Dr Peter K Law is the Founder,
Chairman and Chief Executive Officer of the Cell Therapy
Research Foundation (CTRF) and Cell Therapy, Inc. (CTI).
Founded in 1991, CTRF focuses on developing biologic therapies
in treating hereditary, debilitating and fatal diseases.
He pioneered and holds world patent rights to myoblast
transfer therapy, the only human genome therapy in existence.
A former Professor of Neurology in The University of Tennessee,
Memphis, and Vanderbilt University, Dr Law received his
BSc with honours from McGill University, MSc and PhD from
the University of Toronto and Postdoctorate qualifications
from McMaster University in Canada.
Introduction
Heart muscle degeneration is the leading cause
of debilitation and death in humans. It is the common pathway
underlying congenital and infectious cardiomyopathies, myocardial
infarction, congestive heart failure, angina, coronary artery
disease and peripheral vascular disease, all of which constitute
cardiovascular diseases. Global healthcare spending on cardiovascular
diseases topped US$280 billion in 2001. In the US alone, approximately
US$186 billion is spent every year in treating some 60 million
cardiovascular disease patients. About 50% of the patients
suffering congestive heart failure will die within five years
of diagnosis.
Heart Muscle Degeneration
Heart muscle degeneration cascades with cardiomyocyte
membrane leakage, uncontrolled Ca2+ influx, mitochondrial
adenosine triphosphate (ATP) shutdown, inability to exude
Ca2+ through the cell surface and to reabsorb Ca2+ into the
sarcoplasmic reticulum, myofibrillar hypercontracture and
disarrangement. Apoptosis ensues, and fibroblasts proliferate
and infiltrate. The heart muscle, which was once populated
by live cardiomyocytes with proteinaceous contractile filaments
such as myosin, actin, troponin and tropomyosin, is now partially
occupied by fibrous scars that are incapable of electric conduction,
mechanical contraction and revascularisation. These scars
continue to exert a negative compliance on the heart and the
circulation despite remodelling after a myocardial infarction.
Natural Heart Muscle Repair
Ultimately, heart muscle degeneration results
in loss of live cardiomyocytes, contractile filaments, contractility,
heart function and healthy circulation. The damaged heart
responds by cell division of cardiomyocytes. However, such
regenerative capacity is hardly significant. Cardiomyocytes
in culturo will undergo no more than three to five divisions,
yielding an insufficient number of cells to repopulate any
myocardial infarct.
Cardiomyocytes do not multiply significantly
because the human telomeric DNA repeats in these terminally
differentiated cells are minimal. Telomerasing cardiomyocytes
in vivo still remains a technical challenge. Without significant
mitotic activity, surviving cardiomyocytes cannot provide
enough new cells to deposit the contractile filaments necessary
to maintain normal heart function.
The degenerative heart also transmits biochemical
signals to recruit stem cells from the stroma and the bone
marrow in an attempt to repair the muscle damage. Much of
the recruited stem cells differentiate to become fibroblasts
instead of cardiomyocytes, thus forming fibrous scars and
not contractile filaments. Thus, despite the claimed success
of transmyocardial revascularisation using laser, angiogenic
factors and genes, the damaged myocardium needs additional
live myogenic cells to deposit contractile filaments to regain
heart function, preferably before fibroblast infiltration,
which leads to scar formation.
Myoblasts Regenerate Muscles
Myoblasts are differentiated cells destined
to become muscles. Unlike cardiomyocytes, myoblasts have long
telomere DNA subunits and are capable of extensive mitosis.
Myoblasts obtained from young adults can undergo 50 divisions
without any loss of myogenicity or development of tumourigenicity.
Myoblasts survive and proliferate in intercellular fluid.
Their survival does not depend on vascularisation or nerve
innervation.
During ontogeny, human myoblasts migrate and
fuse spontaneously, beginning at day 53 gestation, sharing
their nuclei in a common gene pool and forming multinucleated
myotubes within the somites. The ability to undergo mitosis,
to migrate and to fuse are conserved in mononucleated satellite
cells that are essentially myoblast reserves in adult muscles.
