Standard Recommendations for the Application of Chinese Clinical Cell Therapy for Neurorestoration (2012)

Abstract

Cell therapy has been shown to be a promising alternative therapy for neurorestoration, and more than 30 different types of cells have been shown to possess some capability to restore lost or damaged neurological functions. Chinese physicians have successfully applied cell therapy to many neurological diseases and damages in the clinic and contributed to establish a discipline of neurorestoratology. To standardize the clinical procedures of cell therapy as one of the strategies for treating neurological disorders, the Chinese Branch of the International Association of Neurorestoratology (IANR) and the Preparatory Committee of Chinese Association of Neurorestoratology recently completed the Standard Recommendations (2012) for the Application of Chinese Clinical Cell Therapy for Neurorestoration. We hope these recommendations will guide clinical practice in applying cell therapy for neurorestoration, which will therein offer a reference for both Chinese and other countries' governments to make relevant official regulations. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Introduction

Neurorestoratology is a subdiscipline of neurological science that studies neural regeneration, repair, and replacement of a damaged nervous system via neuroplasticity, neuroprotection, and neuromodulatory mechanisms of recovery. The goal of neurorestoratology is to promote the recovery of neurological functions (33).

Cell therapy is an important intervention for neurorestoration, and preclinical studies have confirmed that more than 30 types of cells have some capability of neurorestoration (1,4,6,7,11,12,14–18,21–26,31,32,35,36,38–41, 44,47,48,50–55,57,59–62,64,66–69,71,73–75,77–80, 82–85). Currently, cell therapy has been used in humans in over 30 countries, and in most cases safety and some degree of possible beneficial effects have been demonstrated (2,3,5,8,9,13,19,20,27–30,34,37,42,43,45,46,49, 56,58,63,65,70,72,76,81,86). However, its application for neurological diseases currently lacks worldwide consensus standards. China is one of the pioneer countries conducting this therapeutic technology and is leading the development of this frontier. Chinese physicians have applied cell therapy to a variety of intractable neurological diseases and contributed to the establishment and development of the theoretical system of neurorestoratology. Therefore, it is our responsibility to standardize the clinical procedures for promoting the application of cell therapy as one strategy for treating neurological disorders. This will greatly contribute to the international community supporting cell-based neurorestorative therapy.

The standard recommendation for neurorestoration was broadly consulted and drafted by our society members and was approved by the Chinese Branch of the International Association of Neurorestoratology (IANR) and the Preparatory Committee of Chinese Association of Neurorestoratology on August 6, 2011, in Beijing. It was published in the Chinese Journal of Clinicians in October 2011 (10). On the basis of the 2011 version, new developments were approved and added in 2012 by the Chinese Branch of the IANR and the Preparatory Committee of Chinese Association of Neurorestoratology (known henceforth as the Association). These recommendations will guide clinical practice in applying cell therapy for neurorestoration, which will therein offer a reference for both Chinese and other countries' governments to make relevant regulations in the near future. We are aware that this recommendation is based on the current existing knowledge and so may need to be changed; therefore, it will be regularly updated by the working group by integrating the rapid development of science and technology in this field.

Standards

Standards have been created in the following areas: the guiding principles for neurorestorative cell therapy, cell name, cell quality control, cell dose, the patient informed consent, operation name, cell transplantation indications, cell transplantation contraindications, safety evaluation, efficacy evaluation, and additional points.

1. 1.

   The guiding principles for the neurorestorative cell therapy are timeliness, adequate dosage, multiple routes, multiple cell types, multiple courses, and combined treatment.

2. 2.

   Cell name:

3. b.

   The name of cells differentiated in vitro is suggested as “x stem cell-derived x cell.” For example, “embryonic stem cell-derived adipose precursor cells,” “embryonic stem cell-derived neural stem/progenitor cells,” and “mesenchymal stem cell-derived Schwann-like cells” are all adequate cell names.

4. c.

   The name of cells undifferentiated in vitro or adult cell populations is recommended based on the most abundant cell type and indicates sources such as “embryonic stem cells,” “Schwann cells,” and “xx glial cells.”

