Nature Medicine: Stem cell + gene therapy for the treatment of frostbite clinical trial results released, good safety, the future can be expected

Alzheimer's disease, also known as Amyotrophic Lateral Sclerosis (ALS), is one of the five terminal diseases recognized by the World Health Organization (WHO), which is a chronic, progressive degenerative disease involving upper/lower motor neurons and their innervagated trunk, limbs, and head and facial muscles, often manifested as progressively aggravated muscle weakness, muscle atrophy, and muscle bundle fibrillation caused by combined damage to upper/lower motor neurons

Frostbite is the most common type of motor neuron disease, there are about 200,000 patients with frostbite in China alone, the age of onset of patients is mostly between 30-60 years old, more men than women

On September 5, 2022, Clive Svendsen et al.

The study has developed a new treatment for Alzheimer's disease that combines stem cell therapy and gene therapy, using neural progenitor cells to express glial-derived neurotrophic factor (GDNF), a protein that protects motor neurons, to address the inability

The research team conducted the first human clinical trial using this combination therapy, and the results showed that the new therapy was safe for patients with frostbite, and that these neural progenitor cells were able to differentiate into astrocytes and express the GDNF protein

Professor Clive Svendsen, the study's corresponding author, said using stem cells to deliver GDNF proteins to the brain or spinal cord was an effective approach, and the study confirmed that genetically engineered stem cells could be safely transplanted into the

Hawking (left) visits the Clive Svendsen (right) laboratory in 2013

Previous studies have shown that astrocytes that support neuronal function are defective in alzheimer's and cause motor neurons to die

Preclinical studies have shown that transplanting human neural progenitor cells (hNPCs) into the central nervous system (CNS) of rodents, pigs, and non-human primates, these cells survive and differentiate into astrocytes without forming tumors, as well as protect host cells, playing a protective role
in degenerative disease and aging animal models.

However, transplanting wild-type human neural progenitor cells (hNPCs) into the lumbar spinal cord of the SOD1 transgenic model of frostbite rats did not slow the death of motor neurons and the progression of the disease in alzheimer's disease, suggesting that these human neural progenitor cells (hNPCs) also need further nutritional support to function
.

Glial-derived neurotrophic factor (GDNF) is a potent growth factor for dopamine and motor neurons, however, GDNF is unable to cross the blood-brain barrier
.

Previous clinical trials treating Parkinson's disease have confirmed the safety
of intra-parenchymal administration of GDNF.

However, in trials of the treatment of alzheimer's disease administered subcutaneously or intrathecally, GDNF has a short half-life in plasma, so penetration into the brain and spinal cord is low and difficult to play a therapeutic role
.

Clive N.
Svendsen's team hopes to combine astrocyte therapy with GDNF delivered directly to the spinal cord for cell and in vitro gene therapy to protect dying motor neurons
.

Clive Svendsen lab

Unlike human neural progenitor cell (hNPC) transplant treatment alone, hNPC cells genetically engineered to stabilize GDNF production protect motor neurons
in the lumbar spindle of a soD1 rat model after transplantation.

Moreover, these cells can survive long-term after transplantation without forming tumors, and can be safely transported into the spinal cord, where they further differentiate into astrocytes and protect motor neurons
.

Specifically, the team used a sample of human fetal cortex to generate neural progenitor cells, CNS10, which were then transduced to achieve stable GDNF expression
.

These cells are expanded and stored under GMP conditions to obtain a therapeutic product, CNS10-NPC-GDNF
.

The research team first conducted preclinical studies
in rats and pigs.

The research team then conducted the first human clinical trial
of cryogenesis combined with stem cells combined with in vitro gene therapy.

The 12-month Phase 1/2a clinical trial involved 18 patients with frostbite and transplanted CNS10-NPC-GDNF
into the unilateral lumbar spinal cord in increasing doses.

Dr.
Pablo Avalos, co-first author of the paper, said glial cell-derived neurotrophic factor (GDNF) cannot function through the blood-brain barrier on its own, and using neural progenitor cells to express and release GDNF is a new method that can deliver GDNF to the desired location to play a role in protecting motor neurons
.

In fact, these cells themselves and GDNF are able to act as a two-pronged protector of motor neurons
.

The primary goal of this Phase 1/2a clinical trial is to ensure that the delivery of GDNF-expressing neural progenitor cells into the spinal cord creates any safety issues that do not negatively affect
the patient's leg function.

Because the legs of patients with FROST often lose function at a similar rate, the research team only administered unilateral injections of the spinal cord to the patients, thus comparing
the patients' legs as a treatment group and a control group.

The research team has also developed a novel injection device that can safely deliver CNS10-NPC-GDNF into the
patient's spinal cord.

After the injectable transplant, the research team followed the patient for a year to measure the strength of the treated and untreated legs, and the results showed that cell transplant treatment did not negatively affect
the muscle strength of the legs compared to the untreated legs.

In addition, the team's tests of 13 participants who died as a result of disease progression found that these transplanted cells persisted and had the GDNF protein produced
.

The research team said that this clinical trial proved the safety of this treatment, proving that these cells can survive in patients for a long time and are safe in patients, which is the key
to further advancing the clinical trial.

The research team also said that new clinical trials for more patients with alzheimer's disease will soon begin, and more patients with early-stage alzheimer's will be recruited to see the impact of this treatment on
disease progression.

It is worth mentioning that the research team is also conducting another clinical trial for the treatment of alzheimer's disease, which also uses CNS10-NPC-GDNF, but transplants these cells into the cerebral cortex region
that controls hand movement.

At present, the clinical trial has completed the treatment of the first patient (a total of 16 patients participated
).

The main goal of the clinical trial is to prove safety, but it will also evaluate whether the treatment can improve hand motor function
.