Stem Cell Therapy for Male Infertility

(SDTO Trial)

Overseen By Constance John, PhD

Age: 18 - 65

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: CellARTs Inc.

Disqualifiers: Lack of testicles, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Purpose: This clinical trial aims to explore the potential for human sperm production in vitro by sustaining a laboratory-cultured adult testicular environment. It also seeks to identify genetic factors contributing to human sterility and failed spermatogenesis. The study's primary objectives include: 1. Identifying genomic markers associated with sterility and failed spermatogenesis. 2. Developing an ex vivo (outside the body) testis "organ-on-a-chip" ("iTestis") to support stem cell cultivation. 3. Determining whether human spermatogenesis can be re-created in vitro using stem cells nurtured in the iTestis model. Study Description: Researchers will analyze the genomic profiles of fertile and sterile male participants to map genetic abnormalities associated with sterility. Using testicular and skin tissue samples from participants, spermatogonial stem cells and pluripotent stem cells will be isolated and utilized to construct the ex vivo iTestis. This system will integrate genomic insights and prior research to foster human spermatogenesis outside the body. Participant Involvement: Participants will provide the following samples: * Blood sample for serum analysis. * A skin tissue biopsy. * Testicular tissue, obtained through fine needle aspiration (FNA) or testicular sperm extraction (TESE), as part of a routine procedure. All procedures will be conducted by the principal investigator and qualified research staff, ensuring participant safety and adherence to ethical guidelines.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is stem cell therapy for male infertility safe for humans?

Some studies suggest that stem cell therapies, like reprogramming human somatic cells into male germline stem cells, show high safety in terms of normal chromosome structure and function, but more research is needed to confirm safety in humans. ^{1 2 3 4 5}

How does the treatment 'Stem Cell Therapy for Male Infertility' differ from other treatments for this condition?

This treatment is unique because it involves reprogramming somatic cells into male germline stem cells, which can then develop into sperm cells, offering a potential solution for men who cannot produce sperm naturally. Unlike traditional fertility treatments that require existing sperm, this approach aims to create sperm from stem cells, providing a novel option for those with severe infertility issues. ^{3 6 7 8 9}

What data supports the effectiveness of the treatment Stem Cell Therapy for Male Infertility?

Research shows that stem cell therapy can effectively treat azoospermia (a condition where a man has no sperm in his semen) in animal models, and similar techniques have been used to generate functional sperm cells from patients with certain types of infertility. This suggests potential for stem cell therapy to help treat male infertility in humans. ^{3 10 11 12 13}

Who Is on the Research Team?

Paul J Turek, MD

Principal Investigator

Chief Medical Officer

Are You a Good Fit for This Trial?

This trial is for men experiencing infertility due to genetic abnormalities or failed spermatogenesis. Participants will provide blood, skin tissue, and testicular tissue samples. The study excludes details on specific inclusion and exclusion criteria.

Inclusion Criteria

I am a man aged 18-60 with a diagnosis of no sperm count and have been infertile for over a year.

I am a man aged 18-60 with normal fertility undergoing fertility procedures.

Exclusion Criteria

I have not been diagnosed with fertility issues and I do not have testicles.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Sample Collection

Participants provide blood, skin, and testicular tissue samples for analysis

1-2 weeks

1 visit (in-person)

Ex Vivo Testis Development

Development of the iTestis platform using participant-derived stem cells

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after sample collection and iTestis development

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Genetic Reprogramming
• Genetic Screening
• Stem cell

Trial Overview The trial investigates human sperm production in vitro using an 'iTestis' organ-on-a-chip model. It involves genetic screening of participants, stem cell isolation from tissues provided, and attempts to recreate spermatogenesis outside the body.

How Is the Trial Designed?

Group I: Infertile Men with Acquired Sterility Experimental Treatment 4 Interventions

Sterile male participants with acquired infertility from chemotherapy, infection, undecended testicles that are undergoing sperm mapping or testicular sperm retrieval (TESE) procedures. Participants will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Group II: Infertile Males with Genetic Sterility: Sertoli Cell Only Experimental Treatment 4 Interventions

Sterile male participants with unexplained or defined genetic infertility of sertoli cell only that are undergoing sperm mapping or testicular sperm retrieval (TESE) procedures. Participants will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Group III: Infertile Males with Genetic Sterility: Early/Late Maturation Arrest Experimental Treatment 4 Interventions

Sterile male participants with unexplained or defined genetic infertility of early to late maturation arrest that are undergoing sperm mapping or testicular sperm retrieval (TESE) procedures. Participant will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Group IV: Fertile Males Active Control 4 Interventions

Fertile male participants (control group) with no known infertility conditions undergoing a vasectomy reversal. Participants will provide human tissue serum (via blood draw), skin (via biopsy), and testicular tissue (via biopsy).