5. d.

   The name of cells undergoing various developmental stages is not currently clearly defined, and it is therefore recommended to be based on “tissue derived source” or “contains a variety of cell name,” such as “olfactory mucosa cells,” “neural stem/progenitor cells,” “ bone marrow mesenchymal cells or bone marrow mononuclear cells,” “umbilical cord mesenchymal cells,” or “peripheral blood mononuclear cells.”

3.

Cell quality control: Quality control is the foundation of the safety and efficacy of cell therapy and includes cell collection, culture production, identification, induction, amplification, transmission, transfusion operating conditions, composition and content of various cytokines and detection (reactive) cells, the number of generations, exogenous factors, storage, biological effects (proliferation dynamics) testing, transportation, disposal of the whole process before clinical use, etc. These should be strictly implemented following the national standards (the standards should be made by the Association with reference to the internationally accepted principles if no relevant national standards are available). Serum-free cultures are recommended. If not, the fetal bovine (or equivalent) sera in cultures should be removed before applying to patients. Quality control should include, at least, total number of cells, generation in vitro, incubation time, cell viability, cell purity, karyotype analysis, the proportion of surface markers, and detection of infectious disease indicators. In certain low-temperature conditions, the optimal time for the cells from clinical laboratory to surgical implantation in patients is recommended not to exceed more than 2 h (24).

4.

Cell dose: Cells should be used to reach an effective dose but cannot exceed the safe dose. Each cell, administration route, single and cumulative effective dose, and a safe dose have a range. Also, differences are likely to exist among various diseases. The volume of each (target) maximum cell suspension injection is recommended as follows: 200 μl for brain parenchyma, 25 μl for spinal cord parenchyma, 10 ml for cerebrospinal fluid route, and 10–100 ml by vascularity. The Association will regularly revise and refine the standards of safe dose and effective dose on the basis of preclinical safety, effectiveness evaluation, and safe/effective dose range determined by acute toxicity, chronic toxicity, directed differentiation outcome, pathological animal models, and combining empirical clinical dose with evidence-based medicine clinical study. Currently, the prescription of a single dose of cells is commonly recommended as below:

• a.

Glial cells: 2.0–3.0 × 10⁶ for intrathecal injection; 1.0–2.0 × 10⁶ for the spinal cord/brain parenchymal injection.

b.

Neural stem/progenitor cells: 5.0–6.0 × 10⁶ for intrathecal injection; 5.0–6.0 × 10⁶ for spinal cord/brain parenchymal injection.

c.

Umbilical cord mesenchymal stem cells: 0.3–1.0 × 10⁶/kg body weight, the elderly and frail patients, where appropriate, reduce by 1/3 to 1/2, for intravenous infusion; 5.0–10.0 × 10⁶ for intrathecal injection; 5.0–6.0 × 10⁶ for spinal cord/brain parenchymal injection.

d.

Cord blood mononuclear cells: 1.0–2.0 × 10⁶/kg body weight for intravenous infusion, the elderly and frail patients, where appropriate, reduce by 1/3 to 1/2; 5.0–6.0 × 10⁶ for intrathecal injection.

e.

Bone marrow mononuclear cells: 3.0–9.0 × 10⁸ for intravenous infusion; 5.0–6.0 × 10⁶ for intrathecal injection.

f.

Mobilized peripheral blood mononuclear cells: autologous blood nucleated cells obtained from blood cell separator can be handled by the circulation: 1.0 × 10⁹.

5.

Patient informed consent: Informed consent is required for any study. To allow patients to provide this, the patients and their families have the right to know about all the possible benefits and potential risks of matters related with the cell transplantation and procedures. Physicians should continue to learn and master the latest cell therapy-related knowledge in order to provide objective answers.

6.