Satellite cells are found between the basement
membrane and the plasma membrane of every skeletal muscle
fibre. Approximately 11% of all skeletal myonuclei belong
to satellite cells in young rats, declining to about 6% in
the aged. In human beings past age 26, there are fewer satellite
cells, each with shorter telomeres. Their muscle biopsies
thus yield fewer satellite cells that also exhibit less proliferative
vigour in cell culture.
Upon single myofibre injury, the satellite
cells are activated to divide and migrate from beneath the
basement membrane. They divide extensively, forming hundreds
of myoblasts that fuse spontaneously at the site of injury
to repair the host myofibre. They also fuse among themselves
to form new myofibres to substitute for lost function. The
signals to stop myoblast division and to initiate myotube
formation appear to be cell confluence and low serum level.
Newly formed myotubes have to be vascularised
and innervated within 10 days or they will perish. Successfully
innervated and vascularised, they deposit actin, myosin, troponin
and tropomyosin that eventually organise into sarcomeres,
the structural units of muscle contraction. This maturation
process takes approximately three months.
Myoblasts Strengthen
Dystrophic Muscles
Progressive skeletal muscle degeneration is
the hallmark of the 12 forms of human hereditary muscular
dystrophies. An enabling technology called myoblast transfer
therapy (MTT) has been developed in the past 27 years to treat
these degenerative, genetic diseases with success. MTT is
a platform technology of cell transplantation, nuclear transfer
and tissue engineering. It is the only human genome therapy
in existence.
MTT involves taking a two-gram muscle biopsy
from the quadriceps of a young normal male of age between
13 to 26, culturing some 10,000 satellite cells released to
become 50 billion pure myoblasts in 45 days and injecting
the myoblasts into 82 large muscle groups of the dystrophic
patient under general anaesthesia.
The patient takes oral cyclosporine as an
immunosuppressant for two months to suppress rejection of
the allografts. Since myoblast fusion completes within three
weeks after MTT, and since myotubes and mature myofibres do
not express major histocompatibility complex class 1 (MHC-1)
surface antigens, it is not necessary to administer lifelong
immunosuppression as in heart transplants.
As a cell therapy, MTT provides normal myoblasts
that fuse with each other, forming new myofibres to replenish
myofibre loss. As a genome therapy, MTT provides normal myoblasts
that spontaneously insert their nuclei (carrying the software
and the hardware of the complete genome) into the dystrophic
myofibre to effect genetic complementation repair. Whereas
the dystrophic myofibre degenerates because of the deletion
of an essential gene product, the donor myonuclei within the
synctial heterokaryon are now activated to renegerate and
produce the therapeutic messenger ribonucleic acid (mRNA).
The dystrophic gene that is deleted in Duchenne muscular dystrophy
(DMD) is integrated, regulated and expressed at least six
years after MTT.
Results of over 230 MTT procedures (on muscular
dystrophy) in the past 12 years have demonstrated an absolute
safety record, with no death or coma or failure in heart,
lung, kidney or liver function within two years of follow-up
studies. Myoblast-injected DMD muscles showed dystrophin and
improved histology as compared with placebo-injected muscles
that showed no dystrophin but fat and connective tissue. Their
average isometric force increase was 123% compared with the
natural controls at 18 months after MTT.
The Regenerative Heart
The goal to bioengineer the regenerative heart
seems to be within reach with MTT. Five grams of muscle biopsies
would be taken from both quadriceps of a heart patient with
age ranging from 40 to 90, culturing approximately one billion
myoblasts in four weeks and then injecting or surgically implanting
these cells between the vascularised and the nonvascularised
infracted myocardium.
Heart cell therapy (HCT), as this is called,
is administered with the vision that the myoblasts will survive,
develop and function as 'aliens' in the heart and their nuclei
as aliens within cardiomyocytes. The myocardial aliens are
newly formed skeletal myofibres that contribute to cardiac
output through production of contractile filaments. They are
donor in origin and, as skeletal myofibres, will have satellite
cells and regenerative capability. The cardiomyocyte aliens
are donor myoblast nuclei carrying chromosomes with long telomeric
DNA subunits that are essential for mitosis. Upon injury of
this heterokaryotic cardiomyocyte, the myoblast regenerative
genome will be activated to produce foreign contractile filaments
such as myosin.