Who Is Running the Clinical Trial?

CellARTs Inc.

Lead Sponsor

Trials

1

Recruited

100+

The Turek Clinic, Inc

Collaborator

Trials

1

Recruited

100+

Published Research Related to This Trial

Human Sertoli cells can be reprogrammed into male germline stem cells (SSCs) by overexpressing specific factors (DAZL, DAZ2, and BOULE), demonstrating a new method for generating male gametes.

The derived SSCs not only showed the ability to proliferate and differentiate into mature sperm cells in vitro but also maintained normal chromosomes, indicating a high safety profile for potential use in treating male infertility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct reprogramming of human Sertoli cells into male germline stem cells with the self-renewal and differentiation potentials via overexpressing DAZL/DAZ2/BOULE genes. Zhang, W., Chen, W., Cui, Y., et al.[2022]

Stem cell transplantation has been shown to effectively treat azoospermia, a major cause of male infertility, based on a systematic review of 18 studies, indicating its potential as a therapeutic option in animal models.

Among different methods, xenotransplantation and the use of umbilical cord mesenchymal stem cells were particularly effective, enhancing the expression of key meiosis-related genes and promoting spermatogenesis, although further research is needed to confirm these findings in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Cellular Therapy for Azoospermia in Animal Models: A Systematic Review and Meta-Analysis. Qiu, J., Ma, H., Pei, Y.[2023]

This study successfully generated functional spermatids from cryptorchid patients, which is crucial for treating male infertility, particularly in azoospermia cases.

The treatment with retinoic acid and stem cell factor significantly enhanced the development of spermatogonial stem cells, leading to haploid spermatids that have the potential for fertilization and embryo development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of haploid spermatids with fertilization and development capacity from human spermatogonial stem cells of cryptorchid patients. Yang, S., Ping, P., Ma, M., et al.[2020]

In a study involving rat models, researchers successfully restored fertility in DAZL-deficient rats by transplanting as few as 50,000 cultured spermatogonial stem cells, achieving 100% germline transmission to offspring.

This research suggests that similar techniques could potentially be applied to humans, offering hope for treating male infertility caused by genetic mutations or other factors, using minimal testis biopsies to obtain functional stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sterile testis complementation with spermatogonial lines restores fertility to DAZL-deficient rats and maximizes donor germline transmission. Richardson, TE., Chapman, KM., Tenenhaus Dann, C., et al.[2021]

A new transgenic rat model expressing EGFP in spermatogonial stem cells (SSCs) allows for easy identification and isolation of these cells, which are crucial for male fertility and spermatogenesis.

The DDX4-EGFP rat model demonstrated that SSCs can successfully establish spermatogenesis in infertile mouse testes, highlighting its potential for studying male infertility and germline modification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DDX4-EGFP transgenic rat model for the study of germline development and spermatogenesis. Gassei, K., Sheng, Y., Fayomi, A., et al.[2018]

A study on testicular cells from men with obstructive azoospermia found that culturing spermatogonial stem cells (SSCs) in a testicular cell suspension significantly increased colony formation compared to other culture methods, indicating a more effective environment for cell growth.

The testicular cell suspension culture also led to higher expression of germ cell-specific genes while reducing pluripotency gene expression, suggesting that this method promotes the differentiation of SSCs into functional gametes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Epigenetic Assessment of Human Spermatogenic Cells Derived from Obstructive Azoospermic Patients in Different Culture Systems. Zahiri, M., Movahedin, M., Mowla, SJ., et al.[2021]

Embryonic stem cell (ESC)-derived models show promise for screening male reproductive toxicity, as they closely resemble primordial germ cells and can be differentiated into gametes, providing a valuable tool for understanding infertility causes.

Human ESC (hESC) are suggested to be more effective than mouse ESC for in vitro toxicity screening due to their closer similarity to human gamete development, which could lead to better insights into environmental impacts on male reproductive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of human embryonic stem cell-based models for male reproductive toxicity screening. Krtolica, A., Giritharan, G.[2014]

Emerging reproductive technologies, such as using immature sperm precursors like spermatids and secondary spermatocytes, have shown promise in fertilizing human oocytes and resulting in healthy babies, offering hope for infertile couples.