Operation name and operation record: The names of cell transplantation operation include anesthesia, surgical approach, surgical procedure, transplantation method, transplantation site, transplanted cell type, and quantity of transplanted cells. Examples are described below:

• a.

stereotactic brain parenchyma (x target) neural stem/progenitor cell transplantation through the frontal approach under local anesthesia;

b.

x x cell transplantation through ventricle puncture under local anesthesia;

c.

x x cell transplantation by cisterna magna puncture under local anesthesia;

d.

intrathecal x x cell transplantation through cervical, thoracic, or lumbar puncture under local anesthesia;

e.

subarachnoid x x cell transplantation in cervical, thoracic, or lumbar puncture under local anesthesia by X-ray guidance;

f.

x x cell spinal cord parenchyma transplantation in cervical, thoracic, or lumbar segment under general anesthesia;

g.

myelography CT-guided spinal cord parenchyma x x cell transplantation in cervical, thoracic, or lumbar puncture under local anesthesia;

h.

myelography CT-guided spinal subarachnoid x x cell transplantation in cervical, thoracic, or lumbar puncture under local anesthesia;

i.

CT-guided spinal cord parenchyma x x cell transplantation in cervical, thoracic, or lumbar puncture under local anesthesia;

j.

CT-guided spinal subarachnoid x x cell transplantation in cervical, thoracic, or lumbar puncture under local anesthesia;

k.

intravenous x x cell transplantation;

l.

x x cell intravascular transplantation by ultra-artery catheterization;

m.

intramuscular x x cell transplantation.

7.

Cell transplantation indications: Cell transplantation may be a useful mechanism of treatment for the following patients: patients with confirmed diagnosis of neurological diseases, including neurotrauma, neurodegeneration, ischemic/hypoxic brain injury, demyelination, sensory–motor disorders, neuropathic pain, as well as nerve damage caused by intoxication, physical/chemical factors, immune, infectious, inflammatory, hereditary, congenital, developmental, etc. In clinical studies, determined by evidence-based medicine, the Association will regularly revise and refine the items.

8.

Cell transplantation contraindications: Cell transplantation contraindications with which patients cannot tolerate cell transplantation procedures include poor general condition, major organ dysfunction, infection or pressure sores in surgical site, bleeding tendency, coagulation disorder that cannot be corrected, and emotional disturbance. Hypersensitivity and super-aged (>90 years) patients should be recruited with caution.

9.

Safety evaluation: Detailed records must be kept for any cell therapy-related adverse events by using standardized terminology, such as fever, headache, infection, rash, poor wound healing, dyspnea, increased/decreased blood pressure, increased/decreased heart rate, neurological deterioration, cerebrospinal fluid leakage, and so on.

10.

Efficacy evaluation: Uniform evaluation standards and scales that are commonly used in the international community are required to assess patients. Regular training courses are offered nationwide by the Association, and physicians who assess patients should undergo uniform evaluation training. Those who pass the course examination will gain professional qualification for assessing patients.

11.

The exploration of individual treatments should be encouraged for improving the outcome continuously based on the clinical cell therapy application standard.

12.

According to the previous accumulation of clinical practice, the combination of different cells, approaches of combined transplants, setting of treatment course, and comprehensive strategy is crucial in developing research direction. The Association will actively organize multicenter studies for different diseases. Randomized, double-blind, controlled clinical studies should be carried out preferentially; if unsuitable, other types of clinical studies or trials should be started. On the basis of preclinical study, translational medicine, evidence-based medicine, and clinical study, the Association will regularly revise and publish safety programs and efficiency programs of cell therapy for neurorestoration.

13.

All groups that do clinical cell transplantation should promptly analyze and summarize their data for publications to help other physicians refer to, compare with, and provide further validation.

Drafted by the following members of the Association: Xijing He, Huancong Zuo, Lin Chen, Tiansheng Sun, Gengsheng Mao, Guoming Luan, Shiqing Feng, Nanbert Zhong, Qiang Ao, Qin Huang, Zonghui Liu, Zuo Luan, Yong Man, Zuncheng Zheng, Yaojian Rao, Zhihai Fan, Guanghong Xiang, Yunliang Wang, Huailin Wang, Yingjie Lu, Xuefeng Lv, Tongchao Geng, Hongyan Xing, Tong Li, Hongyun Huang.