Critical Supportive Data
Evidence in support of the above HCT mechanisms
was produced from a collaborative effort between Cell Transplants
Singapore Pte. Ltd. (CTS) (a Cell Therapy, Inc. (CTI) subsidiary)
and the National University Hospital (NUH) of Singapore, with
grant support (IDS, INTECH) from the Singapore Economic Development
Board (EDB).
Human myoblasts were manufactured according
to CTS standard operating procedures (SOPs) with a licence
of the US Patent No. 5,130,141. Myoblasts were 90% pure as
determined by desmin staining. Repeated transductions of the
myoblasts with retroviruses carrying Lac-Z yielded highly
efficient 70% to 75% Lac-Z positive cell population. Dye exclusion
tests using trypan blue revealed over 95% cell viability at
the time of injection. The following study was conducted with
a licence of the Singapore Patent No. 34490 (WO 96/18303).
A porcine heart model of chronic ischemia
was created by clamping an ameroid ring around the left circumflex
coronary artery in Yorkshire swine, four weeks prior to cell
transplantation. For cell transplantation, the animals were
anaesthetised and ventilated, and the heart was exposed by
left thoracotomy. Fifteen injections (0.25ml each) containing
300 million cells were injected into the left ventricle endocardially
under direct vision. For control animals, only a culture medium
without cells was injected. The animals were euthanised, and
the heart was explanted and processed for histological examination.
The cryosectioning of the tissue for subsequent staining for
Lac-Z expression, haematoxylin-eosin staining, Mason trichome
staining and immunostaining for skeletal muscle myosin heavy
chain was carried out by standard methods.
Histological examination of explanted porcine
myocardium 10 weeks later showed not only myofibres of human
origin, but also porcine cardiomyocytes and human myonuclei
with Lac-Z gene expression. More than 80% of the Lac-Z positive
porcine cardiomyocytes immunostained positive for human myosin
heavy chain. Control muscle stained sections did not show
any Lac-Z expression nor human myosin immunostain.
Human myoblasts survived and integrated into
the porcine ischemic myocardium, allowing concomitant cell
therapy and genome therapy. Whereas new fibre formation improves
heart contractility, the genetic transformation of cardiomyocytes
in vivo to become regenerative heterokaryons through myoblast
genome transfer constitutes an exciting new therapy for heart
repair.
Functions of the Regenerative Heart
Heartbeat is myogenic in origin and
is initiated by pacemaker activity in the sinoatrial
node. As depolarisation sweeps through the atrioventricular
node, the depolarisation excites the Purkinje fibres
of the bundle of His, which, in turn, signals the ventricles
to contract rhythmically.
Heart function would be impaired if
the rhythmic action potentials do not synchronise the
fibre contractions. In the regenerative heart, where
new skeletal myofibres are present, presumably at different
regions of the left ventricle, such heterogeny might
create undesirable electric aberrant such as arrhythmia.
Excitation of the heterokaryotic cardiomyocytes will
remain unchanged because there is little change in gap
junctions for current flow.
The threshold of excitatory depolarisation
for heart and skeletal myofibres is similar, i.e. between
40mV and 50mV. Whereas the cardiomyocyte action potential
is triggered with an increase in Ca2+ conductance into
the cell, the skeletal myofibre action potential is
triggered with an increase of Na+ conductance. As Ca2+
has greater ionic size than Na+ and therefore lower
ionic mobility, the action potential of cardiomyocytes
has a longer duration (~250ms) than that of skeletal
myofibre (~1.5ms). Conceptually, this difference in
durations is advantageous because the cardiomyocyte
depolarisation can continually excite the myofibres
that are skeletal in origin. Since the action potentials
of skeletal myofibres are of short duration, they will
merge into the compound action potential of the heart.
The skeletal myofibres will cease to fire and stop contracting
once hyperpolarisation of the myocardium reaches approximately
-50mV.