While these innovative methods could provide alternative sources of gametes, their safety must be thoroughly established before being applied in human treatments, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative sources of gametes: reality or science fiction? Tsai, MC., Takeuchi, T., Bedford, JM., et al.[2022]

Chemotherapy and radiotherapy can cause permanent infertility in over 4000 male patients annually in the U.S. due to damage to the gonads, highlighting the need for effective fertility preservation methods.

Spermatogonial stem cells (SSCs) found in the testes of prepubescent boys may offer a promising avenue for restoring fertility, and the proposal of allogeneic testicular stem cell transplantation with an encapsulation device aims to develop a feasible solution for patients unable to produce functional sperm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surrogate testes: Allogeneic spermatogonial stem cell transplantation within an encapsulation device may restore male fertility. Gül, M., Dong, L., Wang, D., et al.[2021]

Spermatogonial stem cells (SSCs) are unique to males and are crucial for producing sperm and passing on genetic information, with the ability to self-renew and differentiate throughout a male's life.

A transplantation technique allows SSCs from fertile males to restore fertility in infertile males, and research indicates that the growth factors needed for SSC self-renewal are likely similar across mammalian species, paving the way for potential human applications in assisted reproduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Technology insight: In vitro culture of spermatogonial stem cells and their potential therapeutic uses. Kubota, H., Brinster, RL.[2022]

Infertility affects not just the ability to have children but also has broader emotional and societal impacts, highlighting the importance of addressing this condition.

The review discusses promising stem cell and gene therapy methods currently being researched that could provide new fertility treatment options for men with azoospermia, a condition where no sperm is produced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental methods to preserve male fertility and treat male factor infertility. Gassei, K., Orwig, KE.[2018]

The study demonstrated that mouse bone marrow-derived mesenchymal stem cells (BMSCs) can be differentiated into male germ-like cells when co-cultured with testicular cells and treated with bone morphogenetic protein 4 (BMP4), indicating a potential new approach for treating azoospermia.

Specifically, the treatment group that involved indirect co-culture with testicular cells showed a significant increase in the expression of male germ-like genes, suggesting that testicular cells release factors that aid in this differentiation process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differentiation of bone marrow derived mesenchymal stem cells into male germ-like cells in co-culture with testicular cells. Malekmohamadi, N., Abdanipour, A., Ghorbanlou, M., et al.[2020]

Pluripotent stem cells (PSCs) have the potential to differentiate into any cell type, including male germ cells, which could lead to new treatments for male infertility.

Current methods for producing functional sperm from PSCs include in vitro differentiation and in vivo transplantation, offering a promising source of autologous gametes for infertility treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retracted article: In vitro derivation of mammalian germ cells from stem cells and their potential therapeutic application. Saito, S., Lin, YC., Murayama, Y., et al.[2019]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Direct reprogramming of human Sertoli cells into male germline stem cells with the self-renewal and differentiation potentials via overexpressing DAZL/DAZ2/BOULE genes. [2022]

2. Turkey pubmed.ncbi.nlm.nih.gov

Efficacy of Cellular Therapy for Azoospermia in Animal Models: A Systematic Review and Meta-Analysis. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Generation of haploid spermatids with fertilization and development capacity from human spermatogonial stem cells of cryptorchid patients. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Sterile testis complementation with spermatogonial lines restores fertility to DAZL-deficient rats and maximizes donor germline transmission. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

DDX4-EGFP transgenic rat model for the study of germline development and spermatogenesis. [2018]

6. Iran pubmed.ncbi.nlm.nih.gov

The Epigenetic Assessment of Human Spermatogenic Cells Derived from Obstructive Azoospermic Patients in Different Culture Systems. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Use of human embryonic stem cell-based models for male reproductive toxicity screening. [2014]

8. England pubmed.ncbi.nlm.nih.gov

Alternative sources of gametes: reality or science fiction? [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Surrogate testes: Allogeneic spermatogonial stem cell transplantation within an encapsulation device may restore male fertility. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Technology insight: In vitro culture of spermatogonial stem cells and their potential therapeutic uses. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Experimental methods to preserve male fertility and treat male factor infertility. [2018]

12. Germany pubmed.ncbi.nlm.nih.gov

Differentiation of bone marrow derived mesenchymal stem cells into male germ-like cells in co-culture with testicular cells. [2020]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Retracted article: In vitro derivation of mammalian germ cells from stem cells and their potential therapeutic application. [2019]