# Advancing lentiviral gene therapy for cystic fibrosis.

> **NIH NIH F31** · UNIVERSITY OF IOWA · 2020 · $36,401

## Abstract

Project Summary
Cystic fibrosis (CF) is a common, life-shortening genetic disease. Mutations in the cystic fibrosis conductance
regulator (CFTR) gene lead to defective or absent CFTR that is unable to effectively transport anions in many
tissues, but pulmonary complications are the most common cause of death. Recent advances in CF treatment
include drugs able to rescue protein function. However, these treatments are mutation-class specific and are
ineffective for some mutations. Thus, there is a persistent need to develop mutation agnostic treatments that can
benefit all people with CF, such as gene addition.
Lentiviral vectors are well suited for CF gene therapy because they have sufficient carrying capacity, and their
ability to integrate into the host’s genome ensures long-term benefits. Currently available vectors, however,
produce low vector titers or inefficiently transduce airway epithelial cells from the apical surface. Despite these
limitations, treatment of newborn CF pigs with a lentiviral vector carrying a functional copy of CFTR partially
rescued CF phenotypes, suggesting that achieving therapeutic CFTR expression is within reach.
My long-term goal is to design a lentiviral vector suitable for the effective treatment of pulmonary CF in humans.
The overall objective of his proposal is to evaluate two independent but complementary strategies, to improve
lentiviral delivery of CFTR to human airway epithelial cells. Lentiviral vectors can accommodate envelopes from
other viruses, termed pseudotyping, which can lead them to preferentially transduce specific cell types. For the
first strategy, I screened seven viral envelopes and identified two derived from baboon endogenous retrovirus
(BaEV) that produce high vector titers and efficiently transduce primary human airway epithelial cells from the
apical surface. The second strategy is to increase CFTR expression in transduced cells. Because airway
epithelial cells are electrochemically coupled through gap junctions, a few cells expressing high levels of CFTR
may perform sufficient CFTR-mediated anion transport to correct CF phenotypes. Increased gene expression
can be achieved through codon optimization. I compared three codon optimized CFTR (coCFTR) sequences
and identified one that significantly increases CFTR-mediated transepithelial Cl- transport. My central hypothesis
is that increasing transduction efficiency and transgene expression will be sufficient to achieve wild type levels
of CFTR-mediated anion transport. To test my hypothesis, I propose the following Specific Aims: 1) Determine
if BaEV pseudotyped lentiviral vectors can efficiently deliver CFTR to primary human airway epithelial cells, and
2) Determine if coCFTR delivery reduces the proportion of complemented cells needed to achieve wild type
levels of CFTR-mediated anion transport. These strategies will be tested in vitro using human CF donor-derived
airway epithelia, and in vivo using the CF pig model. These experiments wil...

## Key facts

- **NIH application ID:** 9989352
- **Project number:** 1F31HL152500-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Laura Isabel Marquez Loza
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,401
- **Award type:** 1
- **Project period:** 2020-07-10 → 2023-12-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989352

## Citation

> US National Institutes of Health, RePORTER application 9989352, Advancing lentiviral gene therapy for cystic fibrosis. (1F31HL152500-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989352. Licensed CC0.

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