Sebastián L. Vega, Ph.D.Regenerative Medicine and Orthobiologics Symposium

September 30, 2020

Stem Cell Therapy: Basic Science and Current Regulations Overview

What are stem cells?

Characteristics of stem cells• ‘Blank cells’• Capable of cell division• Have the potential to give rise to specialized cell types

Cells that can be manipulated to develop into different types of cells in the body

Not all stem cells are created equal

Wikipedia

Totipotent

Pluripotent

Multipotent

Differentiated

1 to 3 days

5 to 14 days

Types of stem cells: embryonic stem cells

Embryonic stem cells come from the blastocyst• Very early stage embryo (< 2 weeks post-fertilization)

blastocyst

outer layer of cells= ‘trophectoderm’

cells inside= ‘inner cell mass’

embryonic stem cells taken fromthe inner cell mass

culture in the labto grow more cells

fluid with nutrients

EuroStemCell

Types of stem cells: somatic (adult) stem cells

Somatic stem cells reside in different niches & are multipotent

EuroStemCell; Gattazzo+ BBA 2014.

musclesskin

eyes brain

intestines (gut)

bone marrow

teeth

• Hematopoietic stem cells (HSCs) can differentiate into blood cells• Mesenchymal stem cells (MSCs) can differentiate into cells in connective tissues (fat, bone, cartilage)

• Follicular epithelial stem cells can differentiate into variety of cell types including interfollicular epidermis, hair follicle structures, sebaceous glands, and corneal epithelial cells

Types of stem cells: induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) are pluripotent• First reported by Dr. Shinya Yamanaka et al. in 2006

• Delivered 24 genes important in ESCs (retroviruses) to mouse fibroblasts, systematically removed one gene at a time until the “Yamanaka factors” were identified. (Oct 3/4, Sox2, Klf4, c-Myc)

R&D Systems

Are stem cells currently being used to treat orthopedic

tissue degeneration, pain, fatigue,

Alzheimer’s disease, cancer, etc.?

Stem cell therapies are easily accessible

351 US businesses engaged in direct-to-consumer marketing of stem cell interventions offered at 570 clinics

Turner & Knoepfler Cell Stem Cell 2016; WebMD; FDA.gov

Called about knee pain, 3 options:• Platelet rich plasma (PRP) injections• Prolotherapy – stimulate body’s natural ability

to repair by injecting an irritant into the joint• Stem cell therapy

Not covered by insurance, stem cell therapy most expensive ($3,000 - $5,000 per treatment).

The efficacy of most/all stem cell therapies offered at these clinics has not been evaluated by the FDA.

The only FDA approved stem cell-based products consist of blood-forming stem cells derived from umbilical cord blood to treat blood cancers and other blood disorders.

8 min drive

Stem cell therapies are easily accessible

351 US businesses engaged in direct-to-consumer marketing of stem cell interventions offered at 570 clinics

Turner & Knoepfler Cell Stem Cell 2016; WebMD; FDA.gov

Called about knee pain, 3 options:• Platelet rich plasma (PRP) injections• Prolotherapy – stimulate body’s natural ability

to repair by injecting an irritant into the joint• Stem cell therapy

Not covered by insurance, stem cell therapy most expensive ($3,000 - $5,000 per treatment).

The efficacy of most/all stem cell therapies offered at these clinics has not been evaluated by the FDA.

The only FDA approved stem cell-based products consist of blood-forming stem cells derived from umbilical cord blood to treat blood cancers and other blood disorders.

8 min drive

To what extent are stem cell therapies regulated?

FDA regulatory scheme for human cells/tissues

Shapiro & Wesoloski FDLI 2007; Childs+ Biochem J. 2020.

