CRISPR Cell Therapy for Genetic
Disorders: Editing HSPCs

Primary immune deficiency diseases (PIDDs) comprise a large and diverse group of 450+ chronic immune system disorders caused by hereditary genetic defects. PIDDs differ significantly by onset, symptoms, severity, and organs or tissues affected, but all result from impaired immune system function due to an underlying mutation.

While PIDDs have traditionally been treated via cell and gene replacement methods, such as allogeneic stem cell transplantation or viral-based autologous gene therapies, CRISPR RNP genome editing therapies can efficiently correct the defective gene without concerns for donor-matching or viral transgene integration ^2,3.

For example, CRISPR RNP editing in HSPCs has demonstrated therapeutic potential for the correction of SCID-X1⁴, XHIM ⁵, X-GCD ⁶, and WAS ⁷. Researchers have also achieved high-efficiency gene insertion of >80-90% using ssDNA repair templates to correct IL2RA and CTLA4 mutations associated with immunodeficiencies ⁸.

Hemoglobinopathies are hereditary disorders affecting red blood cell structure (sickle cell diseases) or production (thalassemias). These disorders are caused by single-gene mutations, making them ideal candidates for CRISPR gene editing therapies ^9,10.

Non-viral CRISPR RNP editing has been used to restore β-globin expression in HSPCs from β-thalassemia patients ¹¹, and to knock-in single-stranded DNA (ssDNA) repair templates in HSPCs from sickle cell patients ¹². Companies such as CRISPR Therapeutics are currently developing CRISPR RNP gene editing therapies for both types of hemoglobinopathies.

Lysosomal storage disorders (LSDs) comprise a group of 70+ rare progressive metabolic diseases, in which mutations to lysosome related enzymes interfere with proper cellular metabolism and cause toxic buildup of fats or sugars in the cell. Targeting these mutations with ex vivo CRISPR gene editing therapies offers great promise for potential treatments ^{13, 14, 15}.

Specifically, CRISPR RNP editing has been used to insert DNA templates to correct the mutations associated with Batten Disease in patient-derived iPSCs ¹⁶ and Mucopolysaccharidosis type I ¹⁷ and Gaucher Disease ¹⁸ in HSPCs. Additionally, RNP editing in HSPCs has demonstrated therapeutic potential in metachromatic leukodystrophy patients ¹⁹.

Hereditary ataxias are a group of neurological disorders in which mutations cause abnormal proteins to disrupt nerve function in the cerebellum and spinal cord, leading to progressive nerve degeneration.

Here, CRISPR RNP editing has shown a therapeutic potential to restore mitochondrial function in HSPCs from patients with Friedreich's ataxia ²⁰.