Uterine Transplantation and Pregnancy Induction in Women Affected by Absolute Uterine Infertility

INTRODUCTION

Absolute Uterine Factor Infertility (AUI) is due to congenital or surgical absence of a
uterus or presence of a nonfunctional uterus. Until 2014 the only option for women affected
by Absolute Uterine Factor Infertility (AUI) was adoption or surrogate motherhood.

Primary Objective

- Successful living or deceased donor uterine transplants resulting in live birth.

- Pregnancy rate via in vitro fertilization.

BACKGROUND

In 1991 the National Transplantation Pregnancy Registry (NTPR) was established to study the
outcomes of female transplant recipients. In 2010 the NTPR had collected data on 2000
pregnancy outcomes. The NTRP database includes data not just on the pregnancy but on
follow-up of both parents and their offspring. The first reported case of pregnancy after
transplant was reported in 1958.

In 2011 25,787 solid organ transplant recipients (kidney, liver, pancreas, small bowel,
heart & lung) of which:

- 9662 were women

- 3505 were of childbearing age

- 765 were less than 17 years old and could potentially become pregnant later in life.

One of the benefits of receiving a kidney, liver, pancreas, small bowel, heart or lung
transplant is the underlying disease that caused the subject to have a transplant is gone,
therefore fertility returns. Pregnancy after transplant is increasingly common. This has led
to an accumulation of data and knowledge on how to best manage this subject population.
These pregnancies are still considered high-risk. Successful pregnancy outcomes are a result
of transplant and obstetrics teams working closely together.

The American Society of Transplantation (AST) recommends for solid organs that pregnancy is
allowable if there has been: no rejection within the past year, there is adequate and stable
graft function, no acute infections that may impact fetal growth and well-being and
maintenance immunosuppression is at stable dosing. Both the NTPR and AST advise waiting one
year until after transplant before conceiving. This one year wait time is associated with
better maternal and neonatal outcomes and fewer obstetric complications.Based on the long
term data from the NPTR on transplant recipient's pregnancy outcomes and the relative safety
of immunosuppressive medications a new area of transplant is being developed. Uterine
transplant may provide an additional option for women with absolute uterine infertility
(AUI).

Pre-clinical research into uterine transplant has been going on for more than a decade.
There have been several studies demonstrating the feasibility of Uterine Transplantation in
animals, both primates and non-primates. In the last year human trials have started in
Europe.

RATIONALE

In Great Britain an estimated 12000 women of childbearing age are affected by AUI. In the US
the number of women affected by AUI may be in the millions considering that 9 million women
of reproductive age have had a hysterectomy.

Congenital absence of the Uterus has been reported in 1/5000 women and in 2005 over 12000
women in reproductive age,15 years to 44 years have been diagnosed with congenital absence
of the Uterus.

In the US, 1000 hysterectomies are performed immediately post-partum for every 1 million
births.

It is estimated that 62 million women in the United States are in the reproductive age and
about 15.4% may have absolute AUI, and about 7 million women may have lost their uterus to
benign causes or obstetric complications. Although the statistics may offer different
interpretation it seems evident that thousands of women in the United States may be
interested in considering Uterine Transplantation as their best option to have children.

Previous Subject Experience

There were two reported attempts at uterine transplantation at other institutions, one of
which was able to carry two pregnancies but not at term. However, the University of
Gothenburg reported the first clinical trial of Uterine Transplantation as nouvelle
treatment for AUI.

In this report 9 living donors and 9 recipients underwent donor hysterectomies and recipient
uterine transplantation. Seven out of the 9 had viable uteri at the time of the report with
1 recipient losing the transplanted uterus to an infection and the other one to a vascular
complication. One donor suffered a surgical grade IIIb complication, an ureterovaginal
fistula, and was successfully treated.

This early report was followed by a subsequent one where the 7 recipients showed regular
menses and 5 out of the seven recipient suffered mild rejection episodes that were all
successfully treated.

