 Feb 2. PMID: 28163160.

In ALS model rats transplanted with iPS-derived neural glial cells, improvement in motor function was observed. Additionally, it was confirmed that motor neurons in the spinal cord of ALS model rats were maintained without degeneration.

REPROCELL is developing iPS cell-derived neural glial cells and conducting research and development for iPS cell-based regenerative medicine products targeting various neurodegenerative diseases. Currently, preclinical studies (animal testing) using iPS-derived neural glial cells are being conducted.

In Japan, in October 2022, REPROCELL was selected for the AMED public project, 'Development of Core Technologies for the Industrialization of Regenerative Medicine and Gene Therapy.' With the support of this project, we aim to accelerate research and development and initiate clinical trials as soon as possible.