Skeletal myofibres are known to adapt
to the frequency of electric excitation to which they
are subjected. In the heart mileau and under the influence
of heart hormones and slow contractile activity, the
skeletal myofibres may develop characteristics of cardiomyocytes.
Further studies will be needed to substantiate this
possibility.
Immunostaining
of Porcine Ventricular Myocardium for Human
Skeletal Muscle Myosin Heavy Chain at Ten
Weeks After Myoblast Injection
(a) More than 80% of the
Lac-Z positive porcine cardiomyoctes immunostained
positive for human myosin (brown) and (b)
at high magnification to show Lac-Z labelled
human myonuclei (bluish green) expressing
human myosin (brown) in porcine cardiomyocytes.
Regardless of the electric outcome, the regenerative
heart is endowed with a greater number of myogenic cells capable
of mitosis and is prepared to regenerate upon injury. These
cells will produce more contractile filaments to augment heart
contractility. The latter is fundamental to the quality of
life and the lifespan of patients suffering various forms
of cardiovascular diseases. The regenerative heart may also
be installed to prevent heart attacks.
How the Regenerate Heart Compares
Most drug therapy such as angiotensin converting
enzyme (ACE) inhibitors and beta-blockers treat symptoms and
provide temporary relief. The implantable cardioverter defibrillator
(ICD) pacemaker and left ventricular assisted device (LVAD)
are acute measures that save lives. Injections of angiogenic
factor(s) or vascular endothelial growth factor (VEGF) genes
produce an increase in the number of capillaries. However,
none of these options are designed to add contractile filaments
that are necessary to regain heart contractility lost in heart
patients.
Being pluripotent, embryonic or adult stem
cells exhibit uncontrolled differentiation into various lineages
to produce bone, cartilage, fat, connective tissue, skeletal
and heart muscles. Until scientists can accurately define
the specific transcriptional factors and pathway to guide
stem cell differentiation into cardiomyocytes, the use of
stem cell injection into the human heart would have a risk-benefit
ratio higher than the use of myoblasts. Myoblasts are differentiated
cells destined to become muscles.
Heart transplant remains the only effective
treatment for end-stage heart failure. With an estimate of
over 50 million heart attack patients worldwide, only a few
thousand donor hearts were available for transplants last
year. Patients who survive heart transplants have to be immunosuppressed
for life with compromised quality of life. The regenerative
heart is the patient's very own and requires no immunosuppression.
HCT is much less invasive than a heart transplant. At a small
fraction of the cost of a heart transplant, the regenerative
heart promises lower healthcare spending if proven safe and
efficacious.
Pure Myoblasts by the Billions
The first human myoblast transfer into the
porcine heart revealed that it was safe to administer one
billion myoblasts at 100million/ml through the Myostar catheter
(Biosense Webster, Inc.) using 20 injections at different
locations inside the left ventricle. It was determined that
0.3ml-0.5ml would be the optimal volume per injection. The
results have been confirmed with both endovascular and epicardial
injections of myoblasts.
Menasche, et al., reported feasibility and
safety data on five patients using 650 million to 1.2 billion
cells during coronary artery bypass surgery. The myoblast
purity was determined using CD56+, an antibody that reacts
with neurons and fibroblasts rather than with myoblasts.
A common pitfall of myoblast culture is fibroblast
contamination. Since myoblast doubling time is 21 hours and
fibroblast doubling time is 15 hours, fibroblast growth often
overtakes the myoblast culture. Fibroblasts do not deposit
contractile filaments but will produce scars. From previous
dose response studies in muscular dystrophies, it is estimated
that the dose of one billion pure myoblasts is optimal to
produce the regenerative heart. This conjecture still has
to be tested in future studies.
Meanwhile, Diacrin, Inc. is sponsoring HCT
trials in the US using 10-30 million myoblasts per heart.
Bioheart, Inc. sponsored the first endovascular injection
into a heart patient on 23 May 2001 using 25 million myoblasts.
It must be emphasised that, without pure, viable myoblasts
in excess of 500 million per heart, the chance of obtaining
HCT efficacy is very slim.
