NHLBI Working Group
Critical Resources for Gene Therapy in Heart, Lung, and Blood Diseases
The National Heart, Lung, and Blood Institute convened a Working Group
of investigators on June 1, 2005, in St. Louis, Missouri, to gain input
on the critical resources needed to successfully translate gene therapy
for heart, lung, and blood diseases into clinical practice. The Working
Group (WG) members focused on five major topics, as discussed below.
The gaps in our knowledge, inability to screen and diagnose cardiomyopathies
in children, and inadequate treatments for children with cardiomyopathies
led to the following recommendations:
1. Producing GMP Vectors and Conducting Preclinical Pharmacology/Toxicology
The WG emphasized the importance of developing new vectors and improving
gene delivery methods, as well as developing suitable, preclinical,
animal models of disease for proof-of-concept studies. Vectors that
can efficiently transduce differentiated cell types, delivery systems
that permit homogenous distribution of the vector to target cell types,
and good animal model systems are all needed. Though gene transfer is
a prerequisite for many clinical applications of gene therapy, obtaining
efficient transfer to different organs in a system-specific manner has
been difficult to achieve, both in vivo and ex vivo. Even
when vectors are efficient, transduction of key cell types within the
target organs may still remain limited.
2. Funding Phase I and Phase II Gene Therapy Trials
Because of extensive regulatory hurdles, it is difficult, if not impossible,
to accurately predict the cost and duration of clinical gene therapy
studies. Traditional funding mechanisms are generally too inflexible,
and a compartmentalized approach that uses different funding mechanisms
for different stages--development, toxicology/production, clinical trials,
and so on--is cumbersome and inefficient. Once basic scientific work
has progressed to trial readiness, an overall funding mechanism and
realistic timeframe should be developed. Trials should be viewed in
their entirety, with support provided in stages, as predetermined milestones
are met. Funding for gene therapy trials must also include the costs
of oversight and compliance.
Ideally, the National Heart, Lung, and Blood Institute (NHLBI) would
support Phase I and Phase II trials, which private industry would then
further augment to bring products to licensure. Although this has worked
successfully for developing conventional drugs, it has not been successful
for gene therapies. Academic gene therapy investigators have little
incentive to conduct the more complex and expensive trials that would
lead to licensure, and private industry may have little interest in
treating orphan disorders for which gene therapy may be most efficacious.
3. Patient Recruitment
Recruitment and enrollment for gene therapy trials have proven to be
difficult. The WG recognized that, although large-scale trials funded
by industry have had fewer problems, NIH-funded trials have been less
successful due to factors such as: (a) highly restrictive inclusion
and exclusion criteria, (b) availability of more conventional alternative
treatments for certain diseases, and (c) the impracticality of involving
multiple centers in studies with very complex protocols.
4. Regulatory Processes
One of the major challenges faced by investigators in gene therapy
is the complex regulatory process. Planning and executing a gene therapy
trial are extremely labor- intensive activities. The regulatory processes
involve not only the Food and Drug Administration, but also institutional
oversight groups (such as IBCs and IRBs) with varying capabilities,
the NIH Recombinant Advisory Committee, peer review groups, and the
NHLBI Data and Safety Monitoring Board. Satisfying the requirements
of these entities, each of which is individually capable of preventing
a study from being conducted, represents a veritable gauntlet for investigators.
Streamlining redundancies in this regulatory process could greatly facilitate
clinical gene transfer research.
5. Opportunities for Joint Public/Private Partnerships
The potential targets of gene therapy range from rare diseases to the
more common diseases/disorders that affect millions of Americans. The
incentives for encouraging gene therapy research in academia are not
necessarily the same as in the for-profit sector. Finding ways to foster
advancement of the entire field of gene therapy, to smoothly transition
work done in academia to the private sector, and to make the entire
process attractive to both entities are key. The NIH can play a pivotal
role in shepherding a viable product through early development in the
academic arena to marketability by the private sector. By facilitating
an integrative approach to product development, the NIH could speed
advances in the field. Public/private partnerships may be possible,
however, only if oversight and funding mechanisms are modified.
The WG envisions an NHLBI program that would support clinical, gene therapy,
Phase I and Phase II trials by providing the resources needed, such as
GMP vector production, preclinical vector production, regulatory affairs
support, and pharmacology/toxicology studies. This program would attempt
to incorporate the majority of the specific recommendations that the WG
made as follows:
- Provide support for GMP vectors and for preclinical pharmacology/toxicology
studies to investigators with NHLBI-approved clinical translational
- Provide support for trials that involve multiple sites in order to
improve patient recruitment.
- Continue to provide NIH support for "teams" of basic and
clinical researchers (through grant mechanisms such as P01s and SCCORs),
who are able to assemble the multiple components required for clinical
gene therapy studies.
- Harmonize the regulatory requirements at the local and federal levels.
- Support clinical and regulatory affairs groups at academic institutions.
- Encourage representation of patient groups on all regulatory and review
- Organize a Workshop of invited speakers to focus on the opportunities
for public/private partnerships.
The report will be posted on the NHLBI web site and the Journal of Molecular
Sonia Skarlatos, Ph.D., NHLBI, NIH
Mary Joyce, R.N., M.B.A., NHLBI, NIH
Last updated: July 20, 2005