HCT/Ps• The FDA classifies novel cellular & tissue-based products as

“human cells, tissues, and cellular or tissue-based products” (HCT/Ps)

• Regulation is based upon statutory authority to prevent spread of communicable diseases

Two types of HCT/Ps regulation:• Section 361 of the Public Health Service Act

• Not subject to premarket clearance/approval• Section 351 of the PHS Act

• If 361 criteria not met, undergoes extra regulation outlined by the Federal Food, Drug, and Cosmetic Act (FDCA)• Device HCT/Ps 510(k) clearance

• Comply with Quality System Regulation (QSR)• Drug HCT/Ps new drug application (NDA) approval

• Comply with good manufacturing practice (GMP)

361 HCT/P Product Criteria• Minimally manipulated• Homologous use as determined by

product labeling• Manufacture does not involve

combination with another article• Depends on activity of living cells

only if intended for autologous/allogeneic use

Manufacturers can self-determine whether to place product on market or seek

advice from FDARisk of legal action, withdrawal

of product from market

FDA regulatory scheme for human cells/tissues

Shapiro & Wesoloski FDLI 2007; Childs+ Biochem J. 2020.

HCT/Ps• The FDA classifies novel cellular & tissue-based products as

“human cells, tissues, and cellular or tissue-based products” (HCT/Ps)

• Regulation is based upon statutory authority to prevent spread of communicable diseases

Two types of HCT/Ps regulation:• Section 361 of the Public Health Service Act

• Not subject to premarket clearance/approval• Section 351 of the PHS Act

• If 361 criteria not met, undergoes extra regulation outlined by the Federal Food, Drug, and Cosmetic Act (FDCA)• Device HCT/Ps 510(k) clearance

• Comply with Quality System Regulation (QSR)• Drug HCT/Ps new drug application (NDA) approval

• Comply with good manufacturing practice (GMP)

361 HCT/P Product Criteria• Minimally manipulated• Homologous use as determined by

product labeling• Manufacture does not involve

combination with another article• Depends on activity of living cells

only if intended for autologous/allogeneic use

Manufacturers can self-determine whether to place product on market or seek

advice from FDARisk of legal action, withdrawal

of product from market

More stringent regulation & clinical testing is needed to evaluate the

efficacy of stem cell therapies

Stem cells have tremendous potential

Tissue engineering / cell manufacturing

Research Gate; Khademhosseini+ PNAS 2005.

Material Properties

soluble cues

Stem cells need instructions

Tissue Engineering (Drs. Langer & Vacanti): applying the principles of engineering and life sciences toward the development of biological substitutes that

restore, maintain, or improve tissue functionScaffolds violate 361 HCT/P Product Criteria• Manufacture cannot be combined

with another article• Would need 510(k) / NDA

Stem cells & scaffolds for future stem cell therapies

Stem cells are cells that can be manipulated to develop into different types of cells in the body

Preventing osteoporotic fractures

macromer macromer

tetrazine norbornene

BMP-2

Restoring damaged vocal folds

macromer macromer

tetrazine norbornene

adhesion

Tet, EDC/NHS

HA backbone

HA-Tet macromer

Hyaluronic acid (HA)

Nor, Boc2O

HA-Nor macromer

• Hydrogels are biomaterials that can manipulate stem cell behavior

• Can deliver stem cells to areas of need

1 mm5 million MSCs/ml

4 mm

• Form hydrogels in minutes• Tunable functionality• Stem cells highly viable

Questions

theVegaLab theVegaLab.com

CollaboratorsTae Won B. Kim, M.D.David Fuller, M.D.Vincent Beachley, Ph.D.Amir Miri, Ph.D.

Previously/currently marketed clinical products containing MSCs

Prices vary greatly based on dose• AlloStem, Cellentra, Trinity

Evolution fall under section 361of HCT/P regulation

No products use differentiated MSCs

Lack of reimbursement from health insurance companies has led to pulling some of these products from market

Childs+ Biochem J. 2020.

Personalized medicine

Bellin+ Nat Reviews Mel Cell Bio 2012

Stem cells have tremendous potential