Future Perspective
The great demand for normal myoblasts, the
labour intensiveness and high cost of cell culturing, harvesting
and packaging and the fallibility of human imprecision will
soon necessitate the production of automated cell processors
capable of manufacturing huge quantities of viable, sterile,
genetically well-defined and functionally demonstrated biologics,
examples of which are the myoblasts and myoblast-derived heterokaryons.
This invention will be one of the most important
results of modern-day computer science, mechanical engineering
and cytogenetics. The intakes will be for biopsies of various
human tissues. The computer will be programmed to process
tissue(s), with precision controls in time, space, proportions
of culture ingredients and apparatus manoeuvres. Cell conditions
can be monitored at any time during the process, and flexibility
is built in to allow changes.
Different protocols can be programmed into
the software for culture, controlled cell fusion, harvest
and package. The outputs supply injectable cells ready for
cell therapy or shipment. The cell processor will be self-contained
in a sterile enclosure large enough to house the hardware
in which cells are cultured and manipulated.
The automated cell processor will replace
the current bulky inefficient culture equipment, elaborate
manpower and their mistakes. It will decentralise cell production,
allowing the latter to be conducted in hospitals where transport
of patients' muscle biopsies and the autologous myoblasts
is cut to a minimum.
The development of CardioChip allows early
diagnosis of cardiovascular diseases using 10,368 expressed
sequence tags (ESTs). Subjects so identified can have a muscle
biopsy taken before any symptom occurs. Myoblasts can be processed
and deposited in a cell bank for future HCT or injected into
the subject to prevent sudden heart attack.
Conclusion
Bioengineering the regenerative heart may
provide a novel treatment for cardiovascular diseases. Through
endomyocardial injections of cultured skeletal myoblasts,
the latter spontaneously transfer their nuclei into cardiomyocytes
to impart myogenic regeneration.
Donor myoblasts also fuse among themselves
to form new myofibres, depositing contractile filaments to
improve heart contractility. These myofibres contain satellite
cells with regenerative vigour to combat heart muscle degeneration.
Human Myoblast Injection into Porcine Heart
P. Law, J. Weinstein, H. Leonhardt, S. Ben-Haim, S. Williams, Q. Fang, T. Hall, T. Goodwin
Heart muscle degeneration is the leading cause of debilitation and death in humans. Heart Cell Therapy aims to repopulate the dying heart with living muscle cells, increasing heart contractility, thus improving the quality of life and lengthening the lifespan of heart patients. We report here the first direct evidence demonstrating the feasibility and safety of delivering human embryonic skeletal muscle cells called myoblasts into the pig heart using an injection catheter. Cells were injected through a catheter (Myostar, Biosense Webster, Johnson & Johnson) threaded through a thigh artery into the left chamber of the heart. Approximately one billion human myoblasts were injected through a needle timed to protrude 6mm from the tip of the catheter into the heart muscle. Twenty injections were made having volumes of 0.1, 0.2, 0.3, 0.5, 1.0 ml, and cell concentration of 100 million per ml. There were no significant changes in heart rate, electrocardiogram and temperature throughout the experiment. Passage through the injection catheter caused less than 5% cell death.
At the completion of the procedure, the heart was processed for examination. There was no perforation of the injected heart. Human myoblasts were found widely and evenly distributed throughout the muscle wall where the cells were injected. A similar study using the Bioheart catheter yielded comparable results.
In Arizona Heart Institute, Heart Cell Therapy involves taking about 5 grams of thigh muscle under local anesthesia from the heart patients. From this biopsy, about one billion purified myoblasts are grown in a sterile laboratory in about 30 days. These cells will then be delivered with 20 injections placed 1 cm apart between the viable (healthy) and infarcted (damaged) areas. Injections can be made through catheters or under direct visualization in an open-heart bypass surgery.
Heart Cell Therapy makes available the patient's own muscle cells to repopulate the infarct, secreting the various regenerative factors and depositing contractile proteins to regain heart function.
