**Neonatal Gene Therapy for Inherited Disorders**

**Neonatal Gene Therapy for Inherited Disorders**

DOI: 10.5772/intechopen.69218

Koichi Miyake, Noriko Miyake and Takashi Shimada Shimada

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

Koichi Miyake, Noriko Miyake and Takashi

http://dx.doi.org/10.5772/intechopen.69218

#### **Abstract**

In spite of developments of neonatal intensive care medicine, it is still difficult or impos‐ sible to treat several inherited genetic disorders using conventional pharmacological methods. Gene therapy is a promising alternate approach for treating a variety of genetic disorders. By the time the patient reaches adulthood, however, it is often too late for effec‐ tive treatment. But in several of these cases, neonatal gene therapy appears potentially useful against inherited disorders that are not obviously treatable through any other methods. This chapter describes the strategy for neonatal gene therapy for inherited disorders and presents preclinical neonatal gene therapy data for two inherited disor‐ ders, metachromatic leukodystrophy and hypophosphatasia. We also discuss the utility, advantages, problems and potential of neonatal gene therapy for inherited disorders.

**Keywords:** neonatal gene therapy, AAV vectors, metachromatic leukodystrophy, hypophosphatasia

#### **1. Introduction**

Although there have been significant advances in neonatal intensive care medicine, several neonatal disorders remain major causes of mortality and morbidity. Consequently, there is an urgent need for development of new safe and effective therapies to improve the outcomes of these intractable and devastating neonatal disorders. Gene therapy is an exciting and promis‐ ing approach to treat many diseases for which there are still no effective therapies. To date, more than 2400 clinical trials of gene therapy protocols have been attempted in effort to treat various genetic diseases as well as many types of cancers and infectious diseases (http://www. abedia.com/wiley/continents.php). The results of preclinical studies suggest that neonatal gene therapies represent potentially effective treatments for currently intractable neonatal

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

disorders [1–6]. However, although neonatal gene therapies have several advantages over similar therapies used in adult patients, there is as yet no clinical protocol for use of gene therapy in newborn infants. This chapter describes a strategy for the use of neonatal gene therapy in the treatment of inherited disorders and presents preclinical neonatal gene therapy data for two inherited disorders, metachromatic leukodystrophy (MLD) and hypophosphata‐ sia (HPP). We also discuss the utility, advantages, problems and the potential of neonatal gene therapeutic approaches for the treatment of inherited disorders.

mice of AAV vector serotypes 1, 8 and 9, harboring the luciferase gene. Expression of luciferase was detected within 3 days and continued for more than 16 weeks with no decrease in expres‐ sion. Serotype 9 mediated the highest expression during the observation period (**Figure 1A, B**). In addition, using an AAV vector encoding green fluorescent protein (GFP), we determined that the organs most efficiently transduced are the liver, heart and muscle (**Figure 1C**). Moreover, although transduction efficiency was not as high, the central nervous system (CNS) was also transduced after intravenous injection of AAV vector, which apparently passes through the blood‐brain barrier (BBB) [14] in neonatal mice [15]. Thus, a systemically administered AAV vec‐ tor was able to transduce several important target organs in neonatal mice, including the CNS,

Neonatal Gene Therapy for Inherited Disorders http://dx.doi.org/10.5772/intechopen.69218 193

Systemic gene transfer to neonates has several advantages over treatment of the adults (**Table 1**). First, as mentioned above, neonatal gene therapy has the potential to overcome the limitation imposed by the BBB on treating genetic disorders of the CNS. Because the BBB is developmentally immature during the perinatal period, AAV‐mediated neonatal gene therapy is a highly promising strategy for treating genetic neurological diseases. Second, because the immune system is immature, neonates are immunologically tolerant of the transgene and/or viral vector [16–18]. Immune rejection of the transgene product by neutralizing antibodies is a severe problem for gene therapy in adults. Third, treatment administered soon after birth may enable prevention of early‐onset genetic disease. Finally, neonates can be effec‐ tively treated with a smaller amount of viral vector than adults. Using smaller amounts of viral vector is superior with respect to both safety and cost. Taken together, these advan‐ tages make systemic neonatal gene therapy a promising method for treating systemic

and mediate expression of a gene of interest for a prolonged period of time.

**3. Advantages of neonatal gene therapy**

**4. Application of neonatal gene therapy**

**4.1. Neonatal gene therapy for metachromatic leukodystrophy**

Metachromatic leukodystrophy is an inherited, autosomal recessive lysosomal storage dis‐ ease (LSD) caused by a deficiency in the lysosomal enzyme arylsulfatase A (ASA), which

genetic diseases.

• Penetrates the blood‐brain barrier • Induces immune tolerance

• Prevents early‐onset genetic diseases • Enables the use of smaller amounts of vector

**Table 1.** Advantages of neonatal gene therapy.