The feasibility of Uterine Transplantation as a cure to AUI was finally demonstrated by the
first live birth after uterus transplantation.

The surgeries have been described by the Gothenburg University Group consist of a total
abdominal hysterectomy and upper vaginectomy with preservation of the major feeding arteries
and veins to the uterus of the donor and the implantation of the uterus in the pelvis of the
recipient. Vascular anastomosis is achieved between the two major arteries and veins of the
uterus, extending to the external iliac vessels of the recipient using transplant
microvascular techniques. Finally the vaginal rim of the transplanted uterus is anastomosed
to the recipient's vaginal vault.

The procedure can be performed also with a uterus obtained from a deceased donor. The
hysterectomy in the deceased donor will proceed as described above. The advantage will be
obtaining the vascular pedicle attached to segments of the iliac artery and vein which will
make the implantation in the recipient technically easier. The preservation solution will
not change and the ischemia time will be kept under 6 hours.

2. STUDY DESIGN This is a prospective study to treat absolute uterine infertility (AUI)
through uterine transplantation resulting in live birth.

There will be three distinct clinical stages in the study after inclusion/exclusion met
criteria & subject consented: Pre-transplant/Screening, Day 0 to embryo transfer/Recovery,
embryo transfer/Pregnancy-Delivery/Explant.

Number of Clinical Sites and Subjects This trial will be conducted at the Annette C. and
Harold C. Simmons Transplant Institute, Baylor University Medical Center in Dallas, TX. A
total of 10 female (biologically) subjects will receive a uterine transplant. Subjects can
either receive a uterus from a living donor or a cadaveric donor. Living donors will be
consented per the living donor research protocol. Uterus recovery from cadaveric donors will
follow UNOS guidelines.

SUBJECT PARTICIPATION and STUDY DURATION

All subjects will be followed for a 5 year period post-transplant. Continued follow up
depends upon the subject status:

- Subjects who received a uterine transplant resulting in live birth then and have the
uterus removed will be followed for 12 months post explant.

- Subjects who received a uterine transplant resulting in live birth and desire another
pregnancy will be followed through the second pregnancy resulting in live birth for 12
months post explant.

- Subjects who have the uterus explanted due to infection, rejection or unable to
maintain pregnancy will be followed for 12 months post explant.

Inclusion Criteria:

1. Women diagnosed with Absolute Uterine Infertility (AUI) and intact native ovaries.

2. Women of childbearing age 20-35.

3. Human papillomarvius negative or received vaccination for human papillomarvius virus
(HPV).

4. Received counseling regarding infertility alternatives to uterine transplant such as
adoption or surrogate pregnancy.

5. Presence of Rokitansky Syndrome or congenital abnormalities that may affect uterine
transplant or ability to carry fetus to term.

6. Willing to undergo in-vitro fertilization and medically cleared for in-vitro
fertilization.

7. Evaluated by a fertility specialist and determined to have good ovarian reproductive
potential and ability to carry fetus to term.

8. Must have the ability to fund, either through third party coverage or through other
their own personal financing, any expenses associated with assisted reproduction
services provided to them.

9. Meets physiological recipient criteria

Exclusion Criteria:

1. Subject has diabetes mellitus Type I and II by medical history or elevated hemoglobin
A1C blood test. (increased blood sugar levels)

2. Subject has known hypersensitivity to Tacrolimus, Thymoglobulin or CellCept

3. Existing hypertension (per investigator's discretion)

4. Prior transplant

5. Subject has been cancer free for less than five years.

6. Body Mass index >30

7. Active Infection

8. Seropositivity for HIV, HBV, HCV, HTLV-I

9. Technical obstacles which pose a high surgical risk in the judgement of the
investigator

10. Subject unwilling or unable to comply with study requirements

11. Subject unable to undergo in-vitro or not cleared for transplant

12. Subject must be a non-smoker within the 12 months of screening. Alcohol or drug abuse
within 12 months of screening