Heart Cell Therapy is a new frontier of Myoblast Transfer Therapy, a platform technology of cell therapy, gene transfer and tissue engineering. Cultured normal myoblasts, when injected into degenerative muscles, fused among themselves, forming normal muscle cells to replenish degenerated ones. They also fused with the host muscle cells, inserting their nuclei and thus the human genome, to effect genetic repair.
Over 230 myoblast transfer procedures in the last 10 years demonstrated no severe adverse event in treating neuromuscular diseases, culminating in a 19% increase in breathing capacity and a 123% increase in strength when 50 billion myoblasts were injected into 80 muscles of Duchenne Muscular Dystrophy patients. Two months of immunosuppression was sufficient to prevent rejection of foreign donor cells called an allograft. Upon review of the study, the FDA encouraged Phase III multicenter clinical trial of myoblast transfer on muscular dystrophy.
Since our initial human myoblast transfer into the porcine heart, deliniating study parameters such as cell number, cell concentration, injection volume, and delivery method, human Heart Cell Therapy has begun. By now more than 10 patients suffering from congestive heart failure have received myoblast injections in conjunction with open-heart bypass surgery in France and the USA. Reportedly two died unrelated to the myoblast administration, and the rest are in stable condition. Some have demonstrated improved heart function since myoblast transfer. One patient received myoblasts through a catheter. All patients used their own myoblasts as autografts.
Like muscular dystrophy, genetically defective hearts will need myoblasts from foreign normal donors. Such allografts will be necessary for treating heart patients with infectious diseases to avoid contamination of the sterile culture laboratories. Allografts utilize well-characterized myoblasts that are available, allowing Heart Cell Therapy to occur within 12 hours of myocardial infarction and potentially eliminating scarring upon regeneration. Scarring is unavoidable in an autograft in which the patient's own myoblasts take 3 to 4 weeks to grow.
Whether autografts or allografts, Heart Cell Therapy is the most logical alternative in prevention and in treatment of heart conditions due to congestion, aging, heredity or trauma. It may be used to enhance heart contractility in anti-aging.
Today, the field of Cell Therapy is perplexed at the controversial stem cell research, whereas Gene Therapy research is tainted by the mishaps of "viral vector" technology. Myoblast Transfer Therapy does not involve the use of controversial stem cells or the use of dangerous viral agents that have been the cause of death in recent trials. It has been proven safe on over 230 human procedures in the past ten years.
Stem cell technology has gained much attention due to the controversy of utilizing cells from human embryos. More critically, scientists do not know the specific factor(s) that trigger stem cells to differentiate only into heart muscle cells, and not into other cell types. Such knowledge is not likely to be available within ten years. Until then, stem cell transplant into the heart may result in bony, cartilageous, fatty and fibrotic elements that are detrimental to heart function. Unlike the pluripotent stem cells, myoblasts are differentiated cells destined to become muscle. Cardiovascular disease is the number one cause of death, and more than $280 billion is spent each year globally in its combat. Heart muscle cells are terminally differentiated and do not divide significantly to regenerate the damaged heart muscle. When compared to a heart transplant, Heart Cell Therapy eliminates the use of lifelong immunosuppressant, which is a major cause of infection and death of heart transplant patients. Heart Cell Therapy is much less invasive, and tissue availability is not an issue. At a fraction of the cost of a heart transplant, it promises health cost reduction.
World's First Human Myoblast Injection into the Heart
Autograft Injection of Human Myoblasts into Human Heart
On May 14, 2002, a 55-year-old patient suffering from ischemic myocardial infarction received 25 injections carrying 465 million myoblast cells into his degenerative heart muscle during coronary artery bypass surgery. The procedure, which was performed within an hour, was the result of collaborative efforts by Cell Transplants Singapore Pte. Ltd. (CTS), and a team of cardiac surgeons in Singapore. Each injection carries about 24 million immature skeletal muscle cells called myoblasts to repopulate the dying heart with live cells. Conceivably, the myoblasts will develop and produce proteins to strengthen heart contractility. The patient is now in stable condition.
The innovative procedure offers new hope to the hundreds of millions of heart attack patients worldwide. Last year, world expenditure in cardiovascular diseases topped 280 billion USD. Less than 6000 donor hearts were available for heart transplants, today's most viable solution for heart failure.
In Cell Transplants Singapore Pte. Ltd., we have a team of dedicated scientists and personnel skilled in cell manufacturing and quality assurance/quality control. CTS was established as the subsidiary in Singapore in 2000, with technology transfer from Cell Therapy, Inc. (CTI) based in Memphis, TN USA. Dr. Gwendolyn Fang, CTI's Vice President of Research and Development, directed the technology transfer into Singapore. "Technology transfer has been smooth and efficient." Fang said. "To-date, CTS produces pure myoblasts by the billions in compliance to cGMP for research and treatment. This project will benefit mankind."
Professor Peter K. Law, CTI's Chairman and CEO, pioneers the Myoblast Transfer Technology and holds world patents for its applications. He was in Singapore during the cardiac procedure. "Singapore has taken a big step to facilitate the implementation of this technology in the orient," Law said. "Within 6 months, this technology should be developed in Shanghai (China). I envision that we can conquer heart failure within 3 to 5 years."
UPDATE:
As of July 1, 2002, the patient is doing well. He is now comfortably returning to daily activities that were once limited.
Autograft Injection of Human Myoblasts into Human Heart
* Procedure performed in collaboration with National University Hospital Singapore
World's First Allograft Injection of Human Myoblasts into the Human Heart
Memphis , TN , January 23, 2003 . On Friday, January 17, 2003 , Cell Transplants International, LLC, (CTI) in collaboration with the Russian Academy of Medical Sciences, completed the world's first allograft injection of human myoblasts into the human heart at the Bakoulev Center in Moscow , Russia . Two patients ages 63 and 49 received 1.1 and 1.2 billion myoblasts respectively. The first transplant began at 11:00 A.M. , and the last transplant was completed at 3:00 P.M. Each procedure lasted approximately ten minutes and was performed open-chest after coronary artery bypass grafting. Before the transplants, all two patients were suffering from angina, myocardial infarction, and shortness of breath. Post-surgery, the patients were in stable condition with no reports of arrhythmia. Six days post-surgery, the patients are continuing to do well and are improving each day. Additional post-surgery analysis will be conducted and the data will be accumulated and published for peer review.
Myoblasts are immature skeletal muscle cells carrying a full complement of normal genes. When transplanted, the cells repair and replace degenerating cells in the defective heart muscle. Because allogenic myoblasts are derived from third-party donors, the patients were administered cyclosporine orally as an immunosuppressant five days prior to transplantation. It is hoped that these myoblasts will repopulate the diseased hearts with live cells in addition to adding some regenerative capacity.
The myoblasts were supplied by CTI through its subsidiary Cell Transplants Singapore Pte. Ltd. (CTS), which has a cGMP facility in the Singapore Science Park . CTS was granted ISO 9000 Certification in November 2002.
Last year, global expenditure in cardiovascular diseases topped 280 billion USD. Less than 5000 donor hearts were available for heart transplants, today's most viable solution for heart failure. With healthcare costs increasing at such a rapid rate and limited availability of donor hearts, this transfer of allogenic myoblasts promises to reduce costs and provide potential treatment to the hundreds of millions of heart attack patients worldwide.
Academician Leo A. Bockeria, M.D., the Chairman of the Bakoulev Scientific Center for Cardiovascular Surgery, was the surgeon responsible for the injections. Academician Bockeria was pleased with the initial results, and he is eager to move forward with the transplantation of the next nine patients included in this study.
Peter K. Law, Ph.D., CTI's Chairman and CEO, pioneered the Myoblast Transfer Technology and holds world patents for its applications. Professor Law was in Moscow as a co-principal investigator during the cardiac procedure. Encouraged by the early results, Professor Law said, "While we are still in the preliminary stages of monitoring the safety and efficacy of this procedure, we are very excited to see that the patients are stable with no arrhythmia. This study, which is the first of its kind in the world, shows tremendous potential to help heart patients worldwide."
World's First Allograft Injection of Human Myoblasts into Human Heart
* Procedure performed on 2 patients in collaboration with Russian Academy of Medical Sciences in Moscow